Luo et al.

Chin Med (2019) 14:48

https://doi.org/10.1186/s13020-019-0270-9 Chinese Medicine

REVIEW Open Access

Naturally occurring anti‑cancer compounds:

shining from Chinese herbal medicine
Hua Luo†, Chi Teng Vong†, Hanbin Chen, Yan Gao, Peng Lyu, Ling Qiu, Mingming Zhao, Qiao Liu, Zehua Cheng,
Jian Zou, Peifen Yao, Caifang Gao, Jinchao Wei, Carolina Oi Lam Ung, Shengpeng Wang, Zhangfeng Zhong*
and Yitao Wang*

Abstract
Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including anti-
proliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug
resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical
path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with
anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin,
ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic
acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline,
Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated
pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in
combined therapy and immunomodulation. In addition, the present review has extended to describe other promis-
ing compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and
cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodula-
tory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and
further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as
modulators of immune checkpoints.
Keywords: Cancer, Chinese herbal medicine, Natural products, Bioactive compounds, Traditional Chinese medicine

Background [6]. British Journal of Pharmacology described that gin-

Cancer is a leading public health problem worldwide with senoside Rh2 inhibits P-glycoprotein (P-gp) activity to
an estimated 18.1 million new cases and 9.6 million can- reverse multidrug resistance [7]. The American Journal of
cer deaths in 2018 [1]. Chinese herbal medicine has been Chinese Medicine demonstrated that curcumin induces
used as anti-cancer agents for a long time, they exhibit autophagy to enhance apoptotic cell death [8]. Journal of
anti-inflammatory activities and contain abundant anti- Ethnopharmacology reviewed that berberine potentially
cancer compounds that exert direct cytotoxicity effects represses tumor progression and is expected to be safe,
and indirect regulation in tumor microenvironment effective and affordable agent for cancer patients [9]. Chi-
and cancer immunity, as well as improve chemotherapy nese Medicine presented that shikonin exerts synergistic
[2–5]. For examples, PNAS reported that epigallocat- effects with chemotherapeutic agent [10]. However, the
echin gallate (EGCG) targeting Laminin receptor (Lam anti-cancer targets of these pharmacodynamic com-
67R) shows promising efficacy in treating prostate cancer pounds are still not clear, and this is the major obstacle
for the application and development of Chinese herbal
medicine.
*Correspondence: zfzhong@aliyun.com; ytwang@um.edu.mo
†
This review in Chinese herbal medicine and cancer
Hua Luo and Chi Teng Vong contributed equally to this work
Institute of Chinese Medical Sciences, State Key Laboratory of Quality
focuses on summarizing experimental results and con-
Research in Chinese Medicine, University of Macau, Macao, China clusions from English literatures reported since 2011.

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Luo et al. Chin Med (2019) 14:48 Page 2 of 58

Literature search was conducted in peer-reviewed Curcumin

and clinical databases, which include PubMed (https​ Curcumin (Fig. 2) is a polyphenol compound extracted
://www.ncbi.nlm.nih.gov/pubme​d), Web of Science mainly from the rhizomes of Curcuma longa, Curcuma
(http://www.webof​knowl​edge.com), Medline (https​:// zedoaria and Acorus calamus L. with many biological
www.medli​ne.com), Scopus (https​://www.scopu​s .com), activities, but it has poor water solubility and stability
and Clinical Trials (https​://clini​caltr​ials.gov) using the [11]. Clinical evidence and extensive studies showed that
following keywords: Cancer, Tumor, Neoplasm, Chi- curcumin has various pharmacology effects, including
nese herbs, Chinese medicine, Herbal medicine. To anti-cancer, anti-inflammatory, and anti-oxidative activi-
provide new insights into the critical path ahead, the ties [12–14]. Curcumin and its analogues are shown to
pharmacological effects, novel mechanism of action, be emerging as effective agents for the treatment of sev-
relevant clinical studies, innovative applications in eral malignant diseases such as cancer. Numerous stud-
combined therapy, and immunomodulation of the pop- ies have shown that curcumin and its preparations can
ular compounds originated from Chinese herbal medi- inhibit tumors in almost all parts of the body, including
cine were reviewed systemically. head and neck, ovarian, skin and gastric cancers [15–20].
Different natural products derived from Chinese Curcumin is shown to exhibit many anti-cancer effects
herbal medicine, including curcumin, EGCG, ber- through the inhibition of cell proliferation, promotion
berine, artemisinins, ginsenosides, ursolic acid (UA), of cell apoptosis, prevention of tumor angiogenesis and
silibinin, emodin, triptolide, cucurbitacins, tanshi- metastasis, and the induction of autophagy [21–25].
nones, ordonin, shikonin, gambogic acid (GA), artesu- Curcumin inhibits cell growth, induces cell cycle arrest
nate, wogonin, β-elemene, and cepharanthine, were and apoptosis in esophageal squamous cell carcinoma
identified with emerging anti-cancer activities, such EC1, EC9706, KYSE450, TE13 cells through STAT3 acti-
as anti-proliferative, pro-apoptotic, anti-metastatic, vation [12]. It also induces oxidative stress, which dis-
anti-angiogenic effects, as well as autophagy regula- rupts the mitochondrial membrane potential and causes
tion, multidrug resistance reversal, immunity balance, the release of cytochrome c, thus inducing apoptosis [26].
and chemotherapy improvement in vitro and in vivo. Besides, curcumin is shown to induce autophagy [8, 21,
These compounds are considered popular with over 27–30]. It induces autophagy through 5′AMP-activated
100 supported publications and are selected to be dis- protein kinase (AMPK) activation, leading to Akt deg-
cussed in more details. Figure 1 shows the word cloud radation, thus inhibiting cell proliferation and migra-
of these compounds. In this review, the advantages and tion in human breast cancer MDA-MB-231 cells [21],
drawbacks of representative Chinese herbal medicine- while it inhibits cell growth partially through autophagy
derived compounds in different types of cancers were induction in human hepatocellular carcinoma HepG2
also highlighted and summarized. cells [29]. Moreover, curcumin can ameliorate Warburg
effect in human non-small cell lung cancer (NSCLC)
H1299, breast cancer MCF-7, cervical cancer HeLa and
prostate cancer PC-3 cells through pyruvate kinase M2
down-regulation, a key regulator of Warburg effect [18].
In addition, tumor metastasis has always been a frustrat-
ing problem for anti-cancer therapy, and curcumin also
exhibits anti-metastasis effects [31–35]. Curcumin inhib-
its cell invasion via AMPK activation in human colorectal
cancer SW-480 and LoVo cells [31], whilst low-toxic level
of curcumin efficiently inhibits cell migration and inva-
sion through the inhibition of Ras-related C3 botulinum
toxin substrate 1/p21 (Rac1) activated kinase 1 (Rac1/
PAK1) pathway in human NSCLC 801D cells, and this
effect is also confirmed in 801D xenograft mice [32]. By
pulmonary administration of curcumin in mice, it over-
comes the problem of its low bioavailability, and inhibits
lung metastasis of melanoma [35].
The main target molecules and signaling involved in the
Fig. 1 The anti-cancer compounds from Chinese herbal medicine
(CHM). The popular anti-cancer compounds in CHM presented as a pharmacological processes include reactive oxygen spe-
“word cloud”, in which the size of each name is proportional to the cies (ROS), matrix metalloproteinases (MMPs), nuclear
number of publications of the compounds factor kappa-light-chain-enhancer of activated B cells
Luo et al. Chin Med (2019) 14:48 Page 3 of 58

Fig. 2 Chemical structures of anti-cancer compounds from Chinese herbal medicine

(NF-κB), signal transducer and activator of transcrip- secretion from activated T cells, and enhances T cell-
tion and cell cycle-related proteins [36–46]. Curcumin is induced cytotoxicity in human esophageal adenocarci-
shown to induce anti-cancer activities through the dis- noma OE33 and OE19 cells, so it increases the sensitivity
ruption of mitochondrial membrane potential and block- of the cells to T cell-induced cytotoxicity [51]. The natu-
ade at G2/M phase of the cell cycle in human epidermoid ral killing (NK) cells can directly kill cancer cells, and
carcinoma A-431 cells [47]. In addition, mammalian tar- curcumin can enhance the cytotoxicity effect of NK cells
get of rapamycin (mTOR) plays a vital role in curcumin- when NK cells are co-cultured with human breast cancer
induced autophagy and apoptosis [30, 48–50]. Curcumin MDA-MB-231 cells, which is highly associated with sig-
induces apoptosis and autophagy through the inhibition nal transducer and activator of transcription 4 (STAT4)
of phosphoinositide 3-kinase (PI3K)/Akt/mTOR path- and signal transducer and activator of transcription 5
way in human NSCLC A549 cells [30], while it induces (STAT5) activation [52]. Besides, myeloid-derived sup-
autophagy by reducing Akt phosphorylation and mTOR pressor cells (MDSCs) are immune-suppressive cells
in human melanoma A375 and C8161 cells [49]. which are found in most cancer patients. Curcumin
Curcumin can also exert immunomodulatory effects decreases interleukin (IL)-6 levels in the tumor tissues
against cancer cells. Theracurmin, a highly bioavailable and serum of Lewis lung carcinoma (LLC)-bearing mice
form of curcumin, decreases pro-inflammatory cytokine to impair the growth of MDSCs, so targeting MDSCs is
Luo et al. Chin Med (2019) 14:48 Page 4 of 58

important for the treatment of lung cancer [13]. More- theracurmin every day with standard gemcitabine-
over, the anti-tumor immune response of curcumin is based chemotherapy. No new adverse effects and no
mediated through increased cluster of differentiation increase in the incidence of adverse effects were observed
(CD)8+ T cell population and decreased regulatory T among these patients. A pilot phase II study demon-
cell ­(Treg) population in tongue squamous cell carcinoma strated encouraging results for the combination of
[53–55]. docetaxel/prednisone and curcumin in patients with cas-
In order to overcome the solubility issues of curcumin tration-resistant prostate cancer. It was found that 59% of
and facilitate its intracellular delivery, a curcumin-loaded patients had prostate-specific antigen response and 40%
nanoparticle, curcumin-PLGA-NP, is synthesized. It has of patients achieved partial response. This study has pro-
a tenfold increase in water solubility compared to cur- vided additional evidence for a high response rate and
cumin, and shows threefold increased anti-cancer activi- better tolerability with the use of curcumin during cancer
ties in human breast cancer MDA-MB-231 and NSCLC therapy [77].
A549 cells [56]. Another curcumin-capped nanoparti-
cle exhibits promising anti-oxidative and selective anti-
cancer activities in human colorectal cancer HT-29 and Epigallocatechin gallate (EGCG)
SW-948 cells [57]. Moreover, a curcumin analog, WZ35, EGCG, also known as epigallocatechin-3-gallate (Fig. 2),
has high chemical stability, and higher efficacy in anti- is the main polyphenol in green tea (Camellia sinensis).
cancer effects compared to curcumin in human gastric Epidemiological studies have indicated that consumption
cancer SGC-7901 cells and SGC-7901 xenograft mice of green tea has potential impact of reducing the risk of
[20]. Another analog, B63, induces cell death and reduces many chronic diseases, such as cardiovascular diseases
tumor growth through ROS and caspase-independent and cancer [78, 79]. EGCG possesses various biological
paraptosis in human gastric cancer SGC-7901, BGC-823 effects including anti-obesity and anti-hyperuricemia,
and SNU-216 cells, 5-fluorouracil-resistant gastric cancer anti-oxidative, anti-viral, anti-bacterial, anti-infective,
cells, and SGC-7901 xenograft mice [58]. anti-angiogenic, anti-inflammatory and anti-cancer activ-
Curcumin can be used with other chemotherapeu- ities [80–84]. It is reported to present anti-cancer effects
tic agents to achieve synergistic effects, reduce adverse in variety of cancer cells, including lung, colorectal, pros-
effects and enhance sensitivity. Tamoxifen and curcumin tate, stomach, liver, cervical, breast, leukemia, gastric,
are packed into a diblocknanopolymer, and this nanopo- bladder cancers [85–90]. Among its anti-cancer activi-
lymer reduces the toxicity of tamoxifen in normal cells ties, EGCG exhibits multiple pharmacological actions,
and exhibits better anti-proliferative and pro-apoptotic including the suppression of cell growth, proliferation,
effects in human breast cancer tamoxifen-sensitive and metastasis and angiogenesis, induction of apoptosis, and
-resistant MCF-7 cells [59]. Triptolide has strong liver enhancement of anti-cancer immunity [85, 86, 91–94].
and kidney toxicities, and when combined with cur- EGCG can inhibit cell proliferation through multiple
cumin, they exert synergistic anti-cancer effects in ovar- ways in many types of cancer cells. It inhibits cell pro-
ian cancer, as well as reduce the side effects of triptolide liferation in human bladder cancer SW-780, breast can-
[60]. In addition, adriamycin, sildenafil, 5-fluorouracil, cer MDA-MB-231 and NSCLC A549 cells, and inhibits
irinotecan, doxorubicin, paclitaxel, sorafenib, Kruppel- tumor growth in gastric cancer SGC-7901 xenograft
like factor 4, emodin, docosahexaene acid and apigenin mice [89, 94, 95]. It also induces apoptosis in human oral
are shown to exhibit synergistic effects with curcumin cancer KB, head and neck cancer FaDu, NSCLC A549,
[61–71]. Similarly, copper supplementation significantly and breast cancer MCF-7 cells [96, 97]. Besides, EGCG
enhances the anti-tumor effects of curcumin in several induces autophagy, and inhibition of autophagy can
oral cancer cells [72], while epigallocatechin-3-gallic acid enhance EGCG-induced cell death in human mesothe-
ester (EGCG) increases the ability of curcumin to inhibit limoa ACC-meso, Y-meso, EHMES-10, EHMES-1 and
cell growth and induce apoptosis in human uterine leio- MSTO-211H, and primary effusion lymphoma BCBL-1
myosarcoma SKN cells [73]. and BC-1 cells [98, 99]. In contrast, it induces cell death
Clinical trials can confirm or reveal the effects, adverse via apoptosis and autophagy in oral squamous cell carci-
reactions and pharmacokinetics of the drugs. As the bio- noma SCC-4 cells [84], so autophagy plays a dual role in
availability of curcumin is very poor, many curcumin EGCG-induced cell death. It can also suppress metastasis
preparations are synthesized and tested in clinical tri- in human melanoma SK-MEL-5, SK-MEL-28, A375 and
als [74–76]. A phase I study was conducted to investi- G361, NSCLC CL1-5, A549 and H1299 cells, and lung
gate the safety and pharmacokinetics of theracurmin in metastasis mice [85, 93, 100]. In addition, EGCG sup-
pancreatic and biliary tract cancer patients who failed presses tumor angiogenesis in human NSCLC A549 cells
with standard chemotherapy [76]. They administered and A549 xenograft mice [101].
Luo et al. Chin Med (2019) 14:48 Page 5 of 58

EGCG mediates apoptosis which involves pro- and xenograft mice [111]. Besides, EGCG-DHA (docosahex-
anti-apoptotic proteins in various cancer cells. It up-reg- aenoic) ester, a lipophilic derivative of EGCG, shows
ulates pro-apoptotic proteins such as Bcl-2-associated X improved anti-oxidative effects compared to EGCG,
protein (Bax), and down-regulates anti-apoptotic pro- and suppresses colon carcinogenesis in mice [112, 113].
teins including B-cell lymphoma 2 (Bcl-2), B-cell lym- In the last decade, many studies were carried out using
phoma-extra large (Bcl-xL) and survivin [97, 102–104]. EGCG-loaded nanoparticles including FA-NPS-PEG and
ER stress also plays an important role in EGCG-induced FA-PEG-NPS (epigallocatechin gallate-β-lactoglobulin
cell death. EGCG inhibits endoplasmic reticulum (ER) nanoparticles), EGCG-SLN (solid lipid nanoparticle),
stress-induced protein kinase R-like endoplasmic reticu- DT-EGCG-nanoethosomes, FCS-EGCG-NPs (chi-
lum kinase (PERK) and eukaryotic translation-initiation tosan coated nanoparticles), EGCG-dispersed selenium
factor 2α (eIF2α) phosphorylation [105]. Besides, poly nanoparticles, 198AuNP-EGCg (gold nanoparticles),
(ADP-ribose) polymerase (PARP) 16 is shown to activate EGCG-loaded microspheres (EGCG/MS), and FCMPs
ER stress markers, PERK and inositol-requiring enzyme (ferritin-chitosan Maillard reaction products) [6, 110,
1α (IRE1α) [106]. ER stress-induced apoptosis, PERK 114–121]. These EGCG nanoparticles can improve the
and eIF2α phosphorylation by EGCG are suppressed in targeting ability and efficacy of EGCG, which greatly pro-
PARP16-deficient hepatocellular carcinoma QGY-7703 mote the clinical application and development of EGCG
cells, so EGCG mediates apoptosis through ER stress, analogs.
which is dependent on PARP16 [105]. Similarly, EGCG EGCG antagonizes toxicity induced by anti-cancer
causes 78-kDa glucose-regulated protein (GRP78) accu- chemotherapeutic agents, and sensitizes chemo-resist-
mulation in the ER, which up-regulates ER stress markers ant cancer cells. It also exerts synergistic effects with
such as activating transcription factor 4 (ATF-4), X-box anti-cancer agents in various cancer cells, such as cis-
binding protein 1 (XBP-1) and C/EBP homologous pro- platin, oxaliplatin, temozolomide, resveratrol, doxoru-
tein (CHOP), and shifts into pro-apoptotic ER stress, bicin, vardenafil, curcumin, erlotinib [122–129]. EGCG
leading to increased caspase-3 and -8 activities [107]. can enhance the sensitivity of cisplatin through copper
Furthermore, it suppresses cell migration and invasion transporter 1 (CTR1) up-regulation, which results in the
by blocking tumor necrosis factor (TNF) receptor-associ- accumulation of cellular cisplatin and cisplatin–DNA
ated factor 6 (TRAF6), MMP-2/c-Jun N-terminal kinase adducts in human ovarian cancer SKOV3 and OVCAR3
(JNK) and transforming growth factor-β (TGF-β) path- cells, and the combination of EGCG and cisplatin sup-
ways [85, 93, 100]. presses tumor growth in OVCAR3 xenograft mice [122].
In addition to anti-cancer effects, EGCG shows a sig- The combined low concentration of EGCG and curcumin
nificant inhibitory effect on interferon-γ (IFN-γ)-induced remarkably inhibits cell and tumor growth in human
indoleamine 2,3-dioxygenase (IDO) expression, an NSCLC A549 and NCI-H460 cells, and A549 xenograft
enzyme that guides cancer to regulate immune response, mice through cell cycle arrest [123].
in human colorectal cancer SW-837 cells [108], so this To evaluate the tolerance, safety, pharmacokinetics and
suggests that EGCG might be useful for chemopreven- efficacy of EGCG in humans, clinical trials have been or
tion and colorectal cancer treatment, and could be a are currently being conducted for cancer treatment. Dur-
potential agent for anti-tumor immunotherapy. EGCG is ing a phase I clinical trial for the treatment of radiation
also found to be a potential immune checkpoint inhibitor, dermatitis, patients with breast cancer received adjuvant
which down-regulates IFN-γ-induced B7 homolog 1 (B7- radiotherapy and EGCG solution. It was found that the
H1) levels, an immunoglobulin-like immune suppressive maximum dose (660 μM) of EGCG was well tolerated and
molecule, in human NSCLC A549 cells [109]. the maximum tolerated dose was undetermined [130].
Although EGCG has numerous biological activities It was concluded that EGCG was effective for treating
through different pathways, its efficacy demonstrated in radiation dermatitis. Moreover, a phase II clinical trial
in vivo studies is not always consistent with the results was conducted to investigate the benefits of EGCG as a
of in vitro studies. This can be due to its low oil solubil- treatment for acute radiation-induced esophagitis (ARIE)
ity, metabolic instability and poor bioavailability [110]. for patients with stage III lung cancer. The oral admin-
Therefore, EGCG analogs and EGCG-loaded nanopar- istration of EGCG was shown to be effective and phase
ticles by modifying EGCG are developed, and they have III clinical trial to study the potential effects of EGCG to
been reported to enhance anti-cancer effects [111–113]. ARIE treatment was anticipated [131].
The peracetate-protected (−)-EGCG, a prodrug of EGCG
obtained by modifying the reactive hydroxyl groups with Berberine
peracetate groups, is shown to increase the bioavailability Berberine (Fig. 2) is an isoquinoline alkaloid mainly
of EGCG and inhibit angiogenesis in endometrial cancer extracted from medicinal plants such as Coptidis
Luo et al. Chin Med (2019) 14:48 Page 6 of 58

chinensis Franch., Mahonia bealei (Fort.) Carr., and Phel- berberine, including down-regulation of cyclins A, D,
lodendron chinense Schneid. [132]. Berberine has diverse cyclin-dependent kinase (CDK) 1, CDK4, MMP-2 and
pharmacological effects and is normally used for the janus kinase 2 (Jak2)/vascular endothelial growth factor
treatment of gastroenteritis [133, 134]. It exhibits sig- (VEGF)/NF-κB/activator protein 1 (AP-1) pathway, and
nificant anti-cancer effects in a wide spectrum of cancers induction of autophagic cell death via mTOR signaling
including ovarian, breast, esophageal, and thyroid can- pathway [149, 155, 156]. Berberine also induces mito-
cers, leukemia, multiple myeloma, nasopharyngeal car- chondrial-mediated apoptosis through the loss of mito-
cinoma, and neuroblastoma, through inducing cell cycle chondrial membrane potential, cytochrome c release,
arrest and apoptosis, inhibiting metastasis and angiogen- caspase and PARP activation, up-regulation of pro-apop-
esis [135–143]. totic Bcl-2 family proteins, and down-regulation of anti-
Berberine can induce cell cycle arrest in various can- apoptotic Bcl-2 family proteins [150, 157–159]. It can
cer cells [137, 144, 145]. Berberine induces G1 and G2/M also activate apoptosis-inducing factor to induce ROS-
phase arrest in murine prostate cancer RM-1 cells, and mediated cell death in pancreatic, breast, and colon can-
G1 cell arrest by regulating cyclins D1 and E expressions cers [158, 160, 161].
in human HER2-overexpressed breast cancer cells [144, Immunotherapy has made great progress to cancer
145]. However, berberine induces G1 phase arrest in treatment over the past few years. Toll-like receptors
human estrogen receptor positive breast cancer MCF-7 (TLRs) can activate innate immune responses for host
cells but not in estrogen receptor negative MDA-MB-231 defense [162]. Berberine inhibits proto-oncogene tyros-
cells [137]. Besides, it inhibits cell proliferation by induc- ine kinase Src activation and TLR4-mediated chemotaxis
ing apoptosis in human colorectal cancer HCT-8 cells in lipopolysaccharide (LPS)-induced macrophages [163].
[146]. In p53-null leukemia EU-4 cells, berberine induces Besides, IDO1 inhibitors are promising candidates for
p53-independent and X-linked inhibitor of apoptosis cancer immunotherapy [164]. Berberine and its deriva-
protein (XIAP)-mediated apoptosis, which is associated tives are shown to exhibit anti-cancer activity through
with mouse double minute 2 homolog (MDM2) and pro- cell killing by NK cells via IDO1 [165]. IL-8 is associated
teasomal degradation [135]. Mitochondrial-mediated with metastasis, and berberine decreases IL-8 levels to
apoptosis with Bcl-2-like protein 11 (Bim) up-regulation inhibit cell growth and invasion in triple-negative breast
and Forkhead box O (FoxO) nuclear retention is vital cancer cells [166].
in berberine-induced apoptosis [147]. In addition, ber- Berberine has low oral bioavailability as well as poor
berine can induce autophagic cancer cell death through intestinal absorption [167]. As it has pronounced anti-
increased GRP78 levels and enhancing the binding ability microbial activity against gut microbiota, high dosage can
of GRP78 to VPS34 in human colorectal cancer HCT-116 translates into adverse events [168]. This limits the clini-
cells [148], whilst it induces autophagy through inhibiting cal use of berberine, and different approaches have been
AMPK/mTOR/UNC-51-like kinase 1 (ULK-1) pathway applied to improve the bioavailability of berberine. d-α-
in human glioma U251 and U87 cells [149]. In contrast, Tocopheryl polyethylene glycol 1000 succinate enhances
berberine induces protective autophagy in human the intestinal absorption of berberine by inhibiting P-gp
malignant pleural mesothelioma NCI-H2452 cells, and activity in rats [167]. A self-microemulsifying drug deliv-
inhibition of autophagy promotes berberine-induced ery system is developed to improve the bioavailability
apoptosis [150]. Therefore, autophagy plays a dual role of berberine, the bioavailability is increased by 2.42-fold
in berberine-induced apoptosis. Furthermore, berberine [169]. Ber8, a 9-alkylated derivative of berberine, has bet-
also inhibits tumor migration and invasion [143, 151]. It ter cytotoxicity and cellular uptake than berberine, and
up-regulates plasminogen activator inhibitor-1 (PAI-1), further inhibits cell proliferation and induces cell cycle
a tumor suppressor that down-regulates urokinase-type arrest in different cell lines, including SiHa, HL-60, and
plasminogen activator (uPA) and antagonizes uPA recep- A549 cells [170].
tor to suppress metastasis in human hepatocellular car- The combination of berberine and chemo- or radio-
cinoma Bel-7402 and SMMC-7721 cells [143]. Berberine therapies provides synergistic anti-cancer effects [171,
also inhibits epithelial mesenchymal transition through 172]. Taxol combined with berberine significantly slows
PI3K/Akt pathway in murine melanoma B16 cells, [151], down cell growth in human epidermal growth factor
and suppresses angiogenesis in glioblastoma U87 xeno- receptor 2 (HER2)-overexpressed breast cancer cells
graft mice and HUVECs [152, 153]. [145], while the combined administration of berberine
Berberine interacts with diverse molecular targets and caffeine enhances cell death through apoptosis and
as it binds to nucleic acids via specific deoxyribonu- necroptosis in human ovarian cancer OVCAR3 cells
cleic acid (DNA) sequences [154]. Several mechanisms [173]. The combination therapy of berberine and nira-
have been identified for the anti-proliferative effects of parib, a PARP inhibitor, markedly enhances apoptosis
Luo et al. Chin Med (2019) 14:48 Page 7 of 58

and inhibits tumor growth in ovarian cancer A2780 KKU-452, KKU-023 and KKU-100, and tongue squa-
xenograft mice [174]. Therefore, combination of berber- mous cell carcinoma Cal-27 cells [190, 198, 199], while
ine with other therapies is a promising treatment for the ART induces autophagy-mediated cell cycle arrest in
alternative cancer therapy. human ovarian cancer SKOV3 cells [200]. DHA is also
Previous pre-clinical research and animal studies shown to induce autophagy by suppressing NF-κB acti-
have demonstrated the anti-tumor action of berberine vation in several cancer cells including RPMI 8226, NB4,
hydrochloride. The people with a history of colorectal HCT-116, and HeLa cells [202]. Furthermore, ART and
cancer might be at higher risk for adenomas, thus they DHA can also inhibit metastasis in various cancer cells
are particularly suitable for the study of the chemopre- such as non-small-cell lung carcinoma (NSCLC), ovar-
ventive effects of berberine hydrochloride in adenomas. ian and lung cancer cells [184, 189, 203]. Apart from
A randomized, double-blind, placebo-controlled trial apoptosis and metastasis, the inhibition of angiogen-
was designed to determine whether the daily intake of esis is also a crucial approach in cancer treatment. ART
300 mg of berberine hydrochloride could decrease the inhibits angiogenesis through mitogen-activated protein
occurrence of new colorectal adenomas in patients with kinase (MAPK) activation in osteosarcoma [204], whilst
a history of colorectal cancer, and it is currently ongoing. DHA exerts strong anti-angiogenic effect by repressing
Another phase II clinical trial of berberine and gefitinib is extracellular signal–regulated kinase (ERK) and NF-κB
also ongoing in patients with advanced NSCLC and acti- pathways in human umbilical vein endothelial cells
vating EGFR mutations. (HUVECs) and pancreatic cancer, respectively [194, 195].
In the past decades, studies have been focused on stud-
Artemisinins ying the anti-cancer mechanisms of ARTs, but there are
Artemisinin (Fig. 2) is a sesquiterpene peroxide derived contentions. ARTs inhibit cancer cell proliferation mainly
from annual wormwood (Artemisia annua L.), which by the induction of apoptosis through mitochondrial-
was originally used as Traditional Chinese Medicine for dependent pathways [196, 205, 206]. ART mediates the
treating malaria and related symptoms such as fever and release of cytochrome c and caspase-9 cleavage, leading
chills [175]. Since the 2015 Nobel Prize in Physiology to increased apoptosis in human breast cancer MCF-7
or Medicine conferred to Chinese scientist, Youyou Tu, cells [196]. DHA induces apoptosis through Bcl-2 down-
artemisinin drew attention to worldwide [176]. Beside regulation in human cervical cancer HeLa and Caski
from their well-established anti-malarial effects, arte- cells [205], and via Bim-dependent intrinsic pathway in
misinin and its derivatives (ARTs), including dihydroar- human hepatocellular carcinoma HepG2 and Huh7 cells
temisinin (DHA), artesunate, artemether and arteether, [206]. Interestingly, ART is demonstrated to be an inhibi-
are also found to exhibit potent anti-cancer activities in tor of anti-cancer target, histone deacetylases (HDAC)
many studies [177–182]. DHA and artesunate are the [196]. In addition, another mechanism of killing tumor
most studied ART derivatives for cancer treatment, and cells by ARTs is iron-dependent cell death called ferrop-
artesunate will be discussed in a separate section. The tosis, a new form of cell death, so ferroptosis becomes an
anti-cancer effects of ARTs are demonstrated in a broad attractive strategy for cancer treatment [183, 207].
spectrum of cancer cells including lung, liver, pancreatic, DHA can enhance the anti-tumor cytolytic activity
colorectal, esophageal, breast, ovarian, cervical, head and of γδ T cells against human pancreatic cancer SW1990,
neck, and prostate cancers [183–191]. The anti-cancer BxPC-3 and Panc-1 cells [208], and ART also potenti-
activities of ARTs include induction of apoptosis and cell ates the cytotoxicity of NK cells to mediate anti-tumor
cycle arrest, inhibition of cell proliferation and growth, activity [209]. Similarly, ART inhibits tumor growth
metastasis and angiogenesis [189, 192–195]. through T cell activation and T ­ reg suppression in breast
ART inhibits cell proliferation, migration and invasion, cancer 4T1 xenograft mice [188]. Therefore, this pro-
and induces apoptosis in human breast cancer MCF-7 vides a novel strategy for treating pancreatic cancer with
cells [193, 196], while DHA suppresses cell growth immunotherapy.
through cell cycle arrest and apoptosis in human hepa- ART has poor water solubility and bioavailability.
tocellular carcinoma HepG2 cells and HepG2 xenograft In order to solve this issue, ART is encapsulated into
mice [178]. Similarly, ART induces apoptosis in murine micelles by nanoprecipitation to form ART-loaded
mastocytome P815 cells and hamster kidney adenocarci- micelles [210]. The ART-loaded micelles enhance the
noma BSR cells, and inhibits tumor growth in P815 xeno- drug exposure time and accumulation in breast can-
graft mice [177]. Moreover, autophagy plays a vital role cer 4T1 xenograft mice, and shows specific toxicity in
in ART-mediated anti-cancer activities [190, 197–201]. human and murine breast cancer MCF-7 and 4T1 cells.
DHA can induce autophagy-dependent cell death in A mitochondrial-targeting analog of ART is also synthe-
human cervical cancer HeLa cells, cholangiocarcinoma sized to specifically target mitochondria for enhancing
Luo et al. Chin Med (2019) 14:48 Page 8 of 58

the inhibition of cell proliferation in various cancer cells 240], and inhibits cell migration in human colorectal can-
including HCT-116, MDA-MB-231, HeLa and SKBR3 cer LoVo, SW-620 and HCT-116 cells [240]. Ginsenoside
cells [211]. Moreover, dimmers of ART are also synthe- Rg3 can also modulate the tumor environment through
sized by polyamine linkers, and they further inhibit cell inhibiting angiogenesis and enhancing anti-tumor
proliferation in human breast cancer MCF-7 cells and immune responses [241]. Moreover, ginsenoside Rh2
angiogenesis in HUVECs [212]. exhibits anti-tumor activity in human NSCLC H1299
Many studies show the synergistic effects of ARTs cells and H1299 xenograft mice, through the induction
with other compounds or therapeutic approaches. The of ROS-mediated ER-stress-dependent apoptosis [242].
combined treatment of ART and resveratrol markedly It also suppresses cell proliferation and migration, and
inhibits cell proliferation and migration, and enhances induces cell cycle arrest in human hepatocellular car-
apoptosis and ROS production in human cervical can- cinoma HepG2 and Hep3B cells, and inhibits tumor
cer HeLa and hepatocellular carcinoma HepG2 cells growth in HepG2 xenograft mice [243]. Compound K,
[213]. Similarly, the use of combined DHA and gemcit- an intestinal bacterial metabolite of ginsenosides, also
abine exhibits strong synergistic effects on the loss of induces cell cycle arrest and apoptosis in human colorec-
mitochondrial membrane potential and induction of tal cancer HCT-116 cells, and suppresses tumor growth
apoptosis in human NSCLC A549 cells [214]. DHA also in HCT-116 xenograft mice [244]. It also efficiently
reinforces the anti-cancer activity of chemotherapeu- inhibits cell proliferation and induces apoptosis through
tic agent, cisplatin, in cisplatin-resistant ovarian cancer mitochondrial-related pathways in human hepatocel-
cells [215]. Studies also demonstrate the enhancement of lular carcinoma MHCC97-H cells [245]. Furthermore,
sensitivity by DHA in photodynamic therapy in esopha- 20(S)-ginsenoside Rg3 induces autophagy to mediate cell
geal cancer [182, 216]. Therefore, this suggests that ARTs migration and invasion in human ovarian cancer SKOV3
could be potential anti-cancer agents. cells [246]. In contrast, it sensitizes NSCLC cells to ico-
The population pharmacokinetic properties of DHA tinib and hepatocellular carcinoma cells to doxorubicin
were investigated using the plasma and saliva of breast through the inhibition of autophagy [247, 248]. Besides,
cancer patients for long-term treatment (> 3 weeks) ginsenoside Rh2 inhibits cell growth partially through the
[217]. The salivary DHA concentration was proportion- coordination of autophagy and β-cateninin signaling in
ally correlated with the plasma DHA concentration, so human heptocellular carcinoma HepG2 and Huh7 cells
saliva is a good use for monitoring DHA levels in the [249]. Compound K induces autophagy-mediated apop-
body. An artemisinin analog, Artenimol-R, was shown tosis through AMPK/mTOR and JNK pathways in human
to improve clinical symptoms and tolerability in patients NSCLC A549 and H1975 cells [250], while it also induces
with advanced cervical cancer [218]. autophagy and apoptosis through ROS and JNK path-
ways in human colorectal cancer HCT-116 cells [251].
Ginsenosides Therefore, autophagy plays a dual role in cancer via dif-
Ginsenosides (Fig. 2) are the main bioactive dammarane ferent signaling routes.
triterpenoids derived from the rhizomes of many plants In recent years, the potential anti-cancer mechanisms
including Panax notoginseng (Burk.) F. H. Chen, Panax of ginsenoside Rg3 have been demonstrated in various
ginseng and Cinnamomum cassia Presl., with various cancer models, which include the inhibition of cell pro-
biological effects including anti-oxidative, anti-inflamma- liferation and induction of apoptosis via down-regulating
tory, and anti-cancer activities [219–222]. Ginsenosides PI3K/Akt, and activation of caspase-3 and -9 and Bcl-2
mainly exert anti-cancer effects in colorectal, breast, liver family proteins [234, 252], induction of cell cycle arrest
and lung cancers, through inhibiting cell proliferation by regulating CDK pathway [240], inhibition of metas-
and migration, angiogenesis, and reversing drug resist- tasis through reducing the expressions of aquaporin
ance [7, 223–230]. Ginsenoside Rg3, ginsenoside Rh2, 1, C–X–C chemokine receptor type 4 (CXCR4) and
and compound K are the primary bioactive compounds hypoxia-inducible factor 1α (HIF-1α) [253–255]. More-
among ginsenosides for cancer prevention. over, 20(S)-ginsenoside Rh2 is shown to bind to recom-
Ginsenoside Rg3 inhibits cell viability and induces cell binant and intracellular annexin A2 directly, and this
apoptosis in human ovarian cancer HO8910 cells [231], inhibits the interaction between annexin A2 and NF-κB
hepatocellular carcinoma Hep1-6, HepG2 and SMMC- p50 subunit, which decreases NF-κB activation [256].
7721, breast cancer MCF-7, MDA-MB-231, MDA- NF-κB is important in cell survival, and 20(S)-ginseno-
MB-453 and BT-549, and NSCLC A549, H23 and Lewis side Rh2 can inhibit cell survival through NF-κB pathway.
lung carcinoma cells [232–238]. It induces cell cycle Furthermore, p53 also plays a vital role in ginsenoside-
arrest at G1 phase in human melanoma A375, and mul- induced anti-cancer activities [244, 257, 258]. Ginse-
tiple myeloma U266, RPMI 8226 and SKO-007 cells [239, noside Rh2 induces cell death through p53 activation
Luo et al. Chin Med (2019) 14:48 Page 9 of 58

in human colorectal cancer HCT-116 and SW-480 cells (TACE) were studied in patients with advanced hepa-
[257], while ginsenoside Rg3 and compound K induces tocellular carcinoma. The results showed that this ther-
apoptosis and cell cycle arrest through p53/p21 up-regu- apy ameliorated TACE-induced adverse effects and
lation in human colorectal cancer HCT-116, SW-480 and prolonged the overall survival compared to the use of
HT-29, and gallbladder cancer NOZ and GBC-SD cells, TACE alone [264].
respectively [244, 258].
For the promotion of immunity, ginsenoside Rg3 can Ursolic acid (UA)
enhance lymphocyte proliferation and T helper type 1 As an ursane-type pentacyclic triterpenic acid, UA
cell (Th1)-related cytokine secretion including IL-2 and (Fig. 2) can be found in the berries and leaves of a series
IFN-γ in hepatacellular carcinoma H22-bearing mice, of natural medicinal plants, including Vaccinium mac-
and inhibit tumor growth partly through the induc- rocarpon Ait. (cranberry), Arctostaphylos uva-ursi (L.)
tion this cellular immunity [259]. Ginsenoside Rg3 can Spreng (bearberry), Rhododendron hymenanthes Makino,
also down-regulate the levels of B7-H1 and B7 homolog Eriobotrya japonica, Rosemarinus officinalis, Calluna
3 (B7-H3), immunoglobulin-like immune suppressive vulgaris, Eugenia jambolana and Ocimum sanctum, as
molecules, to modulate tumor microenvironment and well as in the wax-like protective coatings of fruits such
enhance anti-tumor immunity, and these molecules are as pears, apples and prunes [265]. UA has numerous
negatively associated with overall survival in colorectal biochemical and pharmacological effects including anti-
cancer patients [241]. It also ameliorates cisplatin resist- inflammatory, anti-oxidative, anti-proliferative, anti-ath-
ance by down-regulating B7-H1 levels and resuming T erosclerotic, anti-leukemic, anti-viral, and anti-diabetic
cell cytotoxicity in human NSCLC A549 and A549/DDP effects [266–272]. It also exerts anti-cancer activities in
cells [260]. In addition, ginsenoside Rh2 can also enhance ovarian, breast, gastric, prostate, lung, liver, bladder, pan-
anti-tumor immunity in melanoma mice by promoting creatic, and colorectal cancers [273–281].
T cell infiltration in the tumor and cytotoxicity in spleen UA can be used as a potential therapeutic agent for
lymphocytes [261]. the treatment of various cancers [281–289]. It induces
The combination of ginsenosides with other chemo- apoptosis through both extrinsic death receptor and
therapeutic agents provides significant advantages for mitochondrial death pathways in human breast cancer
cancer treatment. Ginsenoside Rg3 alone demonstrates MDA-MB-231 cells [289], and inhibits cell prolifera-
modest anti-angiogenic effects, and displays additive tion and induces pro-apoptosis in human breast cancer
anti-angiogenic effects in B6 glioblastoma rats when MCF-7 cells by FoxM1 inhibition [282]. UA also inhib-
combined with temozolomide [262]. When it is com- its cell and tumor growth through suppressing NF-κB
bined with paclitaxel, it enhances cytotoxicity and apop- and STAT3 pathways in human prostate cancer DU-145
tosis through NF-κB inhibition in human triple-negative and LNCaP cells, and DU-145 xenograft mice [283], and
breast cancer MDA-MB-231, MDA-MB-453 and BT-549 induces apoptosis in human prostate cancer PC-3 cells
cells [233]. [284]. Similarly, UA induces apoptosis and inhibits cell
Ginsenosides have a long history of use as traditional proliferation in human colorectal cancer HCT-15, HCT-
medicine to treat many diseases in China. Relatively few 116, HT-29 and Caco-2 cells [286, 287]. UA is also shown
clinical studies have been performed in humans even- to induce autophagy to mediate cell death in murine
though ginseng products are widely recognized to have cervical cancer TC-1 cells [290], and promote cytotoxic
therapeutic effects when used alone or in combination autophagy and apoptosis in human breast cancer MCF-7,
with other chemotherapeutic agents. Therefore, clinical MD-MB-231 and SKBR3 cells [291]. It also inhibits cell
studies are needed to confirm the safety of such uses. A growth by inducing autophagy and apoptosis in human
phase II clinical trial is conducting to assess the safety breast cancer cells T47D, MCF-7 and MD-MB-231 cells
and efficacy of ginsenoside Rg3 in combination with first- [279]. In contrast, UA induces autophagy, but the inhi-
line chemotherapy in advanced gastric cancer. Patients bition of autophagy enhances UA-induced apoptosis in
with advanced NSCLC and epidermal growth factor human oral cancer Ca922 and SCC2095, and prostate
receptor-tyrosine kinase inhibitor (EGFR-TKI) muta- cancer PC-3 cells [265, 292]. Therefore, autophagy plays a
tion were recruited in a study that investigated the safety dual role in UA-induced apoptosis via different signaling
and efficacy of the combined therapy, ginsenoside Rg3 pathways. In addition, UA inhibits tumor angiogenesis
and EGFR-TKI. It was shown that this therapy increased through mitochondrial-dependent pathway in Ehrlich
progression-free survival, overall survival and objective ascites carcinoma xenograft mice [293].
response rate compared to EGFR-TKI alone [263]. In Increasing evidence has linked the anti-cancer activi-
another study, the safety and efficacy of combined ginse- ties of UA to the activation of mitochondrial-dependent
noside Rg3 and transcatheter arterial chemoembolization signaling pathways, including mitochondrial energy
Luo et al. Chin Med (2019) 14:48 Page 10 of 58

metabolism, oxidative stress and p53‑mediated mito- A human clinical study was conducted to investigate
chondrial pathways [289, 291, 293]. UA is demonstrated the toxicity and pharmacokinetics of UA-liposomes
to have apoptosis-promoting and anti-proliferative (UAL) including dose-limiting toxicity and maximum
capacities via modulating the expressions of mitochon- tolerated dose in healthy adult volunteers and patients
drial-related proteins such as Bax, Bcl-2, cytochrome with advanced solid tumors [309]. UAL had manageable
c and caspase-9 [289, 293]. It can also induce oxidative toxicities under the dose of 98 mg/m2, as well as a lin-
stress and disruption of mitochondrial membrane per- ear pharmacokinetic profile, so it was suggested that UA
meability to mediate apoptosis in human osteosarcoma could be developed as a potential and safe drug [309].
MG63 and cervical cancer HeLa cells [294, 295]. In
addition, p53 pathway also contributes to the anti-can- Silibinin
cer effects of UA. UA induces apoptosis and cell arrest Silibinin (Fig. 2), one of the flavonoids isolated from Sily-
through p21-mediated p53 activation in human colorec- bum marianum L. Gaertn, is commonly exploited for the
tal cancer SW-480 and breast cancer MCF-7 cells [296, treatment hepatic diseases in China, Germany and Japan.
297], and this p53 activation is through inhibiting nega- In addition, silibinin is also found to display various
tive regulators of p53, MDM2 and T-LAK cell-originated biological activities including anti-oxidative, anti‑pro-
protein kinase (TOPK) [297]. liferative, anti-bacterial, anti-fungal, neuro-protective,
Studies have reported the cancer immunomodulatory anti-leishmanial, anti-osteoclastic and anti-metastatic
activities of UA [279, 293]. UA down-regulates NF-κB to activities [310–317]. Previous studies have reported that
inhibit cell growth and suppress inflammatory cytokine silibinin exerts remarkable effects in numerous cancers
levels including TNF-α, IL-6, IL-1β, IL-18 and IFN-γ in such as renal, hepatocellular and pancreatic carcinoma,
human breast cancer T47D, MCF-7 and MDA-MB-231 bladder, breast, colorectal, ovarian, lung, salivary gland,
cells [279]. It also modulates the tumor environment prostate and gastric cancers, through the induction of
by modulating cytokine production such as TNF-α and apoptosis, inhibition of tumor growth, metastasis and
IL-12 in ascites Ehrlich tumor [293]. angiogenesis [318–328].
UA is insoluble in water, with poor pharmacokinetic Silibinin suppresses epidermal growth factor-induced
properties including poor oral bioavailability, low dis- cell adhesion, migration and oncogenic transformation
solution and weak membrane permeability [298]. Some through blocking STAT3 phosphorylation in triple nega-
new drug delivery technologies have been developed to tive breast cancer cells [329]. It strongly suppresses cell
overcome these problems including the uses of liposomes proliferation and induces apoptosis in human pancreatic
[280, 299–302], solid dispersions [303], niossomal gels cancer AsPC-1, BxPC-3 and Panc-1 cells, and induces
[304], and nanoliposomes [278]. Liposome is the most cell cycle arrest at G1 phase in AsPC-1 cells [330]. It can
commonly used drug delivery system. A chitosan-coated also induce apoptosis via non-steroidal anti-inflamma-
UA liposome is synthesized with tumor targeting and tory drug-activated gene-1 (NAG-1) up-regulation in
drug controlled release properties, and has fewer side human colorectal cancer HT-29 cells [331], and induces
effects [302]. It enhances the inhibition of cell prolifera- mitochondrial dysfunction to mediate apoptosis in
tion and tumor growth in human cervical cancer HeLa human breast cancer MCF-7 and MDA-MB-123 cells
cells and U14 xenograft mice. Besides, a pH-sensitive [332]. Moreover, silibinin induces autophagic cell death
pro-drug delivery system is also synthesized, and this via ROS-dependent mitochondrial dysfunction in human
pro-drug enhances cellular uptake and bioavailability of breast cancer MCF-7 cells [333]. In contrast, it induces
UA [305]. It further inhibits cell proliferation, cell cycle autophagy to exert protective effect against apoptosis in
arrest and induces apoptosis in human hepatocellular human epidermoid carcinoma A-431, glioblastoma A172
carcinoma HepG2 cells. and SR, and breast cancer MCF-7 cells [334–336], and
UA can also be used in combination with other drugs. autophagy inhibition enhances silibinin-induced apop-
The combined treatment of zoledronic acid and UA tosis in human prostate cancer PC-3 cells [337]. Silibinin
enhances the induction of apoptosis and inhibition of cell also induces autophagy to inhibit metastasis in human
proliferation through oxidative stress and autophagy in renal carcinoma ACHN and 786-O cells, and salivary
human osteosarcoma U2OS and MG63 cells [306], whilst gland adenoid cystic carcinoma cells [317]. Therefore,
the combination of UA and curcumin inhibits tumor autophagy plays a dual role in silibinin-induced anti-
growth compared to UA alone in skin cancer mice [307]. cancer effects. In addition, silibinin inhibits angiogenesis
Moreover, UA combined with doxorubicin enhances the in human prostate cancer PCa, LNCaP and 22Rv1 cells
cellular uptake of doxorubicin, and reverses multi-drug [327].
resistance (MDR) in human breast cancer MCF-7/ADR Silibinin exhibits anti-cancer activities mainly due to
cells [308]. the cell cycle arrest [330, 338–341]. It induces G1 phase
Luo et al. Chin Med (2019) 14:48 Page 11 of 58

arrest in human pancreatic cancer SW1990 and AsPC- Silibinin has been widely used as anti-cancer drug
1, and breast cancer MCF-7 and MCF-10A cells [330, in vitro and in vivo, and its combination with other thera-
339, 340], whilst it causes G2 phase arrest in human pies is a promising treatment for cancer, so clinical trials
cervical cancer HeLa, and gastric cancer MGC-803 and are needed to confirm its safety and efficacy in humans,
SGC-7901 cells [338, 341]. It also decreases the expres- and to develop as an anti-cancer drug.
sions of CDKs such as CDK1, CDK2, CDK4 and CDK6
that are involved in G1 and G2 progression [338, 339]. Emodin
Besides, silibinin suppresses metastasis through ERK1/2 Emodin (Fig. 2) is an anthraquinone derivative isolated
and MMP-9 down-regulation in human thyroid cancer from many plants including Rheum palmatum, Polygo-
TPC-1, breast cancer MCF-7, renal carcinoma ACHN, num cuspidatum, Polygonum multiflorum, and Cassia
OS-RC-2 and SW-839, and epidermoid carcinoma A-431 obtusifolia. It exhibits remarkable biological effects such
cells [342–344]. In addition, silibinin induces apopto- as anti-inflammation, anti-oxidant, prevention of intra-
sis and inhibits proliferation through the suppression hepatic fat accumulation and DNA damage [360–366].
of NF-κB activation [345–348]. On the other hand, sili- Many studies have shown that emodin can attenuate
binin is shown to induce apoptosis through the promo- numerous cancers including nasopharyngeal, gall blad-
tion of mitochondrial dysfunction, including increased der, lung, liver, colorectal, oral, ovarian, bladder, pros-
cytochrome c and Bcl-2 levels, the loss of mitochondrial tate, breast, stomach and pancreatic cancers, through the
membrane potential, and decreased adenosine triphos- inhibition of cell proliferation and growth, metastasis,
phate (ATP) levels [332, 333, 349, 350]. angiogenesis, and induction of apoptosis [367–379].
Silibinin has immunomodulatory effects in cancer and Emodin suppresses ATP-induced cell proliferation and
immunity. The MDSCs are associated with immunosup- migration through inhibiting NF-κB activation in human
pression in cancer, and silibinin increases the survival NSCLC A549 cells [380], and induces apoptosis through
rate in breast cancer 4T1 xenograft mice, and reduces cell cycle arrest and ROS production in human hepato-
the population of MDSCs in their blood and tumor [351]. cellular carcinoma HepaRG cells [381]. It also induces
There was also a reduction in macrophage infiltration autophagy to mediate apoptosis through ROS production
and neutrophil population in silibinin-treated prostate in human colorectal cancer HCT-116 cells [382]. Moreo-
cancer TRAMPC1 xenograft mice [352]. These studies ver, emodin can inhibit tumor growth and metastasis in
suggest a role of immunity in its anti-tumor effects. triple negative breast cancer cells, and human colorectal
Silibinin has poor water solubility and bioavailabil- cancer HCT-116 cells [383, 384], whilst it suppresses cell
ity, so it limits its efficacy in anti-cancer activities [353]. migration and invasion through microRNA-1271 up-reg-
Advanced technologies such as nanoprecipitation tech- ulation in human pancreatic cancer SW1990 cells [385].

binin is encapsulated in ­Eudragit® E nanoparticles in the

nique are used to solve this issue [325, 353–356]. Sil- In addition, emodin can also inhibit angiogenesis in thy-
roid and pancreatic cancers [386–388].
presence of polyvinyl alcohol, and these nanoparticles Emodin exerts anti-cancer effects through various
enhance apoptosis and cytotoxicity in human oral cancer mechanisms. It effectively suppresses cell proliferation
KB cells [353]. The silibinin-loaded magnetic nanopar- through inhibiting estrogen receptor α (ERα) genomic
ticles further inhibit cell proliferation in human NSCLC and PI3K/Akt non-genomic pathways in human breast
A549 cells [325], while silibinin-loaded chitosan nano- cancer MCF-7 and MDA-MB-231 cells [389]. Besides,
particles enhances cytotoxicity compared to silibinin mitochondria and ER stress also play an important role
alone in human prostate cancer DU-145 cells [356]. in mediating emodin-induced anti-cancer effects [381,
The combination of silibinin and other drugs are used 390–392]. Emodin induces apoptosis through the loss of
in cancer treatment to enhance the efficacy of anti-can- mitochondrial membrane potential, modulation of Bcl-2
cer effects [324, 357–359]. The combination of curcumin family proteins, and caspase activation in human colo-
and silibinin enhances the inhibition of cell growth and rectal cancer CoCa cells and hepatocellular carcinoma
reduction in telomerase gene expression compared to HepaRG cells [381, 390]. ER stress is activated in emodin-
silibinin alone in human breast cancer T47D cells [357]. treated human osteosarcoma U2OS cells, and emodin-
The mixture of luteolin and silibinin also shows syner- induced apoptosis is suppressed by ER stress inhibition
gistic effects on the attenuation of cell migration and with 4-phenylbutyrate (4-PBA) in human NSCLC A549
invasion, and induction of apoptosis in human glioblas- and H1299 cells [391, 393].
toma LN18 and SNB19 cells [358]. Silibinin and pacli- Emodin has immunomodulatory effects in cancer
taxel combination enhances apoptosis and up-regulates and immunity. It inhibits cell growth and metastasis
tumour suppressor genes, p53 and p21, in human ovarian through blocking the tumor-promoting feed forward
cancer SKOV3 cells [324]. loop between macrophages and breast cancer cells [394].
Luo et al. Chin Med (2019) 14:48 Page 12 of 58

It also down-regulates CXCR4 to suppress C–X–C motif Various effects have been disclosed as key contribu-
chemokine 12 (CXCL-12)-induced cell migration and tions to the anti-cancer effects of triptolide. Triptolide
invasion in hepatocellular carcinoma HepG2 and HepG3 is shown to exhibit pro-apoptosis effects in various
cells [395]. In addition, emodin inhibits the differentia- cancers [427–431]. It induces mitochondrial apoptotic
tion of maturation of DCs [396], and can modulate mac- pathway to mediate apoptosis in Burkitt’s lumphoma
rophage polarization to restore macrophage homeostasis Raji, NAMALWA and Daudi cells, and inhibits tumor
[397]. growth in Daudi xenograft mice [432], and inhibits cell
Aloe-emodin is a derivate of emodin, which exhib- proliferation through microRNA-181a up-regulation
its superior bioactivities in some cancers. It can inhibit in human neuroblastoma SH-SY5Y cells [433]. Moreo-
cell proliferation through caspase-3 and caspase-9 acti- ver, triptolide induces autophagy to induce apoptosis
vation in human oral squamous cell carcinoma SCC-15 and inhibit angiogenesis in human osteosarcoma MG63
cells [398], and induce apoptosis in human cervical can- cells, and breast cancer MCF-7 cells [431, 434]. In con-
cer HeLa and SiHa cells, which is associated with glucose trast, triptolide induces protective autophagy through
metabolism [399]. Another derivative of emodin, rhein, calcium ­(Ca2+)/calmodulin-dependent protein kinase
can also induce apoptosis in human pancreatic cancer kinase β (CaMKKβ)-AMPK pathway in human prostate
Panc-1 cells, and inhibit tumor growth in pancreatic can- cancer PC-3, LNCaP and C4-2 cells, and through Akt/
cer xenograft mice [400]. It also inhibits cell migration mTOR down-regulation in human cervical SiHa cells
and invasion through regulating Rac1/ROS/MAPK/AP-1 [420, 435]. Therefore, autophagy plays a dual role in
signaling pathway in human ovarian cancer SKOV3-PM4 triptolide-induced anti-cancer effects. In addition, trip-
cells [401]. tolide is able to inhibit cell migration and invasion in
The combination of emodin and other chemotherapies human prostate cancer PC-3 and DU-145 cells, and in
is widely used for cancer treatment. Emodin can pro- tongue squamous cell carcinoma SAS cells co-inoculated
mote the anti-tumor effects of gemcitabine in pancreatic with human monocytes U937 cells [417, 419]. Further-
cancer [402–404]. It enhances apoptosis in human pan- more, triptolide also possesses anti-angiogenic effect by
creatic cancer SW1990 cells, and further inhibits tumor inhibiting VEGFA expression in human breast cancer
growth in SW1990 xenograft mice, through suppressing MDA-MB-231 and Hs578T cells, and through COX-2
NF-κB pathway [402, 403]. The combination of emodin and VEGF down-regulation in human pancreatic cancer
and curcumin can also enhance the inhibition of cell pro- Panc-1 cells [436, 437].
liferation, survival, and invasion in human breast can- Triptolide is a natural substance, which exerts its anti-
cer MDA-MB-231, MDA-MB-435 and 184A1 cells [64]. cancer effects through multiple targets. Triptolide is
Moreover, emodin enhances cisplatin-induced cytotoxic- shown to induce mitochondrial-mediated apoptosis in
ity through ROS production and multi-drug resistance- various cancer cells, through decreased mitochondrial
associated protein 1 (MRP1) down-regulation in human membrane potential, Bax and cytochrome c accumula-
bladder cancer T24 and J82 cells [405]. tion, PARP and caspase-3 activation, decreased ATP lev-
Emodin has been shown to have remarkable anti-can- els, and Bcl-2 down-regulation [432, 438–441]. Moreover,
cer effects in vitro and in vivo, and its combination with ERK is also shown to be important in mediating trip-
other therapies is very effective in treating cancer, there- tolide-induced anti-cancer activities. Triptolide induces
fore it is important to evaluate the safety and efficacy of apoptosis through ERK activation in human breast can-
emodin as an anti-cancer drug as the next step. cer MDA-MB-231 and MCF-7 cells [434, 442], and ERK
activation leads to caspase activation, Bax up-regulation
Triptolide and Bcl-xL down-regulation [442]. On the other hand,
Triptolide (Fig. 2) is a natural constituent derived from it can also inhibit metastasis through ERK down-reg-
the root of a traditional Chinese medicine, Tripterygium ulation in esophageal squamous cell cancer KYSE180
wilfordii Hook. F., which possesses diverse effects includ- and KYSE150 cells, and murine melanoma B16F10 cells
ing anti-inflammatory, anti-oxidative, and anti-cancer [443, 444]. Interestingly, ERα is shown to be a potential
activities [60, 406, 407]. For cancer therapy, it has been binding protein of triptolide and its analogues [445]. In
used to treat breast, lung, bladder, liver, colorectal, pan- addition, triptolide-induced metastasis is shown to be
creatic, ovarian, stomach, prostate, cervical, and oral through MMP-2 and MMP-9 down-regulation in human
cancers, melanoma, myeloma, leukemia, neuroblastoma, neuroblastoma SH-SY5Y cells, via decreased MMP-3 and
osteosarcoma, lymphoma, renal, nasopharyngeal, and MMP-9 expressions in T-cell lymphoblastic lymphoma
endometrial carcinoma, through apoptosis, cell cycle cells, and through MMP-2, MMP-7 and MMP-9 down-
arrest, inhibition of cell proliferation, metastasis and regulation in human prostate cancer PC-3 and DU-145
angiogenesis [406, 408–426]. cells [417, 423, 433].
Luo et al. Chin Med (2019) 14:48 Page 13 of 58

Indeed, immunology has been frequently validated of its derivatives and analogs have been used in clini-
to be associated with cancer. The combined use of trip- cal studies to test the safety and efficacy on anti-cancer
tolide and cisplatin enhances the plasma levels of IL-2 effects [432, 455–457]. Omtriptolide, a derivative of trip-
and TNF-α in ovarian cancer SKOV3/DDP xenograft tolide, is highly water soluble, and a phase I clinical trial
mice, which can promote the differentiation of T cells was conducted in Europe with patients who had refrac-
and inhibit tumorigenesis respectively, thus resulting in tory and relapsed acute leukemia [432]. Another phase
an inflammatory microenvironment and leading to can- I clinical trial was completed in patients with refractory
cer cell death [446]. gastrointestinal malignancies to study the dose escalation
The derivatives of triptolide are always needed to and pharmacokinectics of minnelide, a pro-drug of trip-
improve its ant-cancer therapy. Triptolide derivative, tolide [457]. The doses used were 0.16 to 0.8 mg/m2 and
MRx102, shows positive effects on anti-proliferation they were well tolerated except from the common hema-
and anti-metastasis through Wnt inhibition in human tologic toxicity. LLDT-8, another triptolide derivative,
NSCLC H460 and A549 cells, and H460 xenograft mice has anti-cancer and immunosuppressive effects, and is
[447]. Minnelide, a water-soluble pro-drug of triptolide, going to proceed into phase II clinical trial to test its anti-
can inhibit tumor growth in pancreatic cancer MIA cancer effects in China [455, 456]. Moreover, minnelide is
PaCa-2 xenograft mice. Meanwhile, the combination of currently under phase II clinical trial to test anti-cancer
minnelide and oxaliplatin further inhibits tumor growth effects in patients with advanced pancreatic cancer [458].
[448]. Moreover, triptolide is poorly soluble in water
and exhibits hepatotoxicity and nephrotoxicity, selective Cucurbitacins
delivery is an effective strategy for further application in Cucurbitacins (Fig. 2) is a cluster of tetracyclic triter-
cancer treatment. Triptolide loaded onto a peptide frag- penoids originated from various plants like Bryonia,
ment (TPS-PF-A299–585) is specifically targeted to the Cucumis, Cucurbita and Lepidium sativum. Cucurbi-
kidney and with less toxicity [449]. Some modified trip- tacins A–T are twelve main curcurbitacins belonging
tolide-loaded liposomes are reported to contribute a tar- to this family. Cucurbitacins have multiple therapeutic
geted delivery with lower toxicity and better efficacy in effects such as anti-inflammation, anti-proliferation, anti-
lung cancer treatment [450]. Similarly, triptolide-loaded angiogenesis, and anti-cancer [452, 459–462]. Besides,
exosomes enhances apoptosis in human ovarian cancer cucurbitacins have also been elucidated as a potential
SKOV3 cells [451]. candidate for various cancer therapies, including oral cell
Triptolide has some side effects in various organs carcinoma, breast, ovarian, prostate, lung, gastric, blad-
because of excessive dosage, so researchers have been der, and thyroid cancers, neuroastoma, hepatoma, and
looking for alternative triptolide therapies, and combina- osteosarcoma [463–475]. Most of cucurbitacins have
tion therapy has become a hot spot. Triptolide combined been reported with various anti-cancer activities, such as
with gemcitabine markedly enhances pro-apoptosis pro-apoptosis, anti-angiogenesis, autophagy induction,
through Akt/glycogen synthase kinase 3β (GSK3β) path- and inhibition of metastasis [452, 460–462, 476].
way in human bladder cancer EJ and UMUC3 cells Cucurbitacin B is the most abundant source of cucur-
[452]. Triptolide plus ionizing radiation synergistically bitacins which can explain why it receives more atten-
enhances apoptosis and anti-angiogenic effects through tion from researchers than other cucurbitacins do. It
NF-κB p65 down-regulation in human nasopharyngeal suppresses cell proliferation and enhances apoptosis in
carcinoma cells and xenograft mice, which provides a human NSCLC A549 cells, colorectal cancer SW-480 and
new chemotherapy to advanced nasopharyngeal malig- Caco-2 cells [462, 477], and induces G1 phase cell cycle
nancy [425]. The combined therapy of triptolide and arrest in human colorectal cancer SW-480 and Caco-
5-fluorouracil further promotes apoptosis and inhib- 2, and gastric cancer MKN45 cells [477, 478]. Cucurbi-
its tumor growth through down-regulating vimentin tacin D inhibits cell survival in human gastric cancer
in human pancreatic cancer AsPC-1 cells and AsPC-1 AGS, SNU1 and Hs746T cells [479], while cucurbitacin E
xenograft mice [453]. Besides, low concentration of trip- induces cell cycle arrest at G2/M phase in triple negative
tolide potentiates cisplatin-induced apoptosis in human breast cancer cells [480]. Moreover, cucurbitacins B, E
lung cancer HTB-182, A549 and CRL-5810 and CRL- and I are shown to induce autophagy, however inhibition
5922 cells [454], and triptolide with cisplatin synergisti- of autophagy can enhance cucurbitacin-induced apopto-
cally enhances apoptosis and induces cell cycle arrest in sis [481–483]. They also inhibit cell migration and inva-
human bladder cancer cisplatin-resistant cells [409]. sion in human breast cancer MDA-MB-231 and SKBR3,
Triptolide has wide-spectrum activities in pre-clinical NSCLC H2030-BrM3 and PC9-BrM3, and colorectal
studies, but it has strong side effects and water insolu- cancer COLO-205 cells [484–487], as well as angiogen-
bility, so it is not used in clinical studies. However, some esis in HUVECs [461, 488].
Luo et al. Chin Med (2019) 14:48 Page 14 of 58

Various targets have been demonstrated to be respon- nanomicelles show a higher bioavailability and better
sible for the anti-cancer effects of cucurbitacins. STAT3 tumor inhibition [497].
signaling is a very common target for cancer treatment. For a better cancer therapy, some combinations
Cucurbitacins B and D are reported to inhibit prolifera- between cucurbitacins and other drugs have been
tion and induce apoptosis through STAT3 suppression employed. Low doses of cucurbitacin B or methotrexate
in human NSCLC A549 cells and doxorubicin-resistant cannot inhibit tumor growth in osteosarcoma xenograft
breast cancer MCF-7/ADR cells, respectively [462, 489]. mice, however when combined together, they synergisti-
On the other hand, cucurbitacin E induces cell arrest and cally inhibit tumor growth [498]. The combination ther-
apoptosis via STAT3 inhibition in human breast cancer apy of cucurbitacin B and curcumin enhances apoptosis
Bcap-37 and MDA-MB-231 cells [468], and cucurbi- and reverses MDR in human hepatocellular carcinoma
tacin I can inhibit STAT3 pathway to suppress cancer Bel-7402/5-Fu cells [499]. Recently, cucurbitacin B is sug-
stem cell properties in anaplastic thyroid cancer ATC– gested to be a potential candidate when it is applied with
CD133+ cells [463]. Besides, cucurbitacin E induces cell withanone, this combination can enhance cytotoxicity in
cycle arrest through cyclins B1 and D1 down-regulation human NSCLC A549 cells, and inhibit tumor growth and
[480, 490], while cucurbitacin D inhibits cyclin B expres- metastasis in A549 xenograft mice [500]. Cucurbitacin
sion [491]. Moreover, mitochondria and ER stress also I is also shown to be a STAT3 inhibitor to mediate cell
play an important role in cucurbitacin-induced anti- survival and proliferation, and when it is combined with
cancer effects. Cucurbitacins mediate apoptosis through irinotecan, and they further inhibit cell proliferation in
mitochondrial-related pathway, which is characterized human colorectal cancer SW-620 and LS174T cells [501].
by the loss of the mitochondrial membrane potential, The derivatives of cucurbitacins, cucurbitacin
Bcl-2 down-regulation, Bax up-regulation, cytochrome c B-nanomicelles, and the combination therapies show
release, that eventually leads to caspase activation [470, promising treatment for cancer in vitro and in vivo, so
492]. Cucurbitacin I induces cell death through ER stress, clinical trials are needed to confirm their safety and effi-
by up-regulating ER stress markers such as IRE1α and cacy in cancer treatment.
PERK in human ovarian cancer SKOV3 cells and pancre-
atic cancer Panc-1 cells [493]. Tanshinones
Cancer immunotherapy also plays a vital role in cucur- Tanshinone (Fig. 2) is a derivative of phenanthrenequi-
bitacin treatment. Cucurbitacins may influence the none isolated from the dried root or rhizomes of Salvia
production of cytokines and transcription factors that miltiorrhiza Bunge. Tanshinone IIA is the primary bioac-
suppress the immune system, and these mechanisms tive constituent of tanshinones [502], which has various
may help to prevent the development of cancer. Cucur- pharmacological effects, including anti-inflammatory,
bitacin B is able to promote DC differentiation and anti- anti-cancer and anti-atherosclerotic activities, and car-
tumor immunity in patients with lung cancer [494]. The diovascular protection [503–506]. Tanshinone exhibits
combined therapy of cucurbitacin I and recombinant anti-cancer activities in stomach, prostate, lung, breast,
IL-15 is also reported to exhibit immunologic anti-cancer and colon cancers, through inducing cell cycle arrest,
activities in lymphoma with increased C ­ D4+ and C ­ D8+ apoptosis, autophagy, and inhibiting cell migration
T cell differentiation, and promote DC function through [507–515].
TNF-α up-regulation [495]. Tanshinone IIA suppresses cell proliferation and apop-
Although cucurbitacin B has very effective anti-tumor tosis in numerous cancer cells, including human breast
effects, it is shown to exhibit high toxicity, which restricts cancer BT-20, MDA-MB-453, SKBR3, BT-474, MCF-7
its clinical application on cancer therapy. Therefore, and MD-MB-231 [508, 516, 517], and gastric cancer
studies have been focused on tackling this side effect, MKN45 and SGC-7901 cells [518]. It also induces cell
and some cucurbitacin B derivatives have been synthe- cycle arrest at G1 phase in human breast cancer BT-20
sized to screen for effective cancer therapy with safety cells [517], and inhibits cell migration in human gas-
and tolerability. Compound 10b, one of the derivatives tric cancer SGC-7901 cells [514], and cell migration
of cucurbitacin B, shows more potent anti-cancer activ- and invasion in cervix carcinoma stemness-likes cells
ity than cucurbitacin B [496]. The in vivo acute toxicity [519]. Tanshinone I and cryptotanshinone are two other
study also shows that compound 10b has better toler- major bioactive compounds, which also induce cytotox-
ability and safety than cucurbitacin B. In addition, some icity against cancer cells. Tanshinone I induces apopto-
other strategies have been applied to accelerate the clini- sis and pro-survival autophagy in human gastric cancer
cal use of cucurbitacin B. The collagen peptide-modified BGC-823 and SGC-7901 cells [510], while cryptotanshi-
nanomicelles with cucurbitacin B were synthesized to none suppresses cell proliferation and induces cell cycle
enhance the oral availability of cucurbitacin B, and these arrest at G1 phase in murine melanoma B16 cells, and
Luo et al. Chin Med (2019) 14:48 Page 15 of 58

G2/M phase in melanoma B16BL6 cells [520]. In addi- its leukemic activity in human leukemia NB4 cells [537],
tion, tanshinones I and IIA and cryptotanshinone also while the nanoparticles containing tanshinone IIA and
inhibit tumor angiogenesis in endothelial and cancer α-mangostin show increased cytotoxicity in human pros-
cells [521–525]. Furthermore, tanshinone IIA induces tate cancer PC-3 and DU-145 cells [538].
autophagy to inhibit cell growth in human osteosarcoma Tanshinone IIA is shown to enhance chemosensitiv-
143B and MG63 cells and tumor growth in NOD/SCID ity and its efficacy when combined with other therapeu-
mice [526], while it induces autophagy to mediate anti- tic agents. Tanshinone IIA can be an effective adjunctive
cancer activities through activating beclin-1 pathway and agent in cancer, and it enhances the chemosensitivity to
inhibiting PI3K/Akt/mTOR pathway in human oral squa- 5-fluorouracil therapy in human colorectal cancer HCT-
mous cell carcinoma SCC-9, melanoma A375, and gli- 1116 and COLO-205 cells through NF-κB inhibition
oma U251 cells [527–529]. Moreover, tanshinone IIA is [539]. The combination of tanshinone IIA with doxo-
shown to exhibit anti-cancer activities through the inter- rubicin does not only enhance the chemosensitivity of
play between autophagy and apoptosis in human prostate doxorubicin, but also reduces the toxic side effects of
cancer PC-3 cells, mesothelioma H28 and H2452 cells doxorubicin in human breast cancer MCF-7 cells [540].
[502, 530]. In addition, tanshinone IIA and cryptotanshinone syn-
Tanshinone IIA induces apoptosis through mitochon- ergistically enhance apoptosis in human leukemia K562
drial- and caspase-dependent pathways, which includes cells [541].
caspase-3, -9 and PARP activation, cytochrome c release, The anti-cancer effects of Tanshinone IIA have been
and increased ratio of Bax/Bcl-2 in human gastric cancer demonstrated in various cancers in vitro and in vivo, and
MKN45 and SGC-7901 cells, and tumor-bearing mice it can enhance chemosensitivity and its efficacy is very
[518]. It inhibits epithelial–mesenchymal transition by effective when combined with other therapeutic agents.
modulating STAT3-chemokine (C–C motif ) ligand 2 Up to now, the clinical trials of Tanshinone IIA are com-
(CCL2) pathway in human bladder cancer 5637, BFTC pleted only for the treatment of other diseases [542], so
and T24 cells [531], and suppresses cell proliferation and well-designed clinical trials should be done to further
migration via forkhead box protein M1 (FoxM1) down- confirm its safety and efficacy in cancer treatment.
regulation in human gastric cancer SGC-7901 cells [514].
On the other hand, tanshinone I induces apoptosis via Oridonin
Bcl-2 down-regulation in human gastric cancer BGC- Oridonin (Fig. 2) is an ent-kaurane diterpenoid iso-
823 and SGC-7901 cells [510], while cryptotanshinone lated from Rabdosia rubescens (Hemsl.) Hara, which is
induces apoptosis through mitochondrial-, cyclin- and also the main active constituent of Rabdosia rubescens
caspase-dependent pathways in human NSCLC A549 (Hemsl.) Hara [543]. As an orally available drug, oridonin
and NCI-H460 cells [532], as well as via ER stress in is demonstrated to have anti-cancer activities in multi-
human hepatocellular carcinoma HepG2 and breast can- ple cancers over the past decades, including leukemia,
cer MCF-7 cells [533]. lymphoma, osteosarcoma, myeloma, uveal melanoma,
Tanshinone IIA is also shown to exhibit immunomdu- neuroblastoma, hepatocellular, laryngeal, esophageal,
latory effects in cancer [534]. The combination of tanshi- and oral squamous cell carcinoma, lung, colorectal,
none IIA with cyclophosphamide increases C ­ D4+ T cell, breast, gastric, pancreatic, and prostatic cancers [543–
+ +
­CD4 /CD8 T cell and NK cell populations compared 558]. The anti-cancer effects of oridonin are shown in
to single treatment in NSCLC Lewis-bearing mice, so it many aspects, including the induction of cell apopto-
can improve the immunological function in lung cancer sis, autophagy, cell cycle arrest, and the suppression of
[534]. Furthermore, cryptotanshinone becomes a new angiogenesis, cell migration, invasion and adhesion [554,
promising anti-tumor immunotherapeutic agent [535]. 559–564].
It induces mouse DC maturation and stimulates IL-1β, Oridonin induces apoptosis in human hepatocellular
TNF-α, IL-12p70 secretion in DCs, and enhances T cell carcinoma HepG2 and Huh6, oral squamous cell carci-
infiltration and Th1 polarization in Lewis-bearing tumor noma WSU-HN4, WSU-HN6 and CAL27, and laryngeal
tissues [535]. cancer HEp-2 cells [550, 559, 561, 565]. It also induces
Tanshinone IIA has poor bioavailability, so a mixed G2/M cell cycle arrest in human oral squamous cell car-
micelle system is developed to form a tanshinone- cinoma WSU-HN4, WSU-HN6 and CAL27, gastric can-
encapsulated micelle [536]. This micelle has higher cer SGC-7901, prostate cancer PC-3 and DU-145, and
cytotoxicity and pro-apoptotic effects in human hepa- breast cancer MCF-7 cells [555, 561, 566, 567]. Oridonin
tocellular carcinoma HepG2 cells compared to tanshi- is also shown to induce autophagy in many cancer cells,
none IIA alone. The tanshinone IIA-loaded nanoparticles which is associated positively or negatively with apopto-
improve the bioavailability tanshinone IIA and enhance sis. It induces autophagy to mediate apoptosis in human
Luo et al. Chin Med (2019) 14:48 Page 16 of 58

NSCLC A549 and neuroblastoma SHSY-5Y cells [558, in human gastric cancer MGC-803 cells and MGC-
568]. On the other hand, autophagy provides a protective 803 xenograft mice [582]. Oridonin phosphate, another
role against oridonin-induced apoptosis, as autophagy derivative, is reported to induce autophagy, which
inhibitor enhances oridonin-induced apoptosis in human can enhance apoptosis in human breast cancer MDA-
cervical carcinoma HeLa, multiple myeloma RPMI 8266, MB-436 cells [583]. A novel analog of oridonin, CYD
laryngeal cancer HEp-2 and Tu212, and epidermoid car- 6-17, inhibits tumor growth in bladder cancer UMUC3
cinoma A-431 cells [569–572]. The anti-cancer effects of xenograft mice and renal carcinoma 786-O xenograft
oridonin are also shown to be through suppressing angi- mice [584, 585]. In addition, drug delivery system is also
ogenesis and metastasis, which are the primary causes of developed to improve the bioavailability of oridonin.
tumor growth and metastasis. It can inhibit cell migra- The inhalable oridonin-loaded microparticles exhibit
tion and invasion, and tube formation in human breast strong pro-apoptotic and anti-angiogenic effects through
cancer 4T1 and MDA-MB-231, human and murine mela- mitochondrial-related pathways in NSCLC rats [586],
noma A375 and B16F10, osteosarcoma MG63 and 143B, whilst the oridonin-loaded nanoparticles enhance cellu-
and HUVECs, as well as tumor metastasis in HepG2 xen- lar uptake and exert better anti-cancer effects in human
ograft zebrafish and mice, 4T1 xenograft mice, and 143B hepatocellular carcinoma HepG2 cells [587].
xenograft mice [554, 562–564, 573]. The combination of oridonin with other agents plays a
Proteomic and functional analyses reveal that ER potential role in cancer therapy. AG1478, a specific epi-
stress and poly(rC)-binding protein 1 (α-CP1) are poten- dermal growth factor receptor (EGFR) inhibitor, aug-
tial pathways involved in the anti-proliferative and pro- ments oridonin-induced apoptosis through oxidative
apoptotic activities of oridonin [546]. Oridonin inhibits stress and mitochondrial pathways in human epider-
cell growth and induces apoptosis through ER stress and moid carcinoma A-431 cells [588]. The combination of
ASK1/JNK signaling pathways in human hepatocellular γ-tocotrienol and oridonin exerts synergistic anti-can-
carcinoma Huh6 cells [559]. Besides, the mitochondrial cer effects in murine + SA mammary adenocarcinoma
redox change is proved to be a potential mediator for the epithelial cells, which are mainly through the induction
pro-apoptosis effect of oridonin [565]. The anti-prolif- of autophagy [589]. Moreover, oridonin can enhance
erative effect of oridonin is also shown to be associated the pro-apoptotic activity of NVP-BEZ235 in human
with mitochondrial-mediated apoptosis, which is charac- neuroblastoma SHSY-5Y and SK-N-MC cells through
terized by mitochondrial membrane potential reduction, autophagy [558], whilst the combination of oridonin and
subsequent cytochrome c release, PARP, caspase-3 and -9 cetuximab exhibits potent pro-apoptotic effect in human
activation, and decreased Bcl-2/Bax ratio [551, 565, 574, laryngeal cancer HEp-2 and Tu212 cells [572].
575]. Oridonin also inhibits cell proliferation through Clinical trials are essential to test the safety and effi-
bone morphogenetic protein 7 (BMP7)/p38 MAPK/ cacy of oridonin before drug approval. A derivative of
p53 pathway in human colorectal cancer HCT-116 and oridonin, HAO472, is currently under a phase I clinical
SW-620 cells [553, 576, 577], and induces apoptosis via trial for the treatment of acute myelogenous leukemia in
hydrogen peroxide ­(H2O2) production and glutathione China [590].
depletion in human colorectal cancer SW-1116 cells
[578]. Furthermore, the down-regulation of AP-1 is Shikonin
reported to be the initial response to oridonin treatment, Shikonin (Fig. 2) is an active naphthoquinone, which is
which decreases the expressions of NF-κB and MAPK to derived from the dried root of Lithospermum erythrorhi-
inhibit cell proliferation [579]. zon, Arnebia euchroma and Arnebia guttata, and it pos-
Oridonin possesses an immunosuppressive effect sesses anti-oxidative, anti-inflammatory, and anti-cancer
which modulates microglia activation, enhances T cell activities [591–594]. It is effective in treating different
proliferation, alters the balance of Th1-T helper type 2 kinds of cancers, including breast, prostate, ovarian and
cells (Th2), reduces inflammatory cytokine secretion thyroid cancers, Ewing sarcoma, and myelomonocytic
such as IL-2, IL-4, IL-6, IL-10 and TNF-α, and modulates lymphoma [595–600]. Shikonin exerts anti-cancer effects
an anti-inflammatory target, B lymphocyte stimulator mainly by inducing apoptosis, necroptosis, autophagy,
[580]. It also decreases inflammatory cytokine secre- cell cycle arrest, and by inhibiting cell proliferation,
tion in human pancreatic cancer BxPC-3 cells, including growth and metastasis [593, 601, 602].
IL-1β, IL-6 and IL-33 [581]. Shikonin is reported to inhibit cell growth by induc-
The derivatives and analogs of oridonin usually exhibit ing cell cycle arrest and promoting apoptosis in human
more potent anti-cancer activities than oridonin. Geri- NSCLC A549, gallbladder cancer NOZ and EHGB-1,
donin, a novel derivative of oridonin, inhibits cell growth esophageal cancer EC109, and epidermoid carcinoma
and induces G2/M phase arrest through ROS production A-431 cells [601, 603–605]. It can also induce necroptosis
Luo et al. Chin Med (2019) 14:48 Page 17 of 58

via autophagy inhibition in human NSCLC A549 cells naphthazarin ring of shikonin is modified to produce
[593], and through ROS overproduction in human naso- DMAKO-05, which can specifically target cancer cells
pharyngeal carcinoma 5-8F, and glioma SHG-44, U87 instead of normal cells [626]. DMAKO-05 can also sup-
and U251 cells [606, 607]. Moreover, shikonin induces press cell survival in human colorectal cancer HCT-116
autophagy in human melanoma A375, pancreatic can- cells, and inhibits tumor growth in colorectal cancer
cer BxPC-3, and hepatocellular carcinoma Bel-7402 and CT-26 xenograft mice [627]. Besides, it inhibits cell pro-
Huh7 cells [608–610]. However, autophagy provides a liferation and migration, and induces cell cycle arrest
protective role in shikonin-induced apoptosis in human and apoptosis in murine melanoma B16F0 cells [626].
melanoma A375 cells [608]. In addition, shikonin can Another novel shikonin derivative, cyclopropylacetyl-
suppress metastasis by the inhibition of tyrosine kinase shikonin, exhibits strong anti-tumor and pro-apoptotic
c-Met and integrin (ITG) β1 in human NSCLC A549 cells effects in human melanoma WM164 and MUG-MEL2
[602, 611]. cells [628]. In addition, drug delivery system is also
There are multiple mechanisms involved in the anti- developed to promote the intracellular delivery of shi-
cancer effects of shikonin, including ER stress, ROS konin. The shikonin-loaded nanogel enhances RIP1- and
generation, glutathione (GSH) depletion, mitochondrial RIP3-dependent necroptosis in human osteosarcoma
membrane potential disruption, p53, superoxide dis- 143B cells [629]. There is an increased accumulation of
mutase (SOD) and Bax up-regulation, PARP cleavage, shikonin-loaded nanogel in the tumor tissue, and this
catalase and Bcl-2 down-regulation [591, 612–614]. The nanogel can further inhibit tumor growth and metasta-
pro-apoptotic effect of shikonin is also caused by the dis- sis in 143B xenograft mice. Furthermore, the modified
­ a2+ homeostasis and mitochon-
ruption of intracellular C shikonin-loaded liposomes have higher cytotoxicity, and
drial dysfunction, which involves enhanced ­ Ca2+ and inhibit cell proliferation, metastasis in human breast can-
+
potassium ­(K ) efflux, caspase-3, -8 and -9 activation, cer MDA-MB-231 cells [630].
and Bcl-2 family protein modulation [615, 616]. ERK The combination therapy is widely used to provide
pathway also plays a role in shikonin-induced anti-cancer synergistic effects of anti-cancer activities. Shikonin
effects. Shikonin induces apoptosis and inhibits metasta- can enhance the pro-apoptotic effect of taxol in human
sis through suppressing ERK pathway in human NSCLC breast cancer MBA-MD-231 cells, and this combination
NCI-H460 and A549 cells, respectively [611, 617]. c-Myc improves mice survival and inhibits tumor growth in
down-regulation along with inhibition of ERK/JNK/ MDA-MB-231 xenograft mice [631]. Besides, shikonin
MAPK and Akt pathways are also involved in shikonin- can also potentiate the anti-cancer effects of gemcitabine
induced apoptosis and anti-proliferation in acute and through NF-kB suppression and by regulating RIP1 and
chronic leukemia [618–620]. Moreover, the activation of RIP3 expressions in human pancreatic cancer [632, 633].
necroptosis initiators, receptor interacting serine-threo- Shikonin is also reported to promote the efficacy of adri-
nine protein kinase (RIP) 1 and RIP3, by shikonin does amycin in lung cancer and osteosarcoma [634, 635], and
not only contribute to DNA double strand breaks via enhance sensitization to cisplatin in colorectal cancer
ROS overproduction [621], but also facilitates glycolysis [636]. Apart from the synergistic effect of shikonin, the
suppression via intracellular H ­ 2O2 production [622]. In combination of shikonin and paclitaxel reverses MDR in
addition, shikonin induces cell cycle arrest through p21 human ovarian cancer A2780 cells [10].
and p27 up-regulation, cyclin and CDK down-regulation The single or combined therapies with shikonin show
[605]. Therefore, numerous pathways involved in shi- promising anti-cancer effects in vitro and in vivo, so pre-
konin-induced anti-cancer effects may explain the broad clinical data has confirmed its therapeutic use in cancer
range of its activities. treatment, as a result, clinical trials will be carried out to
Shikonin is also shown to modulate the function of further to confirm its safety and efficacy in humans.
the immune system. It can enhance the proliferation of
NK cells and its cytotoxicity to human colorectal cancer Gambogic acid (GA)
Caco-2 cells by regulating ERK1/2 and Akt expressions GA (Fig. 2) is one of the major compounds derived
[623]. It can also bind directly to heterogeneous nuclear from gambogethe resin exuded from Garcinia spe-
ribonucleoprotein A1 to induce immunogenic cell death cies including G. hanburyi and G. Morella [637]. It has
in human breast cancer MDA-MB-231 cells [624]. Shi- multiple biological activities such as anti-oxidative,
konin is also reported to be used as an immunotherapy anti-inflammatory, and anti-cancer activities [638,
modifier in cell-based cancer vaccine systems, suggesting 639]. Plenty of evidence shows that GA inhibits cell
its potential application in cancer immunotherapy [625]. proliferation, invasion, survival, metastasis and chemo-
Derivatives are developed to enhance the anti- resistance, and induces angiogenesis in many types of
cancer and tumor targeting effects of shikonin. The cancers such as gastric and prostate cancers, leukemia,
Luo et al. Chin Med (2019) 14:48 Page 18 of 58

multiple myeloma, osteosarcoma, and renal carcinoma cytokine production including TNF-α, IL-1β and IL-6 by
through multiple signaling mechanisms [640–646]. suppressing p38 pathway in murine macrophage RAW
Many studies have reported the anti-cancer effects 264.7 cells [661].
of GA in human breast cancer [647–650]. GA at low GA has low solubility, instability and poor pharma-
concentrations (0.3–1.2 μM) can inhibit cell inva- cokinetic properties [662]. In order to increase its water
sion without affecting cell viability, while high con- solubility, GA is conjugated with a cell-penetrating pep-
centrations of GA (3 and 6 μM) can induce apoptosis tide, trans-activator of transcription, to form GA-TAT
via ROS accumulation and mitochondrial apoptotic [658]. This GA-TAT enhances apoptosis through ROS
pathway in human breast cancer MDA-MB-231 cells accumulation in human bladder cancer EJ cells. Another
[651]. GA also induces apoptosis via ROS production study uses a co-polymer to encapsulate GA to form GA
in human bladder T24 and UMUC3 cells [652]. At ear- micelles [639]. These GA micelles have better cellular
lier time points, GA induces ROS-mediated autophagy, uptake which can further enhance apoptosis in human
which produces a strong cell survival response. How- breast cancer MCF-7 cells and the anti-tumor effects in
ever, at later time points, caspases are activated which MCF-7 xenograft mice. Moreover, GA is encapsulated
degrade autophagic proteins and cell survival proteins, into the core of the nanoparticles to enhance the stability
and this eventually induces apoptosis. Similarly, GA- of GA and its circulation time [662]. These nanoparticles
induced autophagy via ROS provides a cytoprotective have tumor targeting properties, and enhance the anti-
effect to human pancreatic cancer Panc-1 and BxPC-3 tumor activities of GA without inducing higher toxicity.
cells [653], and ROS scavenger, N-acetylcysteine, can The combination of GA and other chemotherapy agents
reverse GA-induced autophagy in human NSCLC NCI- has been widely used to improve the therapeutic effects
H441 cells [654]. Moreover, GA inhibits cell invasion against various cancers such as osteosarcoma, pancreatic
and migration through reversion-inducing-cysteine- and lung cancers [639, 653, 663, 664]. Cisplatin resist-
rich protein with kazal motifs (RECK) up-regulation ance is a main clinical problem for the treatment of lung
in human NSCLC A549 cells and A549 xenograft cancer, and the treatment of cisplatin with GA is shown
mice [655], and prevents TNF-α-induced invasion in to enhance apoptosis and decrease the cisplatin resist-
human prostate cancer PC-3 cells [656]. It also inhibits ance index in human NSCLC cisplatin-resistance A549/
angiogenesis in HUVECs, and prevents tumor growth DDP cells [663]. Moreover, GA and retinoic acid chloro-
through the inhibition of tumor angiogenesis [657]. chalcone are loaded into glycol chitosan nanoparticles to
ROS-related pathways play a vital role in GA-induced form RGNP [639]. The RGNP exhibits synergistic effects
cell death [642, 646, 647, 651–654, 658]. GA induces to inhibit cell proliferation and induces apoptosis in oste-
apoptosis mainly through ROS accumulation in human osarcoma. The combination of GA with doxorubicin syn-
pancreatic cancer Panc-1 and BxPC-3, NSCLC NCI- ergistically reduces cell viability in human ovarian cancer
H441, castration-resistant prostate cancer PCAP-1, platinum-resistance SKOV3 cells, and this combination
melanoma A375, breast cancer MCF-7 cells [642, 646, also suppresses tumor growth in SKOV3 xenograft mice
647, 653, 654]. It also induces oxidative stress-dependent [665].
caspase activation to mediate apoptosis in human blad- The safety and efficacy of GA at different dosages in
der cancer T24 and UMUC3 cells [652]. Moreover, GA patients with advanced malignant tumors have been
increases the expressions of ER stress markers such as compared in a phase IIa clinical trial [666]. GA had a
GRP78, CHOP, activating transcription factor 6 (ATF-6) safety profile at a dosage of 45 mg/m2. The patients with
and caspase-12, and co-treatment with chemical chaper- GA administration on days 1–5 in a 2-week cycle showed
one, 4-PBA, significantly reduces these expressions and a greater disease control rate and only Grades I and II
apoptosis in human NSCLC A549 cells, so it is suggested adverse reactions. To further investigate the safety and
that GA induces ER stress to mediate apoptosis [659]. efficacy of GA, a phase IIb clinical trial involving a larger
Previous studies have shown some immunomodula- sample size of patients would be needed.
tory activities of GA [660, 661]. The activation of TLRs
is important to initiate immune responses, and TLR4 Artesunate
forms a complex with myeloid differentiation factor 2 Artesunate (Fig. 2) is a semi-synthetic compound derived
(MD2) to recognize its ligand, like LPS. GA is shown to from ART, which is widely used as an anti-malarial
reduce pro-inflammatory cytokine production in LPS- agent [667]. As an analog of ART, artesunate exerts bet-
primed primary macrophages such as TNF-α, IL-1β, ter water solubility and higher oral bioavailability, due
IL-6 and IL-12, and also inhibit the activation of TLR4 by to its special structure with an additional hemisuccinate
disrupting the interaction of TLR4/MD2 complex with group that makes it a better candidate for cancer treat-
LPS [660]. Similarly, it also reduces pro-inflammatory ment [668]. The anti-cancer effects of artesunate have
Luo et al. Chin Med (2019) 14:48 Page 19 of 58

been demonstrated in bladder, breast, cervical, colorec- to mediate apoptosis in murine ovarian cancer ID8 cells
tal, esophageal, gastric, ovarian and prostate cancer, renal [674]. It also exerts anti-tumor effects through suppress-
carcinoma, leukemia, melanoma and multiple myeloma ing NK killing activity and lymphocyte proliferation,
[179, 669–679]. Its anti-cancer effects include induction which results in decreased TGF-β1 and IL-10 levels in
of cell cycle arrest and apoptosis, inhibition of cell pro- colorectal cancer Colon-26 and RKO cells [691]. Besides,
liferation and growth, metastasis and angiogenesis [670, artesunate also exerts immunosuppression through
678, 680]. forkhead box P3 (Foxp3) down-regulation in T cells and
Artesunate can induce apoptosis in various cancers decreases prostaglandin ­E2 ­(PGE2) production in human
including human breast cancer MCF-7, MDA-MB-468 cervical cancer Caski and HeLa cells [671]. Moreover, it
and SKBR3 cells, gastric cancer SGC-7901 and HGC- enhances γδ T cell-mediated anti-cancer effect through
27, colorectal cancer HCT-116, and esophageal cancer augmenting γδ T cell cytotoxicity and decreasing TGF-β1
Eca109 and Ec9706 cells [670, 672, 673, 681–683]. It also levels to reverse immune escape in human hepatocellular
induces cell cycle arrest at ROS-dependent G2/M phase carcinoma HepG2 cells [692].
and ROS-independent G1 phase in human breast can- The treatment of artesunate with other therapies shows
cer MDA-MB-468 and SKBR3, and ovarian cancer HEY1 promising anti-cancer effects in several studies [693–
and HEY2 cells [670, 684], and induces G2/M cell cycle 697]. Artesunate and cisplatin synergistically induce
arrest through autophagy in human breast cancer MCF-7 DNA double-strand breaks and inhibit clonogenic forma-
and MDA-MB-231 cells [685]. Artesunate is also shown tion to mediate cytotoxic effects in human ovarian cancer
to induce autophagy to exert cytoprotective effects in A2780 and HO8910 cells [693]. The combined treatment
human colorectal cancer HCT-116 cells, and the inhibi- of artesunate and erlotinib enhances the inhibition of cell
tion of autophagy enhances artesunate-mediated apop- growth in human glioblastoma multiforme U87MG cells
tosis [179]. Similarly, artesunate-induced mitophagy [694].
provides a protective effects against cell death in human Clinical studies are carried out to investigate the safety
cervical cancer HeLa cells [686]. Moreover, it inhibits and efficacy of artesunate in patients with colorectal and
cell invasion and migration in human prostate cancer breast cancers, and advanced solid tumor malignancies
DU-145 and LNCaP, cervical cancer Caski and HeLa [698–701]. A phase I study is performed to evaluate the
cells, and uveal melanoma cells [675, 678, 687], and sup- safety and the maximum tolerated dose of artesunate in
presses tumor angiogenesis in HUVECs and renal carci- patients with metastatic breast cancer, the oral admin-
noma 786-O xenograft mice [676, 680]. istration of artesunate is safe and 2.2–3.9 mg/kg per day
In most cases, the inhibition effects of artesunate is well tolerated [701]. Another phase I study is assessed
against cancer cells are resulted from apoptosis. Artesu- in patients with advanced solid tumor malignancies, and
nate induces apoptosis through cyclooxygenase-2 the maximum tolerated dose of intravenous artesunate
(COX-2) down-regulation in human bladder cancer T24 is 18 mg/kg [698]. The tolerability and anti-proliferative
and RT4, and gastric cancer HGC-27 cells [669, 683]. properties of oral artesunate are also shown in patients
Mitochondrial pathways also play an important role in with colorectal cancer [699]. Moreover, a study of long
artesunate-mediated anti-cancer effects [673, 681, 683]. term treatment with oral artesunate is performed in
Artesunate inhibits tumor growth through ROS- and patients with metastatic breast cancer, 2.3–4.1 mg/kg per
p38 MAPK-mediated apoptosis in human rhabdomyo- day treatment for up to 1115 cumulative days does not
sarcoma TE671 cells [688]. It also exerts anti-tumor show any major safety concerns [700]. An ongoing phase
activities through the loss of mitochondrial membrane II clinical trial is carried out to study the safety and effec-
potential, Bcl-2 down-regulation, Bax up-regulation, tiveness of neoadjuvant artesunate in patients with stage
and caspase-3 activation in human gastric cancer SGC- II or III colorectal cancer awaiting surgical treatment.
7901 and HGC-27, esophageal cancer Eca109 and Ec9706
cells, and breast cancer MCF-7 xenograft mice [673, 681, Wogonin
683]. In addition, gene expression analysis identifies that Wogonin (Fig. 2) is a plant flavonoid extracted from roots
ER stress is the most relevant pathway for the anti-tumor of Scutellaria baicalensis, Scutellaria amoena and Scutel-
activity of artesunate in B-cell lymphoma [689]. Interest- laria rivularis, and stem of Anodendron affine Druce, and
ingly, artesunate selectively inhibits cell growth through has many pharmacological effects including anti-viral,
iron-dependent and ROS-mediated ferroptosis in human anti-oxidative, anti-inflammatory, anti-cancer and neuro-
head and neck cancer HN9 cells [690]. protective activities [702–705]. It has various anti-cancer
Immunomodulation also plays a vital role in artesu- effects in many cancers, including lung, breast, head and
nate-mediated anti-cancer effects [671, 674, 691, 692]. neck, gastric and colorectal cancers, glioma, leukemia,
Artesunate induces Th1 differentiation into C ­ D4+ T cells lymphoma, and osteosarcoma, through the induction
Luo et al. Chin Med (2019) 14:48 Page 20 of 58

of apoptosis and cell cycle arrest, and inhibition of cell migration through modulating inflammatory microen-
growth, migration, invasion, and angiogenesis [706–716]. vironment via IL-6/STAT3 pathway in human NSCLC
Wogonin can induce apoptosis and inhibit cell prolif- A549 cells [723]. Moreover, immunization with wogonin-
eration in human neuroblastoma SK-N-BE2 and IMR-32, treated tumor cell vaccine effectively inhibits tumor
NSCLC A549, glioma U251 and U87, and hepatocellu- growth in MFC xenograft mice [732]. Targeting TNF
lar carcinoma HepG2 and Bel-7402 cells [704, 706, 711, receptor with wogonin is also suggested to be a potential
717]. It also induces cell cycle arrest in human colorectal strategy for the treatment of chronic lymphocytic leuke-
cancer HCT-116, NSCLC A549, chronic myelogenous mia [712].
leukemia imatinib-resistant K562, and ovarian cancer In order to enhance the accumulation and retention of
A2780 cells [716, 718–720]. Besides, wogonin induces wogonin in cancer cells, wogonin-conjugated Pt(IV) pro-
autophagy in human pancreatic cells Panc-1 and Colo- drug is developed [733]. This pro-drug enhances the anti-
357, and nasopharyngeal carcinoma NPC-TW076 and proliferative and pro-apoptotic effects through casein
NPC-TW039 cells [721, 722]. However, inhibition of kinase 2 (CK2)-mediated NF-κB pathway in human gas-
autophagy promotes wogonin-induced apoptosis in tric cancer SGC-7901 and cisplatin-resistant SGC-7901/
human nasopharyngeal carcinoma NPC-TW076 and cDDP cells, and reverses cisplatin resistance in cisplatin-
NPC-TW039 cells [722]. It also inhibits metastasis in resistant SGC-7901/cDDP xenograft mice. It also fur-
human hepatocellular carcinoma Bel-7402 and HepG2 ther induces cell cycle arrest, enhances ROS production
cells, and NSCLC A549 cells [717, 723], and through and apoptosis, and decreases mitochondrial membrane
MMP-9 suppression in human hepatocellular carcinoma potential compared to wogonin in SGC-7901 cells [734].
MHCC97-L and PLC/PRF/5 cells [724]. In addition, LW-213, a derivative of wogonin, inhibits cell prolifera-
wogonin also represses multiple myeloma-stimulated tion and induces cell cycle arrest in human breast cancer
angiogenesis through c-Myc/von Hippel-Lindau tumor MCF-7 and MDA-MB-231 cells, and suppresses tumor
suppressor (VHL)/HIF-1α signaling pathway [725], LPS- growth in MCF-7 xenograft mice [735]. A synthetic
and ­H2O2-induced angiogenesis through PI3K/Akt/ wogonin derivative, GL-V9, inhibits metastasis in human
NF-κB pathway [726, 727]. breast cancer MDA-MB-231 and MCF-7 cells [736], and
Mitochondrial dysfunction, oxidative stress and ER induces apoptosis and cell cycle arrest in human hepato-
stress play important roles in wogonin-induced anti- cellular carcinoma HepG2 and gastric cancer cells MGC-
cancer effects. Wogonin activates mitochondrial and 803 cells [737–739]. Moreover, targeting cancer cells
ER stress-related pathways including the modulation of specifically is an important strategy in cancer therapy, so
Bcl-2 family proteins, cytochrome c release, GRP78 and wogonin-loaded liposomes are synthesized [740]. These
94-kDa glucose-regulated protein (GRP94) accumula- liposomes accumulate in the liver and prolong its reten-
tion, and caspase activation in human neuroblastoma tion time and exert better inhibitory effects than wogonin
SK-N-BE2 and IMR-32 cells, and induces mitochondrial in human hepatocellular carcinoma HepG2 cells.
dysfunction through IRE1α-dependent pathway [704]. ER The combination therapy has been widely used to
stress markers and downstream pathways are also acti- enhance the anti-cancer effects of wogonin. The com-
vated following wogonin treatment in human leukemia bined treatment of wogonin and oxaliplatin syn-
HL-60 and osteosarcoma U2OS cells, including IRE1α, ergistically inhibits cell growth in human gastric
PERK-eIF2α, ATF-6, CHOP, GRP94 and GRP78 [714, cancer BGC-823 cells and BGC-823 xenograft zebrafish,
728]. Wogonin also enhances ROS production in human through nitrosative stress and disruption of mitochon-
glioma U251 and U87, pancreatic cancer Panc-1 and drial membrane potential [741]. Wogonin also suppresses
Colo-357, and NSCLC A549 cells [711, 721, 729]. Moreo- sorafenib-induced autophagy to exacerbate apoptosis in
ver, it inhibits cell growth and induces apoptosis through human hepatocellular carcinoma Hep3B and Bel-7402
NF-κB suppression in Epstein–Barr virus-positive lym- cells [742], and augments cisplatin-induced apoptosis
phoma cells [730], and suppresses cell proliferation and through ­H2O2 accumulation in human NSCLC A549 and
invasion through NF-κB/Bcl-2 and EGFR pathways in cervical cancer HeLa cells [743].
human hepatocellular carcinoma HepG2 and Bel-7402 As wogonin has various anti-cancer activities, it is cur-
cells [717]. rently under phase I clinical trial to test the safety and
Wogonin has immunomodulatory effects in cancer efficacy as an anti-cancer drug in China [734].
cells. It enhances the recruitment of DCs, T and NK cells
into the tumor tissues in gastric cancer MFC xenograft β‑Elemene
mice, and also down-regulates the level of B7-H1, an β-Elemene (Fig. 2) is a sesquiterpene mixture isolated
immunoglobulin-like immune suppressive molecule, to from various Chinese herbs such as Curcuma wenyujin
promote anti-tumor immunity [731]. It also inhibits cell Y. H. Chen et C. Ling, Rhizoma zedoariae, and Curcuma
Luo et al. Chin Med (2019) 14:48 Page 21 of 58

Zedoary. It has various pharmacological effects includ- A549 cells [747], and up-regulates HIF-1α expression
ing anti-oxidative, anti-inflammatory and anti-cancer via ROS to induce apoptosis in human osteosarcoma
activities [744–746]. It exerts anti-cancer effects in many MG63 and Saos-2 cells [751].
cancers, such as lung, gastric, cervical, breast and blad- β-Elemene has immunomodulatory effects in cancer
der cancers, osteosarcoma, through apoptosis, inhibition and immune cells. It inhibits LPS-induced IL-6, TNF-
of cell proliferation, migration and invasion, angiogenesis α, IL-1β and IL-10 secretion, as well as inducible nitric
[746–752]. oxide synthase in murine RAW264.7 marcophages
β-Elemene is shown to induce apoptosis in human [745]. M2 macrophages are regarded as tumor-associ-
cervical cancer SiHa, NSCLC A549 cells, primary blad- ated macrophages, which can promote tumorigenesis
der cancer cells, and Burkitt’s lumphoma, and inhibit [762]. β-Elemene can induce the polarization of M2
tumor growth in Lewis tumor-bearing mice [746, 747, to M1 macrophages, and can also suppress M2 mac-
749, 753, 754]. It up-regulates insulin-like growth factor- rophage-treated conditioned medium-induced cell pro-
binding protein 1 (IGFBP1) to induce a reciprocal inter- liferation, migration and invasion in mouse lung cancer
action between microRNA 155-5p and FoxO3a, which Lewis cells [762].
leads to the inhibition of cell growth in human NSCLC β-Elemene has poor water solubility, low oral bio-
A549 and H1975 cells [755]. β-Elemene also induces S availability and severe phlebitis, so different deliv-
phase arrest in human NSCLC A549 cells [754], while it ery systems have been developed to solve these issues
induces G0/G1 phase arrest in human glioblastoma U87 [763–765]. β-Elemene-loaded nanostructured lipid car-
cells [756]. Moreover, it induces protective autophagy riers are synthesized to enhance the intravenous deliv-
in human gastric cells MGC-803 and SGC-7901, and ery of β-elemene, and have higher bioavailiabity [763].
NSCLC A549 cells, as autophagy inhibition promotes They inhibit tumor growth compared to β-elemene in
β-elemene-induced anti-tumor effects [748, 757]. How- hepatocellular carcinoma H22 xenograft mice. ETME, a
ever, autophagy inhibition attenuates β-elemene-induced novel β-elemene derivative, synergizes with arsenic tri-
apoptosis in human NSCLC cisplatin-resistant SPC-A-1 oxide to induce cell cycle arrest and apoptosis in human
cells [758]. β-Elemene can also inhibit cell migration and hepatocellular carcinoma SMMC-7721 cells, which is
invasion in human cervical cancer SiHa, murine breast dependent on p53 [766]. Another β-elemene derivative,
cancer 4T1 and melanoma B16F10 cells [749, 752, 759], 13,14-bis(cis-3,5-dimethyl-1-piperazinyl)-β-elemene
whilst it inhibits cell growth and metastasis through (IIi), is shown to inhibit cell proliferation in human gas-
angiogenesis suppression in murine melanoma B16F10 tric cancer SGC-7901 and cervical cancer HeLa cells, and
cells [752]. In addition, β-elemene can reverse drug inhibit tumor growth in sarcoma S-180 xenograft mice
resistance in human NSCLC erlotinib-resistant A549/ER [767]. It also induces autophagy in human breast cancer
cells by inhibiting P-gp expression and P-gp dependent MCF-7 cells, so it can be a potential anti-tumor agent.
drug efflux [760]. The combination therapy is commonly used to
β-Elemene exerts anti-tumor effects through phos- enhance the efficacy of β-elemene for cancer treatment.
phatase and tensin homolog (PTEN) up-regulation and β-Elemene when combined with cisplatin synergisti-
Akt suppression in human primary bladder cancer cells cally enhances apoptosis and inhibits cell proliferation
[746]. It also inhibits cell proliferation and invasion, in human gingival squamous cell carcinoma YD-38 cells
and induces apoptosis via inhibition of Wnt/β‑catenin and YD-38 xenograft mice [768]. β-Elemene potenti-
signaling pathway in human cervical cancer SiHa cells ates the anti-proliferation effect of gefitinib as well as
[749]. β-elemene-induced apoptosis is also shown to be the induction of apoptosis and autophagy in human glio-
through mitochondrial-related pathways, including p21 blastoma multiforme U251 and U87MG cells, through
and Bax up-regulation, caspase-9 activation, Bcl-2 and inhibiting EGFR signaling pathway [769]. It also reverses
survivin down-regulation [754]. On the other hand, it drug resistance in chemo-resistant breast cancer cells by
reverses drug resistance through mitochondrial-medi- reducing resistance transmission via exosomes [770], and
ated apoptosis in human NSCLC cisplatin-resistant enhances the sensitivity to TNF‐related apoptosis‐induc-
A549/DDP cells, via cytochrome c release, caspase-3 ing ligand (TRAIL) partly through death-inducing signal-
activation, Bcl-2 associated agonist of cell death (Bad) ing complex formation in human gastric cancer BGC-823
up-regulation and Bcl-2 down-regulation [761]. ER and SGC-7901 cells [771].
stress also plays a role in β-elemene-induced apoptosis. The Elemene Emulsion mainly containing β-elemene
β-Elemene up-regulates ER stress markers to induce has been approved by China’s State Food and Drug
apoptosis in human NSCLC A549 cells, including Administration, and now it is prescribed as an oral or
PERK, IRE1α, ATF-6, ATF-4 and CHOP [747]. Moreo- injected drug to improve anti-cancer efficacy and reduce
ver, it also enhances ROS production in human NSCLC the side effects as adjuvant therapy.
Luo et al. Chin Med (2019) 14:48 Page 22 of 58

Cepharanthine (CEP) [784]. In addition, CEP is also a potential anti-cancer

CEP (Fig. 2), a natural product derived from Chinese drug for ovarian cancer by markedly increasing p21
herbs such as Stephania cepharantha Hayata and Stepha- expression and decreasing cyclins A and D levels in
nia japonica, is a cationic and amphipathic alkaloid that human ovarian cancer CaOV-3 and OVCAR3 cells [787].
has been reported to decrease the fluidity of biological CEP also plays an important role in immunity. It is
membranes [772]. With the presence of a 1-benzyliso- shown to reduce IL-6 and TNF-α secretion in LPS-stim-
quinoline moiety on alkyl chain, CEP belongs to a class ulated DCs, and inhibits LPS-stimulated DC matura-
of compounds called biscoclaurine alkaloids that have tion and antigen uptake by DCs [793]. CEP-treated DCs
attracted significant attentions to pharmacologists and becomes a poor stimulator of allogeneic T cell activation
clinicians due to their resemblance to polypeptides and reduces IFN-γ production [793]. Therefore, it is sug-
[773]. CEP is widely used in Japan for the treatment of gested that CEP may have potential to be a cancer immu-
many acute and chronic diseases [773]. It exhibits anti- nomodulatory agent.
malarial, anti-viral, anti-inflammatory, anti-metastatic, Targeting P-gp using P-gp inhibitors is one of the main
and anti-cancer activities in various cell lines and animal strategies to reverse MDR, and cepharanthine hydrochlo-
models [772, 774–776]. Among its anti-cancer activities, ride (CEH), a salt form of CEP, is suggested to be a potent
CEP exhibits multiple pharmacological actions, including P-gp inhibitor [779]. CEH exhibits MDR reversal potency
apoptosis and radiation sensitization, inhibition of angio- in various cancer cells [779–781, 788]. CEH can reverse
genesis and metastasis, and reversing MDR [776–789]. MDR-mediated cisplatin resistance in esophageal squa-
CEP induces apoptosis and cell cycle arrest in many mous cell carcinoma [780]. It increases the sensitivity of
types of cancer cells [783–786, 790]. It induces autophagy the cells and induces apoptosis via c-Jun activation, thus
to mediate apoptosis through suppressing Akt/mTOR down-regulating P-gp and enhancing p21 levels. Simi-
signaling pathway in human breast cancer MCF-7 and larly, CEH also reverses P-gp-mediated MDR through
MDA-MB-231 cells [785], and stimulates AMPK-mTOR- suppressing PI3K/Akt pathway in human ovarian cancer
dependent autophagy to induce cell death in apoptosis- A2780/Taxol cells [788]. In addition, by reversing MDR,
resistant cells [791]. In contrast, the inhibition of autophagy CEH induces cell cycle arrest and apoptosis in human
is an effective treatment for NSCLC, and CEP is identified nasopharyngeal carcinoma CNE-1 and CNE-2 cells [789].
as a novel autophagic inhibitor in human NSCLC NCI- In addition to chemotherapy, CEP may act as a radio-
H1975 cells [782]. It inhibits autophagy by preventing sensitizer. Radiotherapy in the presence of CEP exhibits
autophagosome–lysosome fusion and inhibiting lysosomal significant enhancement of tumor responses in human
cathepsin B and cathepsin D maturation. Therefore, this oral squamous cell carcinoma [778]. This pre-clinical data
suggests that autophagy plays a dual role in cancer via dif- indicates that CEP has the potential to be used in clini-
ferent signaling routes. Moreover, CEP is suggested to be cal settings in combination with radiotherapy to treat oral
a potential anti-angiogenic agent, it blocks angiogenesis in squamous cell carcinoma. Moreover, paclitaxel and CEP co-
endothelial cells, zebrafish and xenograft mice by inhibiting loaded nano-particles also enhance the anti-cancer effects
cholesterol trafficking [777]. It can also suppress metasta- in human gastric cancer MKN45 cells and xenograft mice,
sis in a highly metastatic tumor, cholangiocarcinoma, and suggesting that these nano-particles could be a potential for-
markedly inhibit cell migration in human cholangiocarci- mulation for gastric cancer [794]. In addition, CEP enhances
noma KKU-M213 and KKU-M214 cells [776]. the anti-cancer effects of dacomitinib in human NSCLC
CEP has anti-tumor action mainly by inducing apop- NCI-H1975 cells and NCI-H1975 xenograft mice [782], and
tosis and ROS production [783, 784, 786]. ROS is shown cisplatin in lung and breast xenograft mice [777].
to be an important factor to determine cell fate, and it Although CEP has not yet been translated into clini-
can be regulated by p21 [792]. CEP efficiently inhibits cal use for the treatment of cancer, the pharmacological
the growth of p53-mutated colorectal cancer cells that activities and pre-clinical data support its significant clin-
are often resistant to commonly used chemotherapeutic ical potential for anti-cancer therapy.
agents [783]. It also effectively induces cell cycle arrest
and apoptosis through ROS production, p21 up-regula- Conclusions
tion, cyclin A and Bcl‑2 down-regulation [783]. Similarly, Chinese herbal medicine has played, and still plays, an
CEP triggers apoptosis via ROS production and reduc- important role in human health care in China and other
ing mitochondrial membrane potential, thus inducing Asian countries. Natural products orignianted from
caspase-3 and PARP activation in human NSCLC H1299 Chinese herbal medicine has also become a “hot topic”
and A549 cells [786]. It also exerts anti-tumor activity in anti-cancer research. Chinese herbal medicine is also
through ROS production and JNK activation in human recognized worldwide as a rich source for the discovery
choroidal melanoma MEL15-1 cells and xenograft mice of novel drugs in the past decades. Table 1 illustrates the
Table 1 List of anti-cancer natural compounds from Chinese herbal medicines
Luo et al. Chin Med

Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents

Curcumin Curcuma longa, Bladder cancer; breast T24, RT4, MDA- BxPC-3-GemR Anti-angio- Activates caspase-3, -9, PARP; 0–5 μM; 0–15 μM; Gemcitabine; [12, 21,
Curcuma cancer; cervical MB-231, HeLa, SiHa, xenograft mice; C4-2 genesis; Down-regulates Akt, Bcl-2, 0–16 μM; 0–20 μM; NVP-BEZ235; 795–814]
zedoaria, cancer; colorectal HCT-116, HT-29, xenograft mice; PC-3 anti-metastasis; Bcl-xL, CTGF, cyclin D1, cyclin 0–25 μM; 0–40 μM; α-Tomatine
(2019) 14:48

Acorus cancer; esophageal RKO, HCT-15, DLD- xenograft mice; RN5 anti-prolifera- E1, ERK1/2, EZH2, FoxM1, GLI1, 0–50 μM; 0–125 μM;
calamus L. squamous cell carci- 1, EC1, EC9706, xenograft mice; U87 tion; induces ITGA5, Jak1, JNK, MMP-2, Mcl-1, 10–40 μM; 15,
noma; gastrointestinal KYSE450, TE13, AGS, xenograft mice cell cycle NF-κB, Notch1, p15, p16, p62, 25 μM; 25 μM;
cancer; glioma; hepa- U87, T98G, HepG2, arrest; inhibits p70S6 K, ROCK1, RhoA, SHH, 30 μM; 0–6 μg/ml;
tocellular carcinoma; Tu212, A549, H1299, cell viability; SSAT, STAT1, STAT3, Suz12, 5 mg/kg; 60 mg/kg;
laryngeal cancer; lung H460, H292, NCI- pro-apoptosis TROP2, vimentin, WT1, XIAP, 200 mg/kg; 500 mg/
cancer; leukemia; liver H520, NCI-H1373, YAP/TAZ; Enhances cytochrome kg; 25 μg/mouse
cancer; mesothe- NCI-H2170, K562, c release, ROS accumulation;
lioma; neuroblastoma; HL-60, PLC/PRF5, Inhibits CDK2 activity, PI3K/Akt/
oral squamous cell WRL68, Huh7, mTOR, SHH/GLI1, STAT3, TGF-β
carcinoma; pancreatic KMCH, RN5, N2a, pathways; Up-regulates AIF,
cancer; prostate can- SCC-25, Patu8988, Bax, Bex-1, -2, -3, -4, -6, HIF-1α,
cer; renal carcinoma; Panc-1, C4-2, PC-3, microRNA-15a, microRNA-16-1,
retinoblastoma LNCaP, VCaP, Caki, microRNA-99a, p21, p53, p73,
O-Rb50, Y79 PKD1, SMOX
EGCG​ Camellia Biliary tract cancer; BDC, CCSW-1, EGI-1, 4T1 xenograft mice; Anti-angio- Activates caspase-3, -7, PARP; 0–20 µM; 0–40 µM; Bleomycin; Cispl- [93–95, 100,
sinensis bladder cancer; SkChA-1, TFK-1, A549 xenograft mice; genesis; Down-regulates ABCG2, Akt, 0–50 µM; 0–100 µM; atin; Curcumin; 101, 103,
breast cancer; cervical SW-780, MCF-7, 4T1, BCaPT10 xenograft anti-metastasis; AXL, Bcl-2, Bcl-xL, E-cadherin, 0–200 µM; Docetaxel; 123–125,
cancer; colorectal T47D, MDA-MB-231, mice; BCaPM-T10 anti-prolifera- β-catenin, CDK2, CDK4, COX-2, 0–400 μM; 5-Fluorouracil; 815–834]
cancer; gallbladder MDA-MB-436, xenograft mice; tion; induces CTTN, cyclin B1, cyclin D1, cyclin 2–100 μM; 10 μM; Oxaliplatin;
cancer; gastric cancer; SUM-149, SUM-190, CL1-5 xenograft autophagy, D2, cyclin D3, DNMT1, EGFR, 20 μM; 25, 50, Pterostilbene;
glioblastoma; head HeLa, DLD-1, HT-29, mice; Oral squamous cell cycle ERα, ERK1/2, FAK, FN1, GSK3β, 100 μM; 40 μM; 50, Temozolomide
and neck cancer; lung HCT-116, GBC, cell carcinoma arrest; inhibits HDAC1, HER2, HSP90, IKKα, JNK, 100 μM; 80 µM;
cancer; nasopharyn- MzChA-1, MzChA-2, xenograft mice; cell viability, MDR-1, MGMT, MMP-2, MMP-9, 0–60 μg/ml; 10 mg/
geal carcinoma; SGC-7901/FU, PC-12 xenograft epithelial– NANOG, NF-κB, Notch, Oct-4, kg; 10–20 mg/
NSCLC; oral cancer; MGC-803/FU, AGS, mice; SCG-7901/ mesenchymal u-PA, paxillin, P-gp, PI3K, Raf-1, kg; 15 mg/kg;
pancreatic cancer; C6, U251, SHG-44, FU xenograft mice; transition; pro- Snail, SOX2, Sp1, Src, STAT3, 16.5 mg/kg; 20 mg/
pheochromocytoma; U87, K3, K4, K5, SSC-9 xenograft apoptosis survivin, TFAP2A, Tyro3, VEGF, kg; 25 mg/kg;
prostate cancer; skin CL1-5, CL1-0, TW01, mice; SUM-149 xeno- vimentin; Enhances cytochrome 25–100 mg/kg;
cancer TW06, NCI-H1299, graft mice; SW-780 c release, ROS accumulation; 50 mg/kg; 0.025%,
A549, H460, SCC-9, xenograft mice Induces mitochondrial depo- 0.05%; 0.06%
MIA PaCa-2, Panc-1, larization; Inhibits MAPK/ERK,
PC-12, BCaPT1, PI3K/Akt pathways; Reduces ATP
BCaPT10, BCaPM- levels; Represses DNA replica-
T10, LNCaP, A431, tion; Up-regulates Bax, CK1α,
SCC13 endostatin, microRNA-16, p21,
p53, TIMP-1, TIMP-2
Page 23 of 58
 Luo et al. Chin Med

Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents

Berberine Coptidis Breast cancer; cervical MCF-7, MCF-7/ 22RV1 xenograft mice; Anti-angio- Activates caspase-3, -7, -8, -9, 0–10 µM; 0–20 μM; Caffeine; Cetuxi- [139, 140, 144,
(2019) 14:48

cgubebsus cancer; cholangio- HER2, MCF-7/ A2780 xenograft genesis; anti- PARP; Decreases mitochondrial 0–25 μM; 0–40 μM; mab; Doxoru- 145, 147–
Franch., carcinoma; colorectal TAM, MDA-MB157, mice; A549 xenograft proliferation; membrane potential, catalase 0–50 µM; 0–80 μM; bicin; Erlotinib; 149, 153,
Mahonia cancer; endometrial MDA-MB231, mice; BGC-823 xeno- anti-metastasis; and superoxide dismutase 0–90 µM; 0–100 µM; d-limonene; 171, 174,
bealei (Fort.) carcinoma; esopha- MDA-MB453, BT20, graft mice; Eca109 enhances activities; Down-regulates Akt, 0–120 µM; Niraparib; 835–870]
Carr., Phel- geal squamous BT549, Hs578T, xenograft mice; H22 radiosensitiv- AR, Bcl-2, Bcl-xL, Bid, β-catenin, 0–150 μM; Tamoxifen;
lodendron cancer; gastric cancer; T47D, SKBR3, BT474, xenograft mice; ity; induces N-cadherin, CDK1, CDK2, 0–160 µM; Taxol; TRAIL
chinense glioblastoma; head HeLa, SiHa, QBC939, HONE1 xenograft autophagy, CDK4, COX-2, PLA2, cyclin A1, 0–200 µM;
Schneid and neck cancer; KKU-213, KKU-214, mice; LoVo xenograft cell cycle cyclin B1, cyclin D1, cyclin E, 0–250 μM;
hepatocellular carci- SW-480, SW-620, mice; LNCaP xeno- arrest; inhibits DHCR24, DHFR, E2F1, EBNA1, 0–350 μM;
noma; leukemia; lung HT-29, DLD-1; graft mice; MDA- cell viability, EGFR, EF-Tu, ERK, Ezrin, FAK, FN, 0–1000 μM;
cancer; medulloblas- HCT-116, LS174T, MB-231 xenograft epithelial– HER2, HIF-1α, HMGB1, HNF4α, 10–80 μM; 15 µM;
toma; melanoma; LoVo, Eca109, TE13, mice; Medulloblas- mesenchymal ITGβ1, Jak2, JNK, Mcl-1, MEK, 20 μM; 50 μM;
nasopharyngeal KYSE-70, EAC, toma xenograft mice; transition; pro- MMP-1, MMP-2, MMP-9, mTOR, 0–1 µg/ml; 0–80 μg/
carcinoma; oral squa- SKGT4, AN3 CA, MHCC97L xenograft apoptosis c-Myc, NANOG, NF-κB, iNOS, ml; 5 mg/kg; 10 mg/
mous cell carcinoma; HEC-1-A, KLE, MGC- mice; SGC-7901 occludin, Oct-4, p38, p50, p62, kg; 12.5–50 mg/
osteosarcoma; ovar- 803, SGC-7901, AGS, xenograft mice; p100, p105, p70S6 K, paxillin, kg; 20 mg/kg;
ian cancer; pancreatic BGC-823, MKN45, SW-620 xenograft u-PA, PCNA, PDK1, P ­ GE2, PKC-α, 50, 100 mg/
cancer; prostate U87, U251, U118, mice; SiHa xenograft PSA, PTEN, PTTG-1, RAD51, kg; 50–200 mg/
cancer; skin cancer; SHG-44, FaDu, H22, mice; U87 xenograft b-Raf, c-Raf, Septin-8, Slug, Snail, kg; 200 mg/kg;
uterine leiomyoma Hepa1-6, HepG2, mice SOX2, Sp1, Src, STAT3, survivin, 0.01136 g/kg
Bel-7404, Huh7, UQCRC1, VEGF, vimentin, Wnt5α,
WRL68, MHCC97L, ZEBRA; Enhances cytochrome c
K562, A549, B16F10, release, ROS accumulation, SSAT
HONE1, HK1-EBV, activity; Induces DNA damage;
CNE-2, KB, U2OS, Inhibits Akt/mTOR/p70S6 K/
Panc-1, MIA PaCa-2, S6, arachidonic acid metabolic,
LNCaP, DU-145, androgen receptor pathways;
LAPC-4, PC-3, Reduces NO production; Sup-
22RV1, C4-2B, C42, presses Hedgehog signaling
RM-1, A-431 pathway; Up-regulates ACC, AIF,
AMPKα, Apaf-1, ATF-6, Bad, Bak,
Bax, Beclin-1, Bim, E-cadherin,
DR5, FasL, FoxO1, FoxO3a,
GRP78, HRK, Lig4, MST1, p21,
p27, p53, PHLPP2, SSAT, TIMP-2,
TRAIL, ULK1
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Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents
(2019) 14:48

Artemisinins Artemisia Breast cancer; cervical MCF-7, MDA-MB-231, A549 xenograft mice; Anti-metastasis; Activates caspase-3, -8, -9, PARP; 0–75 μM; 0–160 μM; 3CA; Halofugi- [184, 186, 213,
annua L. cancer; colorectal HeLa, HCT-116, BE(2)-C xenograft anti-prolifera- Decreases mitochondrial mem- 0–200 μM; none; 871–883]
cancer; gallbladder SW-480, SW-620, mice; C6 xenograft tion; induces brane potential, MMP activity; 0–250 μM; Holotransferrin;
cancer; gastric cancer; GBC-SD, NOZ, mice; GBC-SD apoptosis, Down-regulates Bcl-2, CDK2, 0–400 μM; Resveratrol
glioma; hepatocel- MGC-803, C6, xenograft mice; HCT- autophagy, cell CDK4, cyclin D1, cyclin E2, Dvl2, 0–500 μM;
lular carcinoma; HepG2, Hep3B, 116 xenograft mice; cycle arrest; ERK1/2, LRP6, MMP-2, NANOG, 0–1000 μM;
Ishikawa endometrial SMMC-7721, Ishi- HepG2 xenograft inhibits cell Oct-4, p38, p62, SOX2, vimentin, 0–1200 μM;
cancer; lung cancer; kawa, A375, A549, mice; NOZ xenograft viability Wnt5α/β; Enhances cytochrome 10–320 μM;
neuroblastoma; oral ASTC-a-1, H1299, mice c release, ROS accumulation; 40–160 μM;
carcinoma; pancreatic BE(2) -C, SHEP1, Induces DNA damage; Inhibits 0–40 μg/ml; 10 mg/
cancer SK-N-AS, SK-N-DZ, Wnt/β-catenin signaling path- kg; 50 mg/kg;
SCC25, RIN way; Up-regulates Axin2, Bax, 60 mg/kg; 100 mg/
E-cadherin, β-catenin, NKD2, kg
p16, TIMP-2
Ginsenoside Panax Breast cancer; colorectal BT549, MDA-MB-231, A375 xenograft mice; Anti-angio- Activates caspase-3, -8, -9, 12, 0–10 μM; 0–30 μM; Cisplatin; Cyclo- [227, 232–234,
Rg3 notoginseng cancer; esophageal MDA-MB-453, A549 xenograft mice; genesis; anti- PARP; Decreases mitochondrial 0–35 μM; 0–60 μM; phosphamide; 236–241,
(Burk.) F. H. carcinoma; gallblad- CT-26, HCT-116, BxPC-3 xenograft proliferation; membrane potential; Down- 0–80 μM; 0–100 μM; Erlotinib; 246, 252–
Chen, Panax der cancer; gastric LoVo, SW-480, mice; CT-26 xeno- anti-metastasis; regulates Akt, AQP1, B7-H1, 0–150 μM; 5-Fluorouracil; 255, 260,
ginseng, Cin- cancer; glioblastoma; SW-620, EC109, graft mice; GBC-SD enhances B7-H3, Bcl-2, Bcl-xL, VE-cadherin, 0–160 μM; Oxaliplatin; 884–900]
namomum glioma; hepatocel- KYSE170, TE1, xenograft mice; radiosensitiv- CDK2, COX-2, CXCR4, cyclin 0–200 μM; Paclitaxel
cassia Presl. lular carcinoma; leu- GBC-SD, Mz-ChA-1, HCT-116 xenograft ity; increases D1, cyclin E, DNMT3A, EGFR, 0–400 μM;
kemia; lung cancer; QBC939, SGC-7901, mice; Hep1-6 cell survival; EPHA2, ERK, FUT4, HDAC3, 0–600 μM;
melanoma; multiple U87MG, U87, Hep1- xenograft mice; H23 induces HIF-1α, HK2, IAP, JNK, LeY, 25 μM; 0–600 ng/
myeloma; ovarian 6, HepG2, Lewis, xenograft mice; autophagy, MMP-2, MMP-9, mTOR, c-Myc, ml; 0–80 μg/
cancer; pancreatic Jurkat, A549, A549/ Lewis tumor-bearing cell cycle NF-κB, p38, p53, PCNA, PD-L1, ml; 0–100 μg/
cancer; prostate DDP, H23, H1299, mice; LoVo xenograft arrest; inhibits PI3K, PKM2, Rb, STAT3, surviving, ml; 0–160 μg/ml;
cancer A375, C8161, SK- mice; MDA-MB-231 chemotaxis, VEGF; Enhances cytochrome c 0–200 μg/ml; 40,
MEL-28, RPMI 8226, xenograft mice; MCF- epithelial– release, ROS production; Inhibits 80 μg/ml; 50 μg/ml;
SKO-007, U266, 7 xenograft mice; mesenchymal the Warburg effect, Wnt/β- 80, 160 μg/ml; 80,
A2780, 3AO, SKOV3, SKOV3 xenograft transition; pro- catenin pathway; Up-regulates 160 mg/ml; 3 mg/
AcPC-1, BxPC-3, mice; SW1990 xeno- apoptosis Atg-5, Atg-7, Bax, CHOP, IRE1, kg; 5 mg/kg; 5, 10,
Panc-1, SW1990, graft mice; SW-620 microRNA-532-3p, p16, p21, 20 mg/kg; 6 mg/
PC-3 xenograft mice p27, p53, PERK kg; 7.5–30 mg/kg;
10 mg/kg; 20 mg/kg
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 Luo et al. Chin Med

Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents
(2019) 14:48

Ursolic acid Vaccinium Bladder cancer; breast BIU-87, T24, MDA- 12-dimethylbenz[a] Anti-angio- Activates caspase-3, -7, -8, -9, 0–4 μM; 0–16 μM; Capecitabine; [274, 276, 281,
macrocarpon cancer; cervical MB-231, MCF-7, anthracene-induced genesis; Fas receptor, PARP; Decreases 0–17.5 μM; 5-Fluorouracil; 283–289,
Ait., Arcto- cancer; colorectal MCF-7/ADR, HeLa, mice; DU-145 xeno- anti-metastasis; mitochrondrial membrane 0–20 μM; 0–40 μM; Oxaliplatin; 293,
staphylos cancer; Ehrlick ascites HCT-8, HCT-116, graft mice; Ehrlich anti-prolifera- potential; Down-regulates 0–50 μM; 0–80 μM; Resveratrol; 901–907]
uva-ursi (L.) carcinoma; leukemia; HT-29, Caco-2, ascites carcinoma tion; enhances AEG-1, Akt, Bcl-2, Bcl-xL, Bid, 0–100 μM; 4 μM; TRAIL
Spreng, Rho- liver cancer; lung SW-480, SW-620, xenograft mice; HCT- chemosensitiv- β-catenin, CD31, cyclin D1, 20 μM; 0–400 μg/
dodendron cancer; melanoma; HCT-15, CO115, 116 xenograft mice; ity; induces EGFR, ERK, cFLIP, FN, HIF-1α, ml; 10 mg/kg;
hymenanthes ovarian cancer; HL-60, HL-60/ADR, HCT-15 xenograft apoptosis, cIAP-1, ICAM-1, IκBα, IKKα/β, IL-8, 25–100 mg/kg;
Makino, prostate cancer; skin Jurkat, K562, K562/ mice; U937 xenograft autophagy, cell Jak2, Ki-67, Mcl-1, MMP-2, MMP- 50 mg/kg; 75 mg/
Eriobotrya cancer ADR, U937, HL-60/ mice cycle arrest; 9, NF-κB, iNOS, p65, u-PA, P-gp, kg; 250 mg/kg;
japonica, ADR, Hep3B, Huh7, inhibits MDR S6 K, Src, STAT3, survivin, mTOR, 2 μmol/mouse
Rosemarinus HA22T, A549, TNF-α, VEGF, Wnt5α/β, XIAP;
officinalis, H3255, Calu-6, Enhances cytochrome c release,
Calluna M4Beu, SKOV3, ­PGE2 levels, ROS production;
vulgaris, DU-145, LNCaP, Inhibits NO production; Up-
Eugenia PC-3 regulates ACC, AMPK, ASK1, Bax,
jambolana, CHOP, DR4, DR5, eIF2α, GRP78,
Ocimum GSK3β, IL-12, JNK, c-Jun, NADPH,
sanctum p21, p52, p53, PERK
Silibinin Silybum Breast cancer; colorectal BT-20, MCF-7, MDA- 786-O xenograft mice; Anti-metastasis; Activates caspase-3, -8, -9, PARP; 0–75 μM; 0–100 μM; Curcumin; [318, 319,
marianum L. cancer; epidermoid MB-231, MDA- Azoxymethane- anti-prolifera- Down-regulates Akt, Bcl-2, EGFR, 0–200 μM; luteolin 329–331,
Gaertn carcinoma; glioblas- MB-468, SKBR3, induced rats; tion; induces ERK, GLI1, IL-1β, FN, MMP-2, 0–300 μM; 334,
toma; hepatocellular T47D, AsPC-1, BxPC- Diethylnitrosamine- apoptosis, MMP-7, MMP-9, NF-κB, iNOS, 0–800 μM; 25, 342–345,
carcinoma; osteo- 3, Panc-1, HT-29, induced mice autophagy, cell PLA2, TNF-α, mTOR; Enhances 50 μM; 120 μM; 357, 358,
sarcoma; pancreatic HCT-116, LoVo, cycle arrest; CYP2E1 activity, cytochrome c 125 μM; 200 mg/kg; 908–910]
cancer; prostate can- SW-480, Caco-2, inhibits cell release, ROS production; Up- 300 mg/kg; 0.5%
cer; renal carcinoma; A-431, LN18, SNB19, viability regulates AIF, Bax, Bid, calpain,
thyroid cancer U87MG, Hep3B, EGR1, ICAD, NAG-1, PTEN
HepG2, SK-Hep-1,
SaOS2, PC-3, 769-P,
786-O, ACHN,
OS-RC-2, SW839,
Caki, TPC-1
Page 26 of 58
Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
Luo et al. Chin Med

effects agents

Emodin Rheum Bladder cancer; breast MBT2, T24, TSGH8301, 4T1 xenograft mice; Anti-metastasis; Activates caspase-3, -9, PARP, 0–10 μM; 0–40 μM; Cisplatin; [64, 367–378,
palmatum, cancer; colorectal 4T1, EO771, MCF-7, 7,12-dimethyl anti-prolifera- chloride currents; Decreases 0–50 μM; 0–60 μM; curcumin; 380, 382,
Polygonum cancer; gallbladder MDA-MB-231, benz(a)anthracene- tion; induces mitochondrial membrane 0–80 μM; 0–100 μM; 5-fluorouracil; 383, 385,
cuspidatum, cancer; gastric cancer; MDA-MB-435, induced golden apoptosis, potential; Down-regulates Akt, 0–250 μM; gemcitabine 389, 394,
Polygonum hepatocellular carci- MDA-MB-453, HCT- Syrian hamsters; autophagy, Bcl-2, Bcl-xL, Bim-1, β-catenin, 0–320 μM; 395, 402,
(2019) 14:48

multiflorum, noma; lung cancer; 116, LoVo, LS1034, EO771 xenograft cell cycle CDK1, CSF1, CSF2, CXCL12, 0–1000 μM; 20 μM; 403, 405,
Cassia nasopharyngeal SGC-996, MKN45, mice; HCCLM3 arrest; inhibits CXCR4, cyclin D1, ERα, ERK, 20–80 μM; 40 μM; 911]
obtusifolia carcinoma; oral car- C3A, Hep3B, tumor-bearing mice; cell viability, FABP4, bFGF, HBP17, HER2, ILK, 0.05 mM; 40 mg/
cinogenesis; ovarian HepG2, PLC/PRF/5, LS1034 xenograft epithelial- Jagged1, Jak1, Jak2, Ki-67, Mcl-1, ml; 20, 40 mg/kg;
cancer; pancreatic SMMC-7721, A549, mice; MDA-MB-231 mesenchymal MCP-1, MMP-2, MMP-9, MRP1, 20, 50 mg/kg; 25,
cancer; prostate CNE-2Z, A2780, xenograft mice; transition NF-κB, p38, p62, u-PA, u-PAR, 50 mg/kg; 40 mg/
cancer SKOV3, AsPC-1, SGC-996 xenograft Slug, Snail, Src, STAT3, survivin, kg; 50 mg/kg
BxPC-3, Panc-1, mice; SKOV3 xeno- Thy-1, VEGF, vimentin, XIAP,
SW1990, SW1990/ graft mice; SW1990 ZEB1; Enhances C ­ a2+ levels,
GZ, PC-3 xenograft mice; T24 cytochrome c release, ROS
xenograft mice production; Up-regulates AIF,
Bax, Beclin-1, E-cadherin, GSK3β,
microRNA-34, Notch1, SHP-1
Triptolide Tripterygium Bladder cancer; breast UMUC3, MDA- 3LL xenograft mice; Anti-angio- Activates caspase-3, -7, -8, 0–10 nM; 0–40 nM; Cisplatin; [408, 410, 411,
wilfordii cancer; colorectal MB-231, MCF-7, A549 xenograft mice; genesis; -9, GSK3β, PARP; Decreases 0–50 nM; 0–80 nM; epirubicin; 414, 415,
Hook. F. cancer; endome- DLD-1, HCT-116, AsPC-1 xenograft anti-metastasis; mitochondrial membrane 0–100 nM; 5-fluorouracil; 417, 419,
trial carcinoma; HEC-1B, MHCC-97H, mice; BE(2)-C anti-prolifera- potential; Down-regulates Akt, 0–160 nM; gemcitabine; 422, 423,
liver cancer; lung HepaRG, HepG2, xenograft mice; tion; enhances AR, BCAR1, Bcl-2, β-catenin, 0–200 nM; hydroxycamp- 425–427,
cancer; lymphoma; H460, H358, CNE xenograft mice; radiosensitiv- Cav-1, CD147, CDK2, CHK1, COX 0–300 nM; tothecin 429, 431–
melanoma; myeloma; A549, A549/Taxol, Daudi xenograft ity; induces IV, CXCR4, cyclin A1, ERK, ETS2, 0–320 nM; 434, 438,
nasopharyngeal HTB182, BEAS-2B, mice; H358 xenograft autophagy, cell FAK, c-FLIP, GRB2, HIF-1α, HSF1, 0–400 nM; 444, 446,
carcinoma; neuroblas- H1299, NCI- mice; H460 xenograft cycle arrest; HSP70, IκBα, ITGβ1, ITGαVβ6, 0–500 nM; 453, 454,
toma; osteosarcoma; H2009, NCI-H460, mice; HEC-1B xeno- inhibits cell JMJD3, JMJD2B, NK, p38 MAPK, 0–0.1 μM; 0–25 μM; 912–925]
ovarian cancer; oral Jurkat, Molt-3, Raji, graft mice; Jurkat viability; pro- Mcl-1, MKP-1, MMP-2, MMP-3, 0–150 μM;
cancer; pancreatic NAMALWA, Daudi, xenograft mice; apoptosis MMP-7, MMP-9, MMP-14, MMP- 0–200 μM; 10 nM;
cancer; prostate B16F10, HS-sultan, MHCC-97H xenograft 19, c–Myc, NF-κB, iNOS, Nrf2, 50, 72 nM; 100 nM;
cancer IM9, RPMI 8226, mice; SAS + U937 p65, PCNA, PI3K, PYK2, ROCK1, 0–8 ng/ml; 0–36 ng/
U266, CNE, MG63, xenograft mice; RhoA, Slug, Snail, SOS1, Src, ml; 0–50 ng/ml;
BE(2)-C, SH-SY5Y, SKOV3/DDP xeno- survivin, mTOR, Twist, UTX, VEGF, 0–400 ng/ml; 5,
SAOS2, U2OS, graft mice; SW1990 vimentin, ZEB1; Enhances C ­ a2+ 10 ng/ml; 5–160 ng/
SKOV3, SKOV3/DDP, xenograft mice levels, cytochrome c release, ml; 8 ng/ml; 250 μg/
A2780, SAS, Panc-1, ROS production; Inhibits Wnt/β- kg; 0–0.8 mg/kg;
AsPC-1, SW1990, Catenin pathway; Up-regulates 0.04–0.36 mg/
BxPC-3, LNCaP, ATM, Bax, Beclin-1, E-cadherin, kg; 0.075 mg/
PC-3, DU-145 cathepsin B, Fas, DKK1, DR5, kg; 0.15 mg/kg;
ENY2, FADD, FRZB, GSK3β, IL-2, 0.25 mg/kg; 0.4 mg/
γ-H2AX, LMP, LSD1, p53, PPARγ, kg; 1 mg/kg;
PTEN, SFRP1, SIRT3, Smac, 1.5 mg/kg; 2–4 μg/
SUV39H1, TNF-α, Wnt3α mouse
Page 27 of 58
 Luo et al. Chin Med

Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents
(2019) 14:48

Cucurbitacin B Bryonia, Breast cancer; cervical 4T1, HCC1937, 4-(methylnitrosamino)- Anti-angiogen- Activates caspase-3, -8, -9, PARP; 0–100 nM; 0–200 nM; Curcumin; [452, 460–462,
Cucumis, cancer; hepatocellular MCF-7, MCF-7/ 1-(3-pyridyl)-1- esis; Anti- Decreases mitochondrial 0–1000 nM; 0.1– docetaxel; 472–475,
Cucurbita carcinoma; lung can- ADR, MDA-MB-231, butanone-induced metastasis; membrane potential; Down- 1000 nM; 0–0.1 μM; gefitinib; 485, 499,
and Lepidium cer; neuroblastoma; MDA-MB-436, mice; 4T-1 xenograft Anti-prolifera- regulates Akt, ACLY, BCAR1, 0–1 μM; 0–1.6 μM; gemcitabine 926–931]
sativum prostate cancer SKBR-3, HeLa, T47D, mice; Bel-7402 xeno- tion; Inducing Bcl-2, β-catenin, CD31, CDK1, 0–30 μM; 0–100 μM;
SK-Hep1, Hep3B, graft mice; MDA- apoptosis, CIP2A, cyclin B1, cyclin D1, EGFR, 0–128 μM; 0.02–
HepG2, Bel-7402, MB-231 xenograft cell cycle ERK, FAK, galectin-3, GSK3β, 62.5 μM; 0–100 μg/
Bel-7402/5-Fu, mice; NNK-induced arrest; Inhibits HER2, HIF-1α, ILK1, ITGA6, ITGB4, ml; 0.1–100 μg/ml;
A549, H1299, H23; mice; PC-3 xenograft epithelial- Jak2, MMP-2, MMP-9, MRP1, 0.1, 0.2 mg/kg; 0.1,
SH-SY5Y; LNCaP, mice mesenchymal c-Myc, nucleophosmin, P-gp, 0.25 mg/kg; 0.5,
PC-3 transition paxillin, RhoA, ROCK1, STAT3, 1 mg/kg; 1, 5 mg/
Src, survivin, TACE, TCF1, mTOR, kg; 2 mg/kg; 10 mg/
Twist, VEGF, VEGFR2, Wnt3; kg; 0.1 μmol/mouse
Enhances cytochrome c release,
PP2A activity, ROS production;
Inhibits Wnt/β-catenin pathway;
Up-regulates ATM, Bax, Bim,
E-cadherin, CDC25C, CHK1,
γ-H2AX, JNK, p21, p53
Tanshinone IIA Salvia miltior- Breast cancer; bladder BT-20, 5637, BFTC 905, HT-29 xenograft mice; Anti-angio- Activates caspase-3, -8, -9, -12, 0–8 μM; 0–20 µM; Adriamycin [514, 515, 517,
rhiza Bunge cancer; cervical can- T24, HeLa, C33 A, MKN45 xenograft genesis; PARP; Down-regulates ALDH1, 0–40 µM; 0–60 µM; 5-fluorouracil; 519, 523,
cer; colorectal cancer; HCT-116, COLO- mice; SGC-7901 anti-metastasis; Bcl-2, BIP, N-cadherin, β-catenin, 0–80 μM; 0–100 µM; TRAIL 531, 539,
esophageal carci- 205, LoVo, HT-29, xenograft mice; 143B anti-prolifera- CD31, COX-2, CTGF, FoxM1, 0–54.4 μM; 0–20 ng/ 932–935]
noma; gastric cancer; SW-620, Eca109, xenograft mice tion; enhances HIF-1α, Ki-67, LEF1, MCP-1, Mfn- ml; 0–4 µg/ml;
NSCLC; osteosarcoma; SGC-7901, MKN45, chemosensitiv- 1, Mfn-2, MMP-2, MMP-9, c-Myc, 0–8 μg/ml; 0–18 µg/
oral squamous A549, H596, H1299, ity, radiosensi- NANOG, Opa-1, p65, PCNA, ml; 0–60 µg/ml;
carcinoma Calu-1, H460, 143B, tivity; induces Slug, Snail, STAT3, survivin, TCF3, 1 mg/kg; 10, 30 mg/
SCC090 autophagy, VEGF, vimentin, YAP; Enhances kg; 20 mg/kg
cell cycle cytochrome c release, ROS
arrest; inhibits accumulation; Reduces mito-
cell viability, chondrial membrane potential;
epithelial– Up-regulates ATF-4, Bax, Bak,
mesenchymal Bad, E-cadherin, CHOP, Drp-1,
transition; pro- DR5, GRP78, p21
apoptosis
Page 28 of 58
Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents
Luo et al. Chin Med

Oridonin Rabdosia Breast cancer; cervical 4T1, MCF-7, 143B xenograft mice; Anti-angio- Activates caspase-3, -8, -9, PARP; 0–1000 nM; 0–1.5 μM; Cisplatin; [544–556,
rubescens cancer; colorectal MDA‑MB‑231, 4T1 xenograft mice; genesis; Decreases mitochondrial 0–4 μM; 0–9 μM; NVP-BEZ235; 558–567,
(Hemsl.) cancer; esophageal SW-48, SW-480, HCT-116 xenograft anti-metastasis; membrane potential; Down- 0–12 μM; 0–15 μM; valproic acid 573–576,
Hara cancer; gastric SW-620, SW-1116, mice; HepG2 anti-prolifera- regulates Akt, AMPK, AP-1, Bcl-2, 0–20 μM; 0–25 μM; 578, 579,
cancer; hepatocellular HeLa, LoVo, xenograft mice and tion; induces Bcl-xL, N-cadherin, CD31, CD44, 0–30 μM; 0–32 μM; 936–946]
carcinoma; laryngeal; HCT-116, HCT-15, zebrafish; HL-60 apoptosis, CDC25C, CDK1, CDK2, Claudin 1, 0–40 μM; 0–50 μM;
xenograft mice; HOS autophagy, cell Claudin 4, Claudin 7, α-CPI, cyc-
(2019) 14:48

leukemia; liver COLO-205, RKO, 0–60 μM; 0–64 μM;

cancer; lung cancer; EC9706, KYSE-30, xenograft mice; cycle arrest, lin B1, cyclin D1, cyclin E, DHFR, 0–80 μM; 0–100 μM;
melanoma; multiple KYSE-150, SGC- K562 xenograft mice; epithelial– EGFR, ERK, GLUT-1, GSK3β, HO-1, 0–160 μM; 36 μM;
myeloma; neuroblas- 7901, AGS, HepG2, KYSE-150 xenograft mesenchymal ICAD, Mcl-1, MCT1, MDM2, 0–10 mM; 0–64 μg/
toma; oral squamous Huh6, MHCC97-H mice; LoVo xenograft transition MMP-2, MMP-9, c-Myc, NF-κB, ml; 5–30 μg/ml;
carcinoma; osteosar- HCC, Hep-2, K562, mice; MV4-11/DDP Notch, Nrf2, NQO1, p38, p62, 1.875, 7.5 mg/ml;
coma; ovarian cancer; K562/ADR, HL-60, xenograft mice; RM-1 PCNA, PI3K, Rac2, Raf, Ras, 1 mg/kg; 2–8 mg/
pancreatic cancer; HL-60/ADR, MV4- xenograft mice; SCC- SERTAD1, Slug, Smad, Snail, kg; 2.5–10 mg/kg; 5,
prostate cancer; uveal 11/DDP, MOLM-13/ 25 xenograft mice; Stathmin, SREBP1, mTOR, vimen- 10 mg/kg; 5–10 mg/
melanoma DDP, A549, SHSY-5Y, SHSY-5Y xenograft tin; Enhances cytochrome c kg; 5–15 mg/
SK-N-MC, LP-1, SCC- mice; SW-480 xeno- release, intracellular ­Ca2+ levels, kg; 7.5–30 mg/
25, HSC-3, HSC-4, graft mice; WSU-HN6 ROS production; Inhibits TrxR kg; 10 mg/kg; 10,
MG63, U2OS, HOS, xenograft mice activity; Up-regulates AIF, ASK1, 20 mg/kg; 15 mg/
Saos-2, 143B, WSU- ATM, Bad, Bax, Beclin-1, Bim, kg; 30 mg/kg; 50,
HN4, WSU-HN6, BMP7, E-cadherin, CHK2, CHOP, 100 mg/kg
CAL27, SKOV3, CKS2, eIF2α, FADD, GADD45AQ,
BxPC-3, PC-3, GRP78, γ-H2AX, HERC5, HSP90,
LNCaP, DU-145, IRE1, JNK, p21, p53, PERK, PPARγ,
RM-1, MUM2B, RECQL4, SFN, PTEN
OCM-1
Shikonin Lithospermum Breast cancer; cervical MCF-7, MDA-MB-231, A549 xenograft mice; Anti-metastasis; Activates caspases-3, -8, -9, -12, 0–2 μM; 0–4 μM; Cisplatin; [593, 595, 600,
erythrorhi- cancer; colorectal SKBR3, HeLa, Glioblastoma stem anti-prolifera- PARP, JNK/c-Jun, p38 MAPK, 0–5 μM; 0–6 μM; 5-fluorouracil; 603, 607,
zon, Arnebia cancer; gallblad- HCT-116, HT-29, cell xenograft mice; tion; enhances PERK/elF2α/CHOP, pathways; 0–10 μM; 0–20 μM; oxaliplatin 611, 614,
euchroma, der cancer; gastric SNU-407, SW-1116, HCT-116 xenograft chemosensitiv- Decreases mitochondrial 0–50 μM; 615, 617,
Arnebia cancer; glioblastoma SW-680, SW-620, mice; NOZ xenograft ity; induces membrane potential; Down- 0.1–0.4 μM; 1 μM; 620, 636,
guttata multiforme; glioma; NOZ, BGC-823, mice; SGC-7901 apoptosis, cell regulates Akt, Bcl-2, CDK4, cyclin 2 μM; 20 mg/kg; 947–952]
hepatocellular carci- SGC-7901, Primary xenograft mice cycle arrest, D1, FoxO3a, ICBP90, ITGβ1, 2 mg/kg
noma; leukemia; lung glioblastoma necroptosis MDM2, MMP-9, c-Myc, RIPK1;
cancer; NSCLC; renal stem cells, C6, Elevates intracellular ­Ca2+ and
carcinoma; pancreatic SHG-44, U87, U251, ROS levels; Enhances ­Ca2+ and
cancer; thyroid cancer SMMC-7721, NB4, ­K+ efflux; Inhibits ERK pathway,
Calu-6, H358, PKM2 activity; Promotes RIP1/
HCC-2279, NCI-H15, RIP3 necrosome formation; Up-
NCI-H460, NCI- regulates Bax, Bim, Cbl-b, CHOP,
H1229, NCI-H1437, cytochrome c, EGR1, eIF2α,
NCI-H1703, A549, GRP78, IRE1α, p16, p21, p53,
789-O, Capan-1, p73, PERK, RIP1, RIP3
Suit-2, 8305C,
8505C, BCPAP, C643,
FTC133, IHH4, K1,
TPC1
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Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents
(2019) 14:48

Gambogic acid G. hanburyi, G. Breast cancer; colorectal 4T1, MCF-7, MDA- 4T1 xenograft mice; Anti-angio- Activates caspase-3, -7, -8, -9, 200–400 nM; Chlorochalcone; [639, 644, 646,
Morella cancer; glioma; hepa- MB-231, HCT-15, A549 xenograft mice; genesis; PARP, JNK pathway; Decreases 0–1 μM; 0–2 μM; Cisplatin; 647, 650,
tocellular carcinoma; HCT-15R, HCT-116, B16F10 and MC38 anti-metastasis; mitochondrial membrane 0–3 μM; 0–5 μM; Doxorubicin; 656, 657,
NSCLC; osteosarcoma; HT-29, SW-480, xenograft mice; anti-prolifer- potential; Down-regulates Akt, 0–8 μM; 0–10 μM; 5–Fluorouracil; 663–665,
ovarian cancer; SW-620, LoVo/L- BxPC-3 xenograft ation; anti- ALDOA, ATG4B, Bcl-2, Bcl-xL, 0–40 μM; 0–50 μM; Gemcitabine; 953–966]
pancreatic cancer; OHP, LoVo/L-OHP/ mice; C26 xenograft tumor growth; β-catenin, ­cFLIPL, cyclin D1, 0–51.8 μM; 0.5 µM; ­Nal131; Oxalipl-
prostate cancer; renal GA, T98G, Hep3B, mice; SKOV3 xeno- enhances DLL1, DLL3, DLL4, ERK, Jagged1, 0–3 μg/ml; 2 mg/kg; atin; Retinoic
carcinoma Huh7, A549, A549/ graft mice chemosensitiv- Jagged2, LRP, p-53, P-gp, Mcl-1, 8 mg/kg acid; TRAIL
DDP, SPC-A-1, ity; induces MMP-2, MMP-9, MRP2, PI3K,
MG63, SKOV3, apoptosis, RRM2, SIRT1, survivin, TOPIIα,
BxPC-3, Capan-1, autophagy, VEGF, XIAP; Enhances ROS
Capan-2, Colo-357, cell cycle accumulation, cytochrome c
MIA PaCa-2, Panc-1, arrest; inhibits release; Inhibits ERK/E2F1/RRM2,
Suit-007, Suit-2, cell viability, MAPK, PI3K/Akt pathways, NF-κB
SW1990, B6WT, survival p65 binding activity, Trx activity;
DU-145, LAPC-4, Up-regulates AIF, Atg-5, Bax,
LNCaP, PC-3, PCAP- CHOP, DUSP1, DUSP5, FoxO3a,
1, ­PTEN−/−/p53−/−, c-Jun, p27, p53
Caki
Artesunate Artemisia B-cell lymphoma; blad- BL-41, Raji, Ramos, BL-41 xenograft mice; Anti-angio- Activates caspase-3, -9, p38 0.1–10 μM; 0–50 μM; Cisplatin; Con- [669, 673, 675,
annua L. der cancer; breast Rec-1, RT4, T24, A2780 xenograft genesis; MAPK pathway; Decreases 0–100 μM; nexin-43; 681, 683,
cancer; colorectal ACHN, BT-474, mice; HO8910 xeno- anti-metastasis; metabolic capacity, mitochon- 0–120 μM; Paclitaxel 688–690,
cancer; gastric cancer; MCF-7, MDA- graft mice; TE671 anti-prolifer- drial membrane potential, ­PGE2 0–200 μM; 693, 695,
head and neck MB-231, BGC-823, xenograft mice; ation; anti- production; Down-regulates 50 μM; 0–50 μg/ 967–971]
cancer; hepatocellular HGC-27, MGC-803, MCF-7 xenograft tumor growth; Bcl-2, CDC25A, COX-2, cyclin ml; 0–160 mg/L;
carcinoma; myelod- SGC-7901, HN3, mice induces B, cyclin D1, cyclin E2, γ-H2AX, 0–200 mg/kg;
ysplastic syndrome; HN4, HN9, SKM-1, apoptosis, cell IGF-1R, Keap1, c-Myc, PAX7, 50 mg/kg; 50,
ovarian cancer; HO8910, SKOV3, cycle arrest, RAD51, STAT3, UCA1, xCT; 150 mg/kg; 100 mg/
pancreatic cancer; AsPC-1, BxPC-3, DNA damage, Enhances ROS production; Up- kg; 200 mg/kg
prostate cancer; rhab- Colo-357, Panc-1, ferroptosis regulates ATF-4, ATM, ATR, Bax,
domyosarcoma DU-145, LNCaP, BRCA1, E-cadherin, CHK1, CHK2,
RD18, TE671 CHOP, HO-1, microRNA-16,
microRNA-133, microRNA-206,
Nrf2, p53
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 Luo et al. Chin Med

Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents

Wogonin Scutellaria Breast cancer; gastric MDA-MB-231, BGC- MDA-MB-231 xenograft Anti-angio- Activates caspase-3, -4, -8, -9, -12, 0–20 μM; 0–40 μM; Cisplatin; [704, 708,
(2019) 14:48

baicalensis, cancer; head and 823, MFC, MGC-803, mice; Raji xenograft genesis; PARP, IRE1α-dependent path- 0–50 μM; 0–60 μM; Paclitaxel; 709, 716,
Scutellaria neck cancer; hepa- MKN45, SGC-7901, mice; AMC-HN4-cisR anti-metastasis; way; Decreases mitochondrial 0–80 μM; 0–100 μM; Oxaliplatin; 717, 719,
amoena, tocellular carcinoma; AMC-HN2, AMC- xenograft mice; anti-prolifer- membrane potential; Down- 0–150 μM; Sorafenib 721, 725,
Scutellaria leukemia; lymphoma; HN3, AMC-HN4, AMC-HN9-cisR xeno- ation; anti- regulates Akt, B7H1, Bcl-2, CDK4, 0–200 μM; 40 μM; 730, 731,
rivularis, melanoma; multiple AMC-HN5, AMC- graft mice; B16F10 tumor growth; CDK6, cyclin D1, cyclin E, EGFR, 50 μM; 0–40 μg/ 741, 742,
Anodendron myeloma; neuroblas- HN9, AMC-HN4- xenograft mice; induces ERK, HIF-1α, IL-8, IκB, IKKα, Ki-67, ml; 0–60 mg/kg; 972–976]
affine Druce toma; osteosarcoma; cisR, AMC-HN9-cisR, BGC-823 xenograft apoptosis, MMP-2, MMP-9, c-Myc, PDK1, 0–80 mg/kg; 8 mg/
ovarian cancer; SNU-1041, SNU- mice and zebrafish; autophagy, cell PI3K, Rac1, RAE-1ε, SGK1, ULK1, kg; 20 mg/kg;
pancreatic cancer; 1066, SNU-1076, MFC xenograft mice; cycle arrest, VEGF; Enhances calreticulin, 60 mg/kg; 12.5 ng/
NSCLC Bel-7402, Hep3B, RPMI 8226 xenograft ER stress, HMGB1, cytochrome c release, zebrafish
HepG2, SMMC- mice mitochondrial ROS accumulation; Inhibits
7721, K562, K562/ dysfunction; 5-LO/BLT2/ERK/IL-8/MMP-9,
A02, K562R, Raji, reverses drug NF-κB pathways; Up-regulates
B16F10, RPMI 8226, resistance ASK, Bax, Bid, GRP78, GRP94,
U266, IMR-32, IRE1α, JNK, p21, p53, PU.1,
SK-N-BE2, ­CD133+ PUMA
CAL72, A549,
A2780, Colo-357,
Panc-1
β-Elemene Curcuma Bladder cancer; bone PBC, Bcap37, A549 xenograft mice; Anti-angio- Activates caspase-3, -7, -8, -9, 0–25 μM; 0–1000 μM; Cisplatin; [746, 747, 749,
wenyujin neoplasms; breast MBA-MD-231, B16F10 xenograft genesis; -10; Down-regulates Akt, Bcl-2, 67.5–1000 μM; Paclitaxel; 752, 754,
Y. H. Chen cancer; cervical MCF-7, MCF-7/ADR, mice; BGC-823 xeno- anti-metastasis; β-catenin, CDC25C, CDK1, cyclin 0–40 μg/ Rapamycin 755, 762,
et C. Ling, cancer; gastric cancer; MCF-7/DOC, 5637, graft mice; Lewis anti-prolifer- B1, cyclin D1, endostatin, ERK, ml; 0–50 μg/ 977–987]
Rhizoma melanoma; NSCLC; SiHa, T-24, BGC-823, tumor-bearing mice; ation; anti- DNMT1, MMP-2, MMP-3, MMP- ml; 0–120 μg/
zedoariae, osteosarcoma; thyroid MKN45, SGC-7901, MG63 xenograft tumor growth; 9, MTA3, c-Myc, STAT3, Sp1, ml; 0–160 μg/
Curcuma cancer B16F10, A549, mice; U2OS xeno- enhances survivin, TCF7, TIMP-1, TIMP-2, ml; 0–200 μg/
Zedoary H358, H460, H1299, graft mice radiosensitiv- VEGF; Enhances ROS accumula- ml; 0–320 μg/
H1650, H1975, ity; induces tion; Induces polarization ml; 0–500 μg/
Lewis, PC9, MG63, apoptosis, from M2 to M1 macrophages; ml; 0–800 μg/ml;
U2OS, FTC-133 autophagy, cell Inhibits Wnt/β-catenin pathway; 0–0.16 mg/ml; 15,
cycle arrest; Up-regulates ATF-4, ATF-6, Bad, 30 μg/ml; 100 mg/
reverses chem- Bax, BTF, CHK2, CHOP, FoxO3a, ml; 1 mg/kg; 20 mg/
oresistance IGFBP1, IRE1α, p15, p21, p53, kg; 50 mg/kg;
Pak1, PAK1IP1, PERK, TOPIIα 75 mg/kg; 200 mg/
kg
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 Luo et al. Chin Med
(2019) 14:48

Table 1 (continued)
Compounds Origins Cancer types In vitro models In vivo models Anti-cancer Underlying mechanisms Dosage Combinational References
effects agents
Cepharanthine Stephania Choroidal melanoma; MEL15-1, COLO-205, A549 xenograft mice; Anti-angio- Activates caspase-3, -9, PARP; 0–15 μM; 0–20 μM; Cisplatin; [777, 782–790,
cepharantha colorectal cancer; HCT-116 HT-29, NCI-H1975 xenograft genesis; Decreases mitochondrial mem- 0–80 μM; 0–100 μM; Dacomitinib; 794, 988]
Hayata, breast cancer; gastric SW-620, MCF-7, mice anti-metastasis; brane potential; Down-regulates 0–120 μM; 2–8 μM; Paclitaxel;
Stephania cancer; leukemia; MDA-MB-231, anti-prolifer- Akt, Bcl-2, Bcl-xL, CDK4, cyclin A, 4, 5 μM; 5–80 mM; TRAIL
japonica nasopharyngeal Jurkat T-cells, A549, ation; anti- cyclin D, c-FLIP, mTOR, p50, p52, 25 mg/kg; 50 mg/kg
carcinoma; NSCLC; H1299, HCC827, tumor growth; survivin; Enhances cytochrome
ovarian cancer; renal NCI-H1299, NCI- induces c release, ROS accumulation;
carcinoma H1650, NCI-H1975, apoptosis, Inhibits lysosomal cathepsin B
CNE-1, CNE-2, autophagy, cell and cathepsin D maturation,
A2780, A2780/Taxol, cycle arrest; Akt/mTOR, NF-κB, pathways;
CaOV-3, OVCAR3, Reverses multi- Up-regulates Atg-7, Bak, Bax,
Caki drug resistance Beclin1, DR5, p38 MAPK, Mcl-1,
­p21Waf1/Cip1, p53
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Luo et al. Chin Med (2019) 14:48 Page 33 of 58

experimental models and conditions, pharmacological regulatory subunit 2; COX-2: cyclooxygenase-2; COX IV: cytochrome c oxidase
subunit 4; α-CP1: poly(rC)-binding protein 1; CSF: colony stimulating factor;
effects, as well as mechanistic actions of the natural com- CTGF: connective tissue growth factor; CTR1: copper transporter 1; CTTN:
pounds derived from Chinese herbal medicine. Despite cortactin; CXCL-12: C–X–C motif chemokine 12; CXCR4: C–X–C chemokine
the unique anti-cancer beneficial features of many com- receptor type 4; CYP2E1: cytochrome P450 2E1; DC: dendritic cell; DHA:
dihydroartemisinin; DHCR24: 24-dehydrocholesterol reductase; DHFR:
pounds derived from Chinese herbal medicine, their dihydrofolate reductase; DLL: delta-like canonical Notch ligand; DKK1:
clinical applications are disproportionally limited. As of Dickkopf-related protein 1; DNA: deoxyribonucleic acid; DNMT: DNA
2019, only preliminary clinical studies have been per- (cytosine-5)-methyltransferase; DR4: death receptor 4; DR5: death receptor 5;
Drp-1: dynamin-related protein 1; DUSP: dual-specificity phosphatase; Dvl2:
formed with artemisinins, emodin, cucurbitacins, tansh- dishevelled segment polarity protein 2; E2F1: E2F transcription factor 1;
iones, shikonin, and CEP in various cancers, without any EBNA1: Epstein–Barr nuclear antigen 1; EF-Tu: elongation factor thermo
approved clinical applications. The phase I safety studies unstable; EGCG​: epigallocatechin gallate; EGFR: epidermal growth factor
receptor; EGFR-TKI: epidermal growth factor receptor-tyrosine kinase inhibitor;
of UA-liposomes, oridonin derivative (HAO472), and EGR1: early growth response protein 1; ENY2: enhancer of yellow 2 transcrip-

tumors. Curcumin, pro-drug of triptolide (minnelide™),

wogonin were evaluated in patients with advanced solid tion factor homolog; eIF2α: eukaryotic translation-initiation factor 2α; EphA2:
ephrin type-A receptor 2; ER: endoplasmic reticulum; ERα: estrogen receptor α;
ERK: extracellular signal-regulated kinase; Ets2: ETS proto-oncogene 2; EZH2:
triptolide derivative (LLDT-8), and GA have been inves- enhancer of zeste homolog 2; FABP4: fatty acid binding protein 4; FADD:
tigated on cancer therapy in phase II clinical trials. The Fas-associated protein with death domain; FAK: focal adhesion kinase; FasL: Fas
phase II clinical trials of berberine hydrochloride, gin- ligand; bFGF: basic fibroblast growth factor; c-FLIP: FLICE-like inhibitory
protein; FN: fibronectin; FoxM1: forkhead box protein M1; FoxO: forkhead box
senoside Rg3, and artesunate are being conducted in O; Foxp3: forkhead box P3; FRZB: frizzled-related protein; FUT4: fucosyltrans-
patients with cancer. EGCG was shown to have potential ferase 4; GA: gambogic acid; GADD45AQ: growth arrest and DNA damage-
anti-cancer effects in a phase III clinical trial. Elemene inducible 45; GLI1: glioma-associated oncogene homolog 1; GLUT-1: glucose
transporter 1; GRB2: growth factor receptor-bound protein 2; GRP78: 78-kDa
Emulsion mainly containing β-elemene was approved by glucose-regulated protein; GRP94: 94-kDa glucose-regulated protein; GSH:
China’s State Food and Drug Administration as a Class 2 glutathione; GSK3β: glycogen synthase kinase 3β; γ-H2AX: phosphorylated
new drug in China. Based on our critical review of those H2A histone family member X; HBP17: human fibroblast growth factor binding
protein 1; HO-1: heme oxygenase 1; H2O2: hydrogen peroxide; HDAC: histone
clinical studies, we conclude that Chinese herbal medi- deacetylases; HER2: human epidermal growth factor receptor 2; HERC5: HECT
cine is a promising source and could be used as a comple- domain and RCC-1-like domain-containing protein 5; HIF-1α: hypoxia-induci-
mentary approach for cancer therapy. ble factor 1α; HK2: hexokinase 2; HMGB1: high mobility group box 1; HNF4α:
hepatocyte nuclear factor 4α; HRK: activator of apoptosis harakiri; HSF1: heat
We believe that as the evidence for safety and efficacy shock factor 1; HSP: heat shock protein; HUVEC: human umbilical vein
continues to develop, this will improve the understand- endothelial cell; IAP: inhibitor of apoptosis protein; ICAD: apoptosis protease
ing about the mechanistic actions and clinical potential activating factor-1; ICAM-1: intercellular adhesion molecule 1; ICBP90: inverted
CCAAT box-binding protein of 90 kDa; IDO: indoleamine 2,3-dioxygenase;
of these compounds. Chinese herbal medicine will also IFN-γ: interferon-γ; IGFBP1: insulin-like growth factor-binding protein 1; IGF-1R:
serve as a huge community from which many promising insulin-like growth factor 1 receptor; IκB: nuclear factor of kappa light
compounds will be developed for clinical use. polypeptide gene enhancer in B-cells inhibitor; IKK: IκB kinase; IL: interleukin;
ILK: integrin-linked kinase; iNOS: inducible nitric oxide synthase; IRE1α:
inositol-requiring enzyme 1α; ITG: integrin; Jak1: Janus kinase 1; Jak2: Janus
kinase 2; JMJD3: Jumonji domain-containing protein D3; JMJD2B: Jumonji
Abbreviations
domain-containing protein 2B; JNK: c-Jun N-terminal kinase; K+: potassium;
4-PBA: 4-phenylbutyrate; 5-LO: 5-lipoxygenase; ABCG2: ATP-binding cassette
Keap1: Kelch-like ECH-associated protein 1; LEF1: lymphoid enhancer-binding
super-family G member 2; ACC​: acetyl-CoA carboxylase; ACLY: ATP-citrate
factor 1; LeY: Lewis Y; Lig4: DNA ligase 4; LLC: Lewis lung carcinoma; LMP:
lyase; AEG-1: astrocyte elevated gene-1; AIF: apoptosis inducing factor;
Epstein–Barr virus latent membrane protein; LRP: low density lipoprotein
ALDOA: aldolase A; ALDH1: aldehyde dehydrogenase 1; AMPK: 5′AMP-acti-
receptor-related protein; LPS: lipopolysaccharide; LSD1: lysine-specific histone
vated protein kinase; AP-1: activator protein 1; Apaf-1: apoptotic protease
demethylase 1; MAPK: mitogen-activated protein kinase; Mcl-1: myeloid cell
activating factor 1; AQP1: aquaporin 1; AR: androgen receptor; ARIE: acute
leukemia 1; MCT1: monocarboxylate transporter 1; MCP-1: monocyte
radiation-induced esophagitis; ART​: artemisinin; ASK: apoptosis signal-regulat-
chemoattractant protein 1; MD2: myeloid differentiation factor 2; MDM2:
ing kinase; ATF-4: activating transcription factor 4; ATF-6: activating
mouse double minute 2 homolog; MDR: multi-drug resistance; MDSCs:
transcription factor 6; ATG4B: autophagy related 4B cysteine peptidase; Atg-5:
myeloid-derived suppressor cells; MEK: MAPK kinase; MGMT: O-6-methylgua-
autophagy related 5 protein; ATM: ataxia-telangiectasia mutated protein
nine-DNA methyltransferase; MHC: major histocompatibility complex; Mfn:
kinase; ATP: adenosine triphosphate; ATR​: ataxia telangiectasia and Rad3-
mitofusin; MKP-1: MAPK phosphatase 1; MMP: matrix metalloproteinase; MRP1:
related protein; Axin2: axis inhibition protein 2; B7-H1: B7 homolog 1; B7-H3:
multi-drug resistance-associated protein 1; MST1: macrophage-stimulating 1;
B7 homolog 3; Bad: Bcl-2 associated agonist of cell death; Bak: Bcl-2
MTA3: metastasis-associated 1 family member 3; mTOR: mammalian target of
homologous antagonist killer; Bax: Bcl-2-associated X protein; BCAR1: breast
rapamycin; NADPH: nicotinamide adenine dinucleotide phosphate oxidase;
cancer anti-estrogen resistance protein 1; Bcl-2: B cell lymphoma 2; Bcl-xL:
NAG-1: non-steroidal anti-inflammatory drug-activated gene 1; NF-κB: nuclear
B-cell lymphoma-extra large; Bex: brain-expressed and X-linked; Bid: BH3
factor kappa-light-chain-enhancer of activated B cells; NK: natural killing;
interacting-domain death agonist; Bim: Bcl-2-like protein 11; BIP: binding
NKD2: naked cuticle 2; NQO1: NADPH quinone oxidoreductase 1; Nrf2: nuclear
immunoglobulin protein; BLT2: leukotriene ­B4 receptor 2; BMP7: bone
factor erythroid 2-related factor 2; NSCLC: non-small-cell lung carcinoma;
morphogenetic protein 7; BRCA1: breast cancer type 1 susceptibility protein;
Oct-4: octamer-binding transcription factor 4; Opa-1: optic atrophy protein 1;
BTF: Bcl-2-associated transcription factor 1; Ca2+: calcium; CAMKKβ: Ca2+/
p70S6K: p70S6 kinase; u-PA: urokinase-type plasminogen activator; u-PAR:
calmodulin-dependent protein kinase kinase β; Cav-1: caveolin-1; Cbl: casitas
urokinase-type plasminogen activator receptor; PAI-1: plasminogen activator
B-lineage lymphoma; CD: cluster of differentiation; CDC25A: cell division cycle
inhibitor 1; PAK1: p21-activated protein kinase 1; PAK1IP1: p21-activated
25A; CDC25C: cell division cycle 25C; CDK: cyclin-dependent kinase; CEH:
protein kinase-interacting protein 1; PARP: poly (ADP-ribose) polymerase;
cepharanthine hydrochloride; CEP: cepharanthine; CHK: checkpoint kinase 1;
PAX7: paired box 7; PCNA: proliferating cell nuclear antigen; PERK: protein
CHOP: C/EBP homologous protein; CIP2A: cancerous inhibitor of protein
kinase R-like endoplasmic reticulum kinase; PD-L1: programmed death-ligand
phosphatase 2A; CK1α: casein kinase 1α; CKS2: cyclin-dependent kinases
1; PDK1: pyruvate dehydrogenase kinase 1; PGE2: prostaglandin ­E2; P-gp:
Luo et al. Chin Med (2019) 14:48 Page 34 of 58

P-glycoprotein; PHLPP2: pH domain and leucine Rich repeat protein Competing interests
phosphatase 2; PLA2: phospholipase A2; PI3K: phosphoinositide 3-kinase; The authors declare that they have no competing interests.
PKC-α: protein kinase Cα; PKD1: polycystin 1; PKM2: pyruvate kinase isozyme
M2; PP2A: pyrophosphatase (inorganic) 2; PPARγ: peroxisome proliferator- Received: 20 August 2019 Accepted: 23 October 2019
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