REVIEW ARTICLE

Promising Anti-tumor properties of Bisdemethoxycurcumin: A Naturally Occurring

Curcumin Analogue†

Running title: Anti-tumor Effects of Bisdemethoxycurcumin

Mahin Ramezani,a Mahdi Hatamipour,a Amirhosein Sahebkarb*

a
Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical

Sciences, Mashhad 91775-1365, Iran

b
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

* Corresponding author: Amirhossein Sahebkar, PharmD, PhD, Department of Medical

Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran,

P.O. Box: 91779-48564, Iran. Tel: 985118002288; Fax: 985118002287; E-mail:

sahebkara@mums.ac.ir; amir_saheb2000@yahoo.com; amirhossein.sahebkar@uwa.edu.au

†
This article has been accepted for publication and undergone full peer review but has not been

through the copyediting, typesetting, pagination and proofreading process, which may lead to

differences between this version and the Version of Record. Please cite this article as doi:

[10.1002/jcp.25795]

Received 7 January 2017; Accepted 10 January 2017

Journal of Cellular Physiology

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DOI 10.1002/jcp.25795

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Abstract

Curcuminoids are turmeric-extracted phytochemicals with documented chemopreventive and

anti-tumor activities against several types of malignancies. Curcuminoids can modulate several

molecular pathways and cellular targets involved in different stages of tumor initiation, growth

and metastasis. Bisdemethoxycurcumin (BDMC) is a minor constituent (approximately 3%) of

curcuminoids that has been shown to be more stable than the other two main curcuminoids i.e.

curcumin and demthoxycurcumin. Recent studies have revealed that BDMC has anti-tumor

effects exerted through a multimechanistic mode of action involving inhibition of cell

proliferation, invasion and migration, metastasis and tumour growth, and induction of apoptotic

death in cancer cells. The present review discusses the findings on the anti-tumor effects of

BDMC, underlying mechanisms and the relevance of finding for translational studies in human.

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Key words: Curcuminoids; Curcumin; Bisdemethoxycurcumin; Cancer

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Introduction

Turmeric is a famous and widely used dietary spice with a history of cuisine and medicinal use

for centuries in India and South Asia, and in several traditional systems of medicine including

Ayuverda, Chinese Traditional Medicine and Iranian Traditional Medicine (Prasad and

Aggarwal, 2011). The orange/yellow color of turmeric is due to the presence of pigments known

as curcuminoids. Notably, curcuminoids are also bioactive compounds that account for many

medicinal benefits of turmeric. Curcuminoids comprise curcumin, demethoxycurcumin, and

bisdemethoxycurcumin (BDMC) (Figure 1), and possess numerous pharmacological actions

such as antioxidant (Panahi et al., 2016b; Panahi et al., 2016e; Panahi et al., 2012a; Sahebkar et

al., 2013), anti-inflammatory (Panahi et al., 2012b; Sahebkar, 2014a), pro-apoptotic (Seo et al.,

2016), anti-ischemic (Sahebkar, 2010), epigenetic-modifying (Momtazi et al., 2016a; Momtazi et

al., 2016b), analgesic (Sahebkar and Henrotin, 2016; Sahebkar et al., 2016b), lipid-lowering

(Mohammadi et al., 2013; Panahi et al., 2016a; Panahi et al., 2014a; Panahi et al., 2016f;

Sahebkar, 2014b), neuroprotective (Cole et al., 2007) and immunomodulatory (Derosa et al.,

2016; Ganjali et al., 2014; Ghandadi and Sahebkar, 2016; Karimian et al., 2016; Panahi et al.,

2016d; Sahebkar et al., 2016a) effects. Such a multi-mechanistic mode of action enables the

efficacy of curcuminoids in treating several pathophysiological conditions and human diseases

such as cancer (Mirzaei et al., 2016; Momtazi and Sahebkar, 2016; Rezaee et al., 2016;

Teymouri et al., 2016), metabolic syndrome (Sahebkar, 2013), depression (Esmaily et al., 2015;

Panahi et al., 2015), osteoarthritis (Panahi et al., 2014b), chronic obstructive pulmonary disease

(Lelli et al., 2017; Panahi et al., 2016c), non-alcoholic fatty liver disease (Rahmani et al., 2016)

and diabetes (Chuengsamarn et al., 2012). Curcuminoids can interact with numerous molecular

targets involved in tumorigenesis including DNA polymerases (Takeuchi et al., 2006), focal

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adhesion kinase (Leu et al., 2003), thioredoxin reductase (Fang et al., 2005), microRNAs

(Momtazi et al., 2016a; Momtazi et al., 2016b), DNA methyltransferases (Yu et al., 2013),

protein kinase (PK) C (Reddy and Aggarwal, 1994), histone deacetylases (Chen et al., 2013),

cyclooxygenase (Su et al., 2006b), lipoxygenase (LOX) (Skrzypczak-Jankun et al., 2003), metal

ions (Baum and Ng, 2004; ISHIHARA and SAKAGAMI, 2005) and tubulin (Gupta et al., 2006).

Moreover, curcumin has an inhibitory action against the growth and proliferation of cancerous

cells via modulating intracellular and extracellular signaling pathways including cell

proliferation pathway (cyclin D1, c-myc) (Choudhuri et al., 2005), cell survival pathway (Bcl-2,

Bcl-xL, cFLIP, XIAP, c-IAP1) (Mackenzie et al., 2008), caspase activation pathway (caspase-8,

3, 9) (Sikora et al., 2006; Su et al., 2006a; Tan et al., 2006), tumor suppressor pathway (p53,

p21) (Ko and Prives, 1996; Levine, 1997) death receptor pathway (DR4, DR5) (Hussain et al.,

2008; Jung et al., 2006), mitochondrial pathways(Anto et al., 2002), and protein kinase pathway

(JNK, Akt, and AMPK) (Suh et al., 2007).

Curcumin is almost insoluble in water at acidic or neutral pH and decomposes at high pH

(alkaline) conditions. These physicochemical properties contribute to a low intestinal absorption

and rapid metabolism of curcumin, thereby resulting in a low systemic bioavailability. Whilst the

biological activity of curcumin metabolites has been demonstrated, low plasma levels of parent

compound is generally referred to as a main reason to explain the lack of complete translation of

experimental findings on the anti-tumor effects of curcumin to clinical practice (Kharat et al.,

2016; Liu et al., 2016).

In spite of extensive research, most of the studies have been focused on curcumin while there is

evidence that other curcuminoids such as BDMC possess promising biological and

pharmacological effects. In this context, it is worth noting that the stability of curcumin is low

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and it can be easily degraded in vivo. Therefore, the use of other stable curcuminoids such as

BDMC may offer aditional benefits relevant to the treatment of cancer (Sandur et al., 2007).

BDMC has been reported to have increased stability and improved nuclear cellular uptake

compared with curcumin (Basile et al., 2009). Recent studies have revealed that BDMC inhibits

the proliferation and survival of several types of tumor cells including colon cancer cells (Basile

et al., 2009; Broekgaarden, 2016) breast cancer cells (Boonrao et al., 2010), leukemia cells

(Anuchapreeda et al., 2008) and glioma cells (Luthra et al., 2009). In addition, BDMC

suppresses cancer invasion and has the highest anti-metastatic potency in HT1080 human

fibrosacroma cells among the three curcuminoids (Boonrao et al., 2010; Yodkeeree et al., 2009).

BDMC has been reported to possess anti-oxidant and anti-inflammatory activities (Ravindran et

al., 2010). However, the underlying molecular mechanisms responsible for the inhibitory action

of BDMC on tumor invasion and migration have remained largely unknown. More interestingly,

the anti-cancer effects of BDMC are comparable to and sometimes more potent than those of

curcumin in different conditions (Anuchapreeda et al., 2008; Kamalakkannan et al., 2005; Syu et

al., 1998; Yodkeeree et al., 2009). This review aims to summarize available evidence on the anti-

tumor effects of BDMC and highlight the underlying mechanisms for these effects.

Lung Cancer

It is generally known that for the survival and appropriate functioning of a cell, maintenance of

genomic integrity is essential. It has been shown that DNA damage is a leading initiator and

causal factor for aging and development of many diseases (Lindahl, 1993). However, this

mechanism could be reversely applied for killing cancerous cells. DNA damage, inhibition of the

DNA repair system, induction of programmed cell death and induction of cell cycle arrest are

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important mechanisms of action for anticancer drugs. Hong et al. explored the impact of BDMC

treatment on DNA damage and condensation in NCI-H460 cells and found that viable cell count

(1) is decreased and DNA damage is increased after BDMC (35 µM) treatment in a time-

dependent manner. Moreover, the proteins levels of 14-3-3r, MGMT, BRCA1 and MDC1 were

found to be decreased in human lung cancer NCI-H460 cells following treatment with BDMC

while the levels of p-p53 and p-H2A.X were increased (Yu et al., 2015b). S-phase is the part of

the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. YANG et

al. revealed that BDMC induces morphological changes and alterations in the S phase, and also

induces DNA damage and condensation in NCI H460 cells in a dose-dependent manner (Yang et

al., 2015). In addition, Yu et al. showed that the expression of genes associated with cell cycle,

cell migration and invasion, and tumor progression is altered in NCI-H460 cells treated with

BDMC (35 μM) (Yu et al., 2015a). Inactivation of apoptosis is critical to the initiation and

development of cancer (Brown and Attardi, 2005). BDMC induced apoptotic cell death in non-

small cell lung cancer (NSCLC) cells; an effect that was accompanied by the induction of

autophagy (Xu et al., 2015c). Xu et al. reported that treatment with 1, 5 and 10 µM BDMC for a

period of 24 hours upregulates E-cadherin that is involved in the inhibition of invasion and

migration of 95D cells (Xu et al., 2015b). WNT pathway and its downstream effector molecules

are implicated in different processes (e.g. cell senescence, death and differentiation) that are

integral to tumor initiation, growth and metastasis (Anastas and Moon, 2013). Many efforts have

been made to improved drug candidates that can alter WNT signaling in preclinical tumor

models. Liu et al. showed that BDMC can directly down-regulate the activity of DNA

methyltransferase-1 (DNMT1) and enhance promoter demethylation and protein expression of

WIF-1 in lung cancer cells. These alterations led to the suppression of nuclear-catenin and the

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canonical Wnt pathway (Liu et al., 2011). BDMC also suppressed the Wnt signaling pathway via

inducing WIF-1 protein expression. Further evaluations revealed that WIF-1 modulation might

serve as a key mechanism mediating the regulation of epithelial-mesenchymal transition, and

tumor cell invasion and migration(Xu et al., 2015a).

Gastric cancer

Mitochondria are integral to the maintenance of cell survival by generating ATP during oxidative

phosphorylation. Mitochondrial function also produces reactive oxygen species (ROS) which

play a key role in regulating the balance between cell death and proliferation; hence,

mitochondrial function is a significant determinant for tumor growth (Boland et al., 2013). In an

in vivo study in nude mice, Lue et al. revealed that BDMC mitigates the growth of gastric

adenocarcinoma and this effect is mediated by mitochondrial dysfunction, reduction of ATP

production, enhanced ROS production and cytochrome c release from the mitochondria (Luo et

al., 2015).

Breast cancer

As mentioned earlier, ROS are involved in several basic cellular functions including proliferation

and differentiation. In normal cells, cellular redox homeostasis is tightly maintained through a

delicate balance between ROS generation and elimination. In contrast, higher levels of ROS,

which are in part due to the activation of oncogenes, abnormal metabolism, mitochondrial

dysfunction and the dysfunction of p53, can lead the cells towards death (Pelicano et al., 2004;

Trachootham et al., 2009). Li, et al, showed that BDMS treatment can trigger accumulation of

ROS and cause a reduction in mitochondrial potential in MCF-7 cells. Moreover, it was reported

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that 20 μM of BDMC activates p53/p21 pathway, as an intracellular sensor of oxidative insult,

by enhancing the phosphorylation of p53 and expression of p21 (Li et al., 2013).

Liver cancer

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-associated deaths in

humans worldwide (S Darvesh et al., 2012). Numerous studies have shown that natural products

can serve as chemopreventive agents that could effectively prevent and cure various types of

cancers. Chen et al. indicated that BDMC induces cell cycle arrest in HepG2 cells via decreasing

the expression of Cdc2 and cyclin B. Moreover, BDMC inhibited HepG2 cell growth and led to

DNA damage with up-regulation of the expression levels of phosphorylated ATM and p53 (Chen

et al., 2015).

Ovarian cancer

NF-κB is a transcription factor with central role in the regulation of inflammation and a putative

role in cancer initiation and progression. NF-κB binds to the regions of DNA that regulate

cellular processes. Constitutive NF-κB activity has been shown in several types of human

cancers that are characterized by an inflammatory microenvironment. NF-κB activity enhances

tumor cells proliferation, suppresses apoptosis, and up-regulates the expression of tumor-

promoting cytokines (Xia et al., 2014). Pei et al. revealed that BDMC is able to inactivate NF-κB

pathway which includes subunits of p50 and p65. Transcriptional activity of NF-κB necessitates

phosphorylation of p65. Following BDMC treatment, phosphorylation levels of p65 and IκB-α

were markedly reduced. These results indicated that BDMC is able to prevent the activation of

NF-κB pathway in SKOV-3 cells (Pei et al., 2016b). In addition Duan et al. showed that BDMC

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significantly affects the morphology of SKOV3 cells and makes these cells smaller, more

condensed and more prone to death (Ma et al., 2011).

Comparative studies of BDMC vs. curcumin

From the physicochemical standpoint, the role of methoxy group on the stability of curcuminoids

in physiological pH is critical. In a comparative study between curcumin and BDMC, it was

shown that BDMC is not autoxidized at all due to the lack of both methoxy groups present in the

molecular structure of curcumin (Gordon et al., 2015).

According to several studies, BDMC is the most potent and stable curcuminoid in biological

systems (Cashman et al., 2008; Fiala et al., 2007; Sandur et al., 2007). Sivabalan et al. showed

that BDMC exhibits potent antioxidant activity in comparison with curcumin, and this activity is

exerted through mitigation of the iron-ascorbate-induced lipid peroxidation in a dose-dependent

manner (Sivabalan and Anuradha, 2010). Lee et al. evaluated the cytotoxic effects of BDMC and

curcumin, at 30 μΜ for 24 h, on the HSC-T6 cell line and showed that BDMC induces a more

potent apoptotic effect through reducing the levels of heme oxygenase-1, BCL-2 (an anti-

apoptotic protein), and increasing ROS production. Further mechanistic evaluations revealed that

the pro-apoptotic effect of BDMC is mediated by its binding to cannabinoid receptor-2 and

activation of its downstream effectors such as Fas-dependent death pathway, caspase-8 and

caspase-3 (Lee et al., 2015). AKR1B10 is a human aldo-keto reductase that is overexpressed in

hepatic and lung carcinomas (Cao et al., 1998; Fukumoto et al., 2005; Zeindl‐Eberhart et al.,

2004), as well as in esophageal and uterine cancers (Breton et al., 2008; Yoshitake et al., 2007),

suggesting its potential role as a cancer biomarker. Matsunaga et al. reported that BDMC could

act as a selective and competitive inhibitor of AKR1B10 (Ki= 22 nM) and its inhibitory activity

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and selectivity were higher compared with curcumin and demethoxycurcumin (Matsunaga et al.,

2009).

Conclusion

There is evidence indicating that BDMC can suppress carcinogenesis via blunting tumor

formation, promotion and development stages. Similar to curcumin, the anti-tumor properties of

BDMC appears to be exerted through multiple mechanisms and involves modulation of several

key molecular targets implicated in cancer (Figure 2). BDMC induces apoptosis and cell cycle

while inhibiting cancer cell invasiveness and metastasis as an advanced stage of carcinogenesis.

Further investigations are warranted to explore the potential therapeutic value of this promising

curcuminoid analogue in experimental models of tumor and in proof-of-concept clinical trials.

Conflict of interests

The authors have no competing interests to disclose.

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Figure legends

Figure 1. Chemical structure of curcuminoids.

Figure 2. Molecular targets and pathways modulated by bisdemethoxycurcumin in cancer.

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Table 1. Summary of the anti-tumor effects of bisdemethoxycurcumin (BDMC).

Treatment
Model Dose Findings Reference
duration

1and 2.5 µM 48 h
lung cancer 95D BDMC exerted an inhibitory effect on the migration and
(Xu et al.,
cells invasion of 95D cells
2015a)

0, 5, 10, 20, 40 or expression of vimentin was downregulated. (Xu et al.,

95D-cell 24 h
80 µM E-cadherin expression was upregulated 2015b)
24 h, 48 h, BDMC induced apoptotic cell death and autophagy and
NSCLC, A549, 10-80 µM (Xu et al.,
and 72 h inhibited the viability of NSCLC cells
95D cells 2015c)
decreased SMO and Gli1 expression
0, 15, 20,
NCI-H460 Human 25, 30, and 35 BDMC induced DNA damage and condensation and affect (Yu et al.,
48 h.
Lung Cancer Cells µmol/L DNA repair proteins in NCI-H460 cells in vitro 2015b)

BDMC decreased methylation level of WIF-1 promoter with 20

μM
BDMC (0.5 μM) inhibit directly DNMT1 activity through
A549, H460, SPC- strong hypomethylation (Liu et al.,
0 to 100 μM 72 h
A-1 and A427 20 μM BDMC reduced the transcriptional activity of - 2011)
catenin/Tcf signaling in A549 cells
BDMC Induces Apoptosis in A549 and NCI-1395 Cells in a
dose-dependent manner
diet
In vivo NOD/SCID supplemented dietary BDMC inhibited tumor formation and reduced tumor (Liu et al.,
mice with
six weeks size 2011)
1% BDMC
100 mg/kg/day BDMC inhibited the tumor growth and reduced the rapid (Luo et al.,
n vivo nude mice 3 weeks
BDMC in mice growth of cancer cells and activity in the tumor 2015)
at 10 and 30 μΜ concentrations, for 24 h. BDMC potently
10 and 30 μΜ (Lee et al.,
HSC-T6 cell line 24 h induced apoptosis
concentrations 2015)
BDMC suppresses cell proliferation, reduced colony formation
and induced G2/M
MCF-7 breast (Li et al.,
5–40 µM 24, 48 or 72 h cell cycle arrest.
cancer cell 2013)

Natural borneol enhances bisdemethoxycurcumin-induced cell

(Chen et al.,
HepG2 cells 10, 20, 40, 80 μM 72 h cycle arrest in the G2/M phase through up-regulation of
2015)
intracellular ROS in HepG2 cells
BDMC suppressed the cell population growth of SKOV-3 cell
line in a dose- and time- dependent manner.
BDMC (15 μM, 24 h) treatment significantly inhibited cell (Pei et al.,
SKOV-3 cells 5, 10, 15 μM 6, 12, 24 h
attachment to matrigel and fibronectin 2016a)
BDMC significantly reduced the invasion and migration of
cancer cells in a dose-dependent manner.
BDMC (24 h with 15
(Ma et al.,
SKOV3 cells 5, 10, 15 μM 6, 12, 24 h µM) suppressed proliferation and induced apoptosis in human
2011)
ovarian cancer cell SKOV3

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Figure 1

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Figure 2

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