The Biochemistry of Alternative Medicine

Curcumin
Old Spice Is a New Medicine

Joseph R. Cronin, Ph.D. Web site over this period under the search term “curcumin.” 9
Nearly 400 of these research papers have been published within
the last 4 years. This recent research has focused on the antioxi-

T
he condiment turmeric is the powdered root and rhizome dant, hepatoprotective, anti-inflammatory, anticarcinogenic, and
of the plant curcumin (Curcuma longa; also called Curcuma antimicrobial properties of curcumin. The U.S. Patent Office
domestica) a member of the zingiberaceae family and relat- records show an equally dramatic surge of commercial interest in
ed to the ginger (Zingiber officinale) plant. Other species in its the plant’s medical applications during the past few years. Twen-
genus include: Javan turmeric (Curcuma xanthorrhiza) and Shoti ty-six U.S. patents were issued for medically related uses of cur-
or Zedoary (Curcuma zedoaria). The curcumin plant is traditional- cumin in 2001 and 2002, while only twelve were granted in the
ly cultivated in India, China, and other countries in tropical Asia. previous 10 years.
It has been a staple of both culinary and therapeutic use in the The curcumin content of the C. longa rhizome varies over a
East for thousands of years. Ayurvedic medicine holds it to be a wide range (0.6–5 percent of the dry mass). 7,10–12
treatment for arthritic pain, inflammation, skin disease, dysen- Up to 1993 clinical trials of curcumin therapy showed efficacy
tery, fever, infection, and jaundice. Traditional Chinese Medicine for treating various disorders. Trials showed positive results for
uses turmeric to treat liver and gallbladder disorders, to control treating gastric ulcer 13 and dyspepsia, 14 lowering serum choles-
bleeding, and to treat chest congestion and menstrual discomfort. terol, 15 relievin g sym p toms related to extern al canc erous
lesions, 16 and for treating postoperative inflammation. 17
A recent uncontrolled clinical trial in Thailand examined the
Extraction of Curcuminoids
effect of turm eric on pep tic ulc ers. A gr oup of 25 subjec ts
Curcuminoids are normally obtained by alcohol extraction of received five doses of 600 mg of turmeric per day for 12 weeks.
the powdered turmeric rhizome. Individual compounds are Endoscopic examinations showed that 19 of the subjects were
obtained by fractional crystallization of the extract. The raw alco- free from ulcers after 12 weeks. 18
hol extract contains these related cucuminoids: curcumin, bis- A National Cancer Institute (NCI) clinical trial development
desmethoxycurcumin, desmethoxycurcumin, and alpha and beta plan appeared in the Journal of Cell Biochemistry in 1996.19 How-
curc umen e as well as the sesquiterpenoids : zinge rberene , ever, no report of this study has yet appeared in the literature.
turmerone, and ar-turmerone. A recent phase I trial of curcumin in Taiwan examined the
The volatile fraction, extracted by steam distillation, is an oil dose/toxicity response of 25 subjects who had various high-risk
that contains a different spectrum of components. The major con- cancerous or precancerous conditions. 20 The study reported no
stituent is alpha curmerene. 1 toxic reactions in any subject who received doses of up to 8 g per
The components of the aqueous extract have not been well- day for 3 months. The report on the study included some prelim-
characterized but the extract has been used in some studies 2–4 inary therapeutic results of the regimen as follows: “One [1] of 4
The principal component may be the polypeptide turmerin. 5,6 patients with CIN [cervical intraepithelial neoplasm] and 1 of 7
patients with oral leucoplakia proceeded to develop frank malig-
nancies in spite of curcumin treatment. In contrast, histologic
Curcumin Studies
improvement of precancerous lesio ns was seen in 1 out of 2
While the U.S. government’s Agricultural Research Service (ARS) patients with recently resected bladder cancer, 2 out of 7 patients
lists 133 chemicals found in the plant,7 the diketone curcumerin, of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of
with the systematic name of 1,7-bis (4-hydroxy-3-methoxyphenyl)- the stomach, 1 out of 4 patients with CIN and 2 out of 6 patients
1,6-heptadiene-3,5-dione, is receiving the most research attention. with Bowen’s disease.”
The figure shows the compound in its enol form. The ARS lists 78 The remaining subjects experienced no reduction of their pre-
referenced biologic activities associated with curcumin, ranging cancerous lesions during the course of the 3-month study. This
from anti-HIV to antiulcerogenic activities.8 phase I study was designed to establish the safety of the treat-
The Western medical research history of the Curcuma plant and ment and not necessarily its efficacy.
its curcuminoid and sesquiterpenoid compounds extends back Another phase I clinical study examined the effect of an alco-
over 30 years with more than 760 articles listed on the PubMed hol Curcuma extract on patients with colorectal cancer.21 Fifteen

34
ALTERNATIVE & COMPLEMENTARY THERAPIES—FEBRUARY 2003 35

(15) subjects with advanced colorectal cancer that had proved

refractory to standard chemotherapies received a Curcuma extract
daily for up to 4 months at doses between 440 and 2200 mg per
day, containing 36–180 mg of curcumin. These doses were well-
tolerated throughout the course of the study.
In October and November of 2002, the University of Michigan
Comprehensive Cancer Center, Ann Arbor, was recruiting sub-
jects for a phase I trial of curcumin under the sponsorship of the
NCI. This phase I trial aims to establish the dose/toxicity charac-
teristics of curcumin in preparation for testing its efficacy for pre-
venting colorectal cancer. 22

Antitumor and Antiproliferative Effects

Most research reports on curcumin come from work on animal
models or in vitro experiments. Several recent results are associ-
ated with the control of angiogenesis. This blood vessel–generat-
ing process has undergone intense investigation since it was
found to be critical to the growth and spread of cancerous tumors
by Folkman in 1971.23 It is not always an unwanted process, of
course. It is also a vital step in wound healing.
Recent work on the in vitro mechanism of angiogenesis has
shown curcumin to be effective for controlling squamous-cell
carcinoma. The study showed a reduced occurrence of chemical-
ly induced tumors by 50 percent. 24 Curcumin also appears to
inhibit the in vitro expression of major angiogenesis factors vas-
cular endothelial growth factor (VEGF) and basic fibroblast
growth factor (FGF) in breast cancer–cell cultures.25 In a study
of prostate cancer cells that were intro duced into mice, the
resulting tumors excised from curcumin-treated animals showed Curcuma longa. Photograph ©2002 by Holly Shull Vogel, Green Farma-
marked decreases in cell proliferation, increases in apoptosis, cy, Fulton, Maryland.
and significant decreases in microvessel density compared to
controls. 26,27
Recent work on the mechanism of angiogenesis has shown cur-
cumin to be effective for controlling squamous-cell carcinoma, 24 tumors is reduced by curcumin in a dose-dependent fashion.30,31
breast cancer, 25 and prostate cancer. 26,27 The plant has also been The natural lifespan of cells is regulated by apoptosis. This nat-
found to be effective for reducing the destructive angiogenesis ural regulator of the cell’s lifecycle is activated when the protein
associated with diabetic retinopathy.28,29 p53, a DNA-binding protein, recognizes the need to stop the cell-
Angiogenesis is a complex process that proceeds through the growth cycle for either cell repair or cell death. Some cancerous
agency of a number of transcription factors and growth factor cells overcome this regulation by suppressing apoptosis. Recent
proteins. Metastasis cannot proceed without the spread of blood in vivo experiments, on mice who were implanted with tumor
vessels from one tumor site to another. This tumor spreading and cells related to human prostate cancer, showed curcumin to be
sustaining process begins with proliferation of endothelial cells effective for enhancing apoptosis.26 Inclusion of curcumin in the
to form the spreading blood vessels. The process requires the animals’ diets (2 percent, for up to 6 weeks) induced cell death in
function of proteins such as VEGF and FGF for which the genetic the tumor-cell population by inhibiting apoptosis-suppressor
expressions, in turn, are controlled by various transcription-fac- proteins. It was also concluded that curcumin suppressed prolif-
tor proteins. This chain of protein factors can be interrupted by eration of the tumor cells by blocking growth-factor receptor sig-
inhibition of any of the proteins along the way. nals. 26
A recent study on breast cancer–cell cultures showed that one The value of curcumin in a therapeutic role has recently been
of the modes of curcumin action was via inhibiting the two examined in a report on multidrug-resistance. 32 The cytotoxicity
growth-factor proteins VEGF and FGF as well as by inhibiting of cancer treatment drugs is often thwarted by an overexpression
estrogen-receptor genes. 25 of P-glycoprotein on the surface of cancer cells. In this study, a
The motility of the endothelial cells in the construction of the culture of multidrug-resistant human cervical cancer cells was
new vasculature is a constraint on angiogenesis as well as on the treated with curcumin in the range of 1–55 µM. In this range, cur-
metastasis of tumor cells. A recent study has shown that the basal cumin decreased the expressi on of the P-glyc oprotein and
motility of endothelial cells associated with certain cancerous increased the cells’ sensitivity to the anticancer drug vinblastine.
36 ALTERNATIVE & COMPLEMENTARY THERAPIES—FEBRUARY 2003

Rabbits who are fed a high-cholesterol diet develop atheroscle-

rosis. A recent report showed protection against the development
of fatty streak lesions in the thoracic and abdominal aorta of rab-
bits who were given a dietary supplement of a crude extract of C.
longa compared to controls. Depletion of a-tocopherol (vitamin
E) and coenzyme Q10 was lower in the test group also, implying
that the dietary extract affected the animals’ antioxidant status
positively.40
A recent review of the mechanisms of the anti-inflammatory
and antioxidant properties of curcumin suggests that the mecha-
nisms discussed above may be the core of its anticarcinogenic
The enol form of curcumin. effects. 41

Toxicity, Dosage, and Pharmacokinetics

Hepatoprotection and Antitoxin Effects There have been no reports of particular adverse drug interac-
tions to date but warnings about potential interaction between
Recent studies have confirmed curcumin’s ability to protect the blood-thinning drug warfarin and turmeric deserve some
animal livers from various toxic substances (e.g., carbon tetra- attention. 42 Many anti-inflammatory drugs are known to interact
chloride, a compound that is particularly toxic to the human with warfarin to risk enhanced bleeding. Anti-inflammatory sub-
liver) . Curcumin decreased liver inju ry in rats at both acute stances such as green tea extract, ginseng (Panax spp.), and vita-
(intraperitoneal injected) and subacute (oral ingestion) levels of min E have been associated with potential warfarin interaction. 42
CCl4. In cultures of human hepatocytes, three curcuminoids, Some reports of liver toxicity have appeared over the past 25
including curcumin, showed strong protection agains t cell years. Most of these incidents have involved large dietary doses
destruction by the drug tacrine, a drug with known hepatotoxic given to rats or mice. 43 Conversely, there are several reports in
side-effects that is used for treating Alzheimer’s disease. Cur- clinical studies of the high tolerance of humans to curcumin.20,21
cumin itself was nearly ten times more effective than ascorbic Low bioavailability of curcumin is a well-known problem
acid.34 However, a 1996 study on carbon tetrachloride toxicity in re p o rte d in m any s tud ie s. The r eas on s are n o t cl ear an d
mice showed that curcumin had no protective effects at dosages researchers say only that much of the compound is excreted or
of 200 mg per kg. 35 metabolized rapidly. In rats, 40–75 percent of orally administered
curcumin is excreted in the feces and blood levels of less than 5
µg per mL, indic ating poor absorption from the gut. 44,45 In
Antioxidant and Anti-Inflammatory Effects
human pharmacokinetic studies, similar results have appeared.
Curcumin has long been known as a potent antioxidant com- In a phase I clinical study, it was reported that after taking, 4-, 6-,
pound, on a par with vitamins C and E. 8 A recent study of cultured or 8-g doses of curcumin, subjects had average peak serum con-
endothelial cells from bovine aorta showed that 18-hour incubation centrations of 0.5, 0.6, and 2 µM, respectively. No urinary excre-
of the cultured cells with curcumin, in the concentration range of tion of curcumin was detectable.20
5–15 µM, induced the expression of heme oxygenase, an enzyme Any conclusions to be drawn about “bioavailability” of cur-
that reacts to oxidative stress, to produce the antioxidant biliverdin, cumin must include the possibilities that only low levels of
and enhanced resistance to oxidative damage to the cells.36 serum curcumin are necessary to account for observed effects,
Singlet oxygen is a highly reactive oxygen species that is pro- the metabolites of curcumin are equally as important or more so
duced in some photochemical reactions and in some biochemical than curcumin, and, finally, that the action of curcumin or its
transformations.37 Curcumin’s ability to quench singlet oxygen metabolites is centered in cell membranes and not in cytoplasm
in an aqueous system has recently been reported. 38 Using a sin- or serum.
glet oxygen trapping technique, researchers found that, at a level There are severa l reports about syne rg istic intera ctions
of 3 µM, curcumin inhibited the formation of this reactive species between curcumin and other phytochemicals. Piperine ((E,E) 1-
by 50 percent. Using other radical trapping techniques, the same [5-(1,3-benzodioxol-5-yl)-1-oxo-2, 4-pentadienyl]piperidine) is
researche rs sugges ted that curcumin is not a very efficient extracted from black pepper. When healthy human subjects took
quencher of superoxide (24 percent maximum quenching at 80 a 2 g dose of curcumin accompanied by 20 mg of piperine, the
µM) and may not be an efficient hydroxyl radical scavenger. extent of absorption, the serum level, and the bioavailability of
However, another study on the role of reactive oxygen species in curcumin increased twentyfold compared to these values in sub-
curcumin-enhanced apoptosis showed that human cancer-cell jects who took 2 g of curcumin alone.46
lines that are most susceptible to this enhancement were those Green tea and its extract seem to enhance the effect of dietary
that exhibited superoxide production.39 This may indicate that curcumin. A 1994 report noted that the combination of catechin, a
the antioxidant properties of curcumin may not explain fully the polyphenol from gree n tea, and curcumin in hibited tumor
anti-proliferation seen in vitro. growth in mice and hamster model s. The ind uction of oral
ALTERNATIVE & COMPLEMENTARY THERAPIES—FEBRUARY 2003 37

tumors in golden hamsters was delayed by catechin and dietary References

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dietary turmeric, inhibited both the gross tumor yield and bur- from Curcuma longa by gas chromatography-mass spectrometry. Hu Se
Pu 1998;16:528–529.
den more effectively than the individual components did alone
2. Azuine MA, et al. Protective role of aqueous turmeric extract against
in both tumor models. 47 A more recent report suggested that a mutagenicity of direct-acting carcinogens as well as benzo apyrene-
combined green tea extract and curcumin dietary regimen had a induced genotoxicity and carcinogenicit y. J Cancer Res Clin Oncol
synergistic effect in reducing oral squamous-cell carcinomas in 1992;118:447–452.
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longa in mice. J Ethnopharmacol 2002;83:161–165.
4. Madan B, et al. Curcuma longa activa tes NF-kappaB and promotes
Caveats and Suggestions adhesion of neutrophils to human umbilical vein endothelial cells. J
Ethnopharmacol 2001;75:25–32.
Suggestions regarding the proper therapeutic dose of curcum- 5. Cohly HH, et al. Effect of turmeric, turmerin and curcumin on H2O 2-
in, or indeed of turmeric itself, must be deduced from readings of induced renal epithelial (LLC-PK1) cell injury. Free Radic Biol Med
1998;24:49–54.
a small number of clinical trials. An average daily chemopreven-
6. Srinivas L, et al. Turmerin: A water soluble antioxidant peptide from
tive dosage of curcumin is approximately 500 mg per day or its turmeric (Curcuma longa). Arch Biochem Biophys 1992;292:617–623.
equivalent. 21 In terms of an average curcumin content of 3 per- 7. Online document at: www.ars-grin.gov/cgi-bin/duke/farmacy2.p
cent in the rhizome, this represents a daily intake of 170 g or 6 l?331
ounces of turmeric powder or raw rhizome. This seems to be an 8. Online document at: www.ars-grin.gov/cgi-bin/duke/chemical.pl?
CURCUMIN
untoward amount of turmeric powder to consume every day, to
9. Onl ine document at: w ww.ncbi .nlm.nih.gov:80/entrez/
say the least. At any rate, it is not clear that, in a therapeutic situ- query.fcgi?CMD=search&DB=PubMed
ation, raw turmeric powder or rhizome is the proper form for 10. Online document at: www.curcuminoids.com/page7.htm
administering the compound. 11. Marínela P M, et al. Histochemical evaluation of the rhizome of Cur-
Can curcumin or turmeric be recommended as a daily sup- cuma longa cultivated in Venezuela. Trop Agronomy 1999;49:349–359.
12. Garg SN, et al. Variation in the rhizome essential oil and curcumin
plement? Certainly turmeric’s use as a culinary ingredient can
contents and oil quality in the land races of turmeric Curcuma longa of
be recommended without reservation. What about capsules of North Indian plains. Flavour Fragrance J 1999;14:315–318.
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Late Breaking News. . . 18. Prucksunand C., et al. Phase II clinical trial on effect of the long
Recent results from the University of Rochester Medical Cen- turmeric (Curcuma longa Linn.) on healing of peptic ulcer. Southeast
Asian J Trop Med Public Health 2001;32:208–215.
ter’s (Rochester, New York) study of curcumin and radiation
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therapy for cancer were announced on the Medical Center’s Web 1996;26(suppl.):72–85.
site and in the press on October 7, 2002, while this article was in 20. Cheng AL, et al. Phase I clinical trial of curcumin, a chemopreventive
preparation.48 Part of the announcement read: agent, in patients with high-risk or pre-malignant lesions. Anticancer Res
2001;21:2895–2900.
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of radiation and scientists waited 20 days to assess skin damage. The 2001;7:1894–1900.
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2 4 . L i N , e t a l . I n h i b i t i o n o f 7 , 1 2 - d i m e th y l b e n z [ a ] a n th r a c en e
While doctors are not ready to say that curcumin is the answer to
(DMBA)–induced oral carcinogenesis in hamsters by tea and curcumin.
preventing skin damage, researchers believe the results demonstrate
Carcinogenesis 2002;23:1307–1313.
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No doubt, a full report will eventually appear in the peer-
cancer: III. Curcumin inhibits proliferation, induces apoptosis, and
rev iewed literature. For further information contact: Leslie inhibits angiogenesis of LNCaP prostate cancer cells in vivo. Prostate
White, (585) 273-1119, or leslie_white@urmc.rochester.edu n 2001;47:293–303.
38 ALTERNATIVE & COMPLEMENTARY THERAPIES—FEBRUARY 2003

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37. Kanofsky JR. Singlet oxygen production by biological systems. Chem To order reprints of this article, write to or call: Karen Ballen, ALTERNA-
Biol Interact 1989;70:1–28. TIVE & COMPLEMENTARY THERAPIES, Mary Ann Liebert, Inc., 2
38. Das KC, Das CK. Curcumin (diferuloylmethane), a singlet oxygen Madison Avenue, Larchmont, NY 10538-1961, (914) 834-3100.