Curcumin & Cancer

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Curcumin & Cancer - Clinical Summary

Derived from the rhizome and root. Turmeric is routinely used as a spice and coloring agent. Oral administration of turmeric is well tolerated, but bioavailability is relatively low (5) (15). Following absorption, turmeric is rapidly metabolized. In vitro and animal studies suggest anti-proliferative and preventative effects of turmeric against cancer (10) (11) (12) (13) (16) (17). Results from a pilot study indicate that turmeric, with its active ingredient curcumin, may help alleviate symptoms of irritable bowel syndrome (14). No significant adverse events have been reported. Patients with gastrointestinal disorders should not take curcumin. Recent animal studies indicate that dietary turmeric may inhibit the anti-tumor action of chemotherapeutic agents such as cyclophosphamide in treating breast cancer (3). More research is necessary, but it may be advisable for breast cancer patients undergoing chemotherapy to limit intake of turmeric and turmeric-containing foods. Data from an epidemiological study are suggestive of improved cognitive performance in elderly Asians who consumed turmeric in the form of curry powder (18).

Purported Uses of Curcumin

* Cancer prevention
* Infections
* Inflammation
* Kidney stones
* Stomach and intestinal gas

Mechanism of Action ot Curcumin

The mechanism of action is not fully understood. Turmeric has anti-inflammatory and choleretic action. Anti-inflammatory action may be due to leukotriene inhibition. Its curcuminoids (curcumin) and volatile oil are both partly responsible for the anti-inflammatory activity. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450. Turmeric acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. It also inhibits activation of NF-kB4, c-jun/AP-1 function, and activation of the c-Jun NH2-terminal kinase (JNK) pathway. In vitro and animal models of breast cancer show turmeric may inhibit chemotherapy-induced apoptosis via inhibition of the JNK pathway and reactive oxygen species generation. The isolated constituent alpha r-turmerone has been shown to arrest the reproduction and slaughterer activity of human lymphocytes, which may contribute to its anti-inflammatory action. Curcumin is more effective by parenteral injection than by oral ingestion. Curcumin has displayed antitumor activity and may be protective against some cancers, such as colon cancer. In laboratory tests, curcumin's antitumor actions appear to be due to interactions with arachidonate metabolism and its in vivo antiangiogenic properties.

Pharmacokinetics of Curcumin

Bioavailability of curcumin is approximately 60-65% following oral administration. Metabolism is primarily via glucuronidation to glucuronide and glucuronide/sulfate metabolites (4). In vitro studies indicate inhibition of Cytochrome P450 1A1. Excretion of parent compound is primarily in the feces with metabolites present in the urine (5).

Warnings of Curcumin

Recent laboratory findings indicate that dietary turmeric may inhibit the anti-tumor action of chemotherapeutic agents such as cyclophosphamide in treating breast cancer. More research is necessary, but it may be advisable for breast cancer patients undergoing chemotherapy to limit intake of turmeric and turmeric-containing foods. (3)

Contraindications of Curcumin

Patients with bile duct obstruction, gallstones, and GI disorders (including stomach ulcers and hyperacidity disorders) should not take curcumin(6).

Adverse Reactions of Curcumin

None known

Herb-Drug Interactions

Reserpine: Turmeric may reduce efficacy (7).
Indomethacin: Turmeric may reduce efficacy (7).
Anticoagulants / Antiplatelets: Turmeric may increase risk of bleeding (7).
Camptothecin: Turmeric inhibits camptothecin-induced apoptosis of breast cancer cell lines in vitro (3).
Mechlorethamine: Turmeric inhibits mechlorethamine-induced apoptosis of breast cancer cell lines in vitro (3).
Doxorubicin: Turmeric inhibits doxorubicin-induced apoptosis of breast cancer cell lines in vitro (3).
Cyclophosphamide: Dietary turmeric inhibits cyclophosphamide-induced tumor regression in animal studies (3).

Literature Summary and Critique
Human data:
James J. Curcumin: clinical trial finds no antiviral effect. AIDS Treat News 1996;242:1.
A randomized study of 38 patients to either high-dose or low-dose turmeric powder. Following 8 weeks of treatment, there was no demonstrated effect of turmeric on HIV viral load. A small increase in CD4 cells in the high-dose group and a consistent fall of CD4 cells in the low-dose group were documented, but neither result was statistically significant. This report of an abstract presented at the third annual Conference on Retroviruses and Opportunistic Infections demonstrated no efficacy of turmeric in treating HIV.

Animal / In vitro data:
Li JK, et al. Mechanisms of cancer chemoprevention by curcumin. Proc Natl Sci Counc Repub China B 2001;25:59-66.
Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third-generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C and EGF-receptor tyrosine kinase. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells.

Venkatesan N. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol 2000;129:231-4.
This study investigated the effect of curcumin on Adriamycin (ADR) nephrosis in rats. The results indicate that ADR-induced kidney injury was remarkably well prevented by treatment with curcumin. Treatment with curcumin markedly protected against ADR-induced proteinuria, albuminuria, hypoalbuminemia and hyperlipidemia. Curcumin restored renal function in ADR rats, as judged by the increase in GFR. The data also demonstrate that curcumin protects against ADR-induced renal injury by suppressing oxidative stress and increasing kidney glutathione content and glutathione peroxidase activity. This suggests that administration of curcumin is a promising approach in the treatment of nephrosis caused by ADR.

Kawamori T, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999;59:597-601.
This study was designed to investigate the chemopreventive action of curcumin when administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. The study also monitored the modulating effect of this agent on apoptosis in the tumors. The results showed that the administration of 0.2% curcumin during both the initiation and post initiation periods significantly inhibited colon tumorigenesis. In addition, administration of 0.2% and of 0.6% synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon.

Mehta K, et al. Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines. Anticancer Drugs 1997;8:470-81.
The antiproliferative effects of curcumin against several breast tumor cell lines, including hormone-dependent, hormone-independent, and multidrug lines, were studied. Curcumin preferentially arrested cells in the G2/S phase of the cell cycle. Curcumin-induced cell death was due neither to apoptosis nor to a significant change in the expression of apoptosis-related genes, including Bcl-2 p53, cyclin B and transglutaminase.

Rao CV, et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 1995;55:259-66.
This study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and the modulating effect of curcumin on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. The results indicate that the administration of curcumin significantly inhibited incidence of colon adenocarcinomas (p<0.004) and the multiplicity of invasive, non-invasive, and total adenocarcinomas. Curcumin also significantly suppressed the colon tumor volume by more than 57% compared to the control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.

References

1. Leung AY, et al. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics, 2nd ed. New York: Wiley; 1996.
2. Blumenthal, et al. Herbal Medicine, Expanded Commission E Monographs. Austin: American Botanical Council; 2000.
3. Somasundaram S, et al. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 2002;62:3868-75.
4. Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci 2000;67:2785-93.
5. Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology 1980;16:259-65.
6. McGuffin M, et al. American Herbal Products Association's Botanical Safety Handbook. Florida: CRC Press; 1997.
7. Brinker F. Herbal Contraindications and Drug Interactions, 2nd ed. Sandy (OR): Eclectic Medical Publications; 1998.
8. James J. Curcumin: clinical trial finds no antiviral effect. AIDS Treat News 1996;242:1.
9. Li JK, et al. Mechanisms of cancer chemoprevention by curcumin. Proc Natl Sci Counc Repub China B 2001;25:59-66.
10. Venkatesan N. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol 2000;129:231-4.
11. Kawamori T, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999;59:597-601.
12. Mehta K, et al. Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines. Anticancer Drugs 1997;8:470-81.
13. Rao CV, et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 1995;55:259-66.
14. Bundy R, et al. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study. J Altern Complement Med. 2004 Dec;10(6):1015-8.
15. Garcea G, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):120-5.
16. Siwak D, et al Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of 1kB kinase and nuclear factor kB activity and are independent of the B-Raf/Mitogen activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer 2005;104(4):879-90.
17. Uddin S, et al. Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma. Oncogene 2005:1-9.
18. Ng TP, Chiam PC, Lee T, et al. Curry consumption and cognitive function in the elderly. Am J Epidemiol 2006; 164(9):898-906.

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