Variety IN the Spice of Life: An Update on the Pleiotropic Therapeutic Potential of Curcumin

By Nancy J. Selfridge, MD, and Santy Daya, PhD. Dr. Selfridge is Associate Professor, Integrated Medicine, Ross University School of Medicine, Freeport, Grand Bahama. Dr. Daya is Professor of Pharmacology, Foundations of Medicine, Ross University School of Medicine, Freeport, Grand Bahama; they report no financial relationship to this field of study.

The traditional culinary and medicinal spice turmeric (curcuma longa) is sometimes referred to as the "golden spice of life." Native to South and Southeast Asia, this plant is now widely cultivated. The rhizome of the plant is harvested, boiled, dried in a hot oven, and ground to produce a brilliant yellow powder used extensively as a culinary spice in the curries and cooking of India and Asia.1 In Ayurvedic medicine, turmeric is used as a dosha (fundamental constitutional bioenergy necessary for optimum health) balancing agent, a demulcent for cough and respiratory ailments, an antidiarrheal agent, and a treatment for gastrointestinal disorders including helminthic infections. It is also traditionally applied as a poultice or paste to wounds, eye infections, and a variety of skin conditions.1 Curcumin, a polyphenol, has been isolated and identified as the active ingredient in turmeric. Research interest in curcumin has exploded recently as its pleiotropic mechanisms of action, targeting myriad cellular processes in diverse tissues and cell types, and its complex chemistry have been defined, suggesting multiple possible therapeutic uses. A demand for and interest in natural medicines has further driven this interest.

Anti-inflammatory Effects

Curcumin exhibits in vitro ability to suppress acute and chronic inflammation by inhibiting lipooxygenase (LOX) and cyclooxygenase-2 (COX-2) activities as well as nitric oxide production and reactive oxygen species in macrophages. Production of pro-inflammatory cytokines and other proteins is also curtailed by this agent, as is lipid peroxidation in some tissue preparations. In vivo animal studies affirm curcumin's ability to inhibit inflammation induced by several substances.2

Curcumin's antioxidant and free radical-scavenging functions suggest that it might be useful in the treatment of a wide array of diseases with an inflammatory pathophysiology, including arthritis, COPD, cardiovascular disease, inflammatory skin disorders, and mood disorders. Some clinical potential for curcumin has been shown in patients with inflammatory bowel disease.3,4

Chemoprevention Effects

With the worldwide search for anticancer agents, curcumin has rapidly come under intense scrutiny and the results look promising. A review by Hatcher et al, published in March 2008, lists 19 ongoing or not yet open curcumin clinical trials, and eight others in India of indeterminate status.2 Disease targets in these studies include colon, oral, cervical, gallbladder, and pancreatic cancers, myelodysplasia, and multiple myeloma.

It appears that curcumin inhibits the development of a number of cancers, interfering with multiple steps in the genesis of malignancy. Animal studies have shown that curcumin has a dose-dependent chemopreventive effect in colon, stomach, esophageal, duodenal, and oral cancers and is cytotoxic against bladder tumors in mice. In addition, it appears to have a protective effect against radiation-induced and diethylstilbestrol-stimulated mammary tumors. In other studies, curcumin has a chemosensitizing affect, enhancing activities of antineoplastic agents. This has been demonstrated for cisplatin, the death ligand TRAIL (TNF-related apoptosis-inducing ligand), doxorubicin, tamoxifen, daunorubicin, vincristine, and others. A number of studies have also shown that curcumin has an ability to counteract multi-drug resistance in some cancer cell lines. Angiogenesis, an important process in cancer growth and metastasis, is inhibited by this agent.2

Cytoprotective Effects

The ability of curcumin to protect normal cells against radiation injury while radiosensitizing cancer cells, has also been demonstrated, the mechanism remaining unknown.2 Researchers the world over are trying to unravel curcumin's molecular actions in the hope that it will emerge as a therapeutic tool in cancer prevention and treatment.

For curcumin to exhibit these cytoprotective properties, it would be expected to regulate multiple cell-signaling pathways. This has indeed been demonstrated in studies where curcumin displays activities similar to tumor necrosis factor (TNF)-inhibitor drugs (e.g., Humira®, Remicade®, Enbrel®), vascular endothelial cell growth factor blocker (e.g., Avastin®), human epidermal growth factor receptor blocker (e.g., Erbitux®), and human epidermal growth factor receptor 2 (HER2) blocker (e.g., Herceptin®).5 It also interferes with control of the cell cycle by several mechanisms related to inhibition of NFkB proteins and induces apoptosis in a number of cancer cell lines, again by several mitochondrial pathways and by suppressing anti-apoptotic proteins.2

While interfering with pathways important to tumor cell survival, curcumin also appears to have a cytoprotective effect on non-cancer cells such as increasing activity of glutathione transferases and heme oxygenase, as well as inhibiting procarcinogen enzymes such as cytochrome P45001A.2

Many cytoprotective agents also have metal-scavenging properties and curcumin is no exception. In this respect it has been shown to act as an iron (II) chelator both in vivo and in vitro,6 thus inhibiting the formation of the dangerous hydroxyl free radical. It is therefore not surprising that it attenuates liver damage induced by iron overdose and even provides hepatoprotection in chole-stasis and carbon tetrachloride and ethanol poisoning.7

Antimicrobial Effects

Curcumin's multifaceted actions also embrace antimicrobial effects. Researchers at the University of Michigan have shown that curcumin inhibits drug-resistant forms of lethal malaria parasite Plasmodium. falciparum8 and exhibits in vitro activity against Candida species and Paracoccidioides brasiliensis (the cause of paracoccidioidomycosis).9 An Iranian study showed that curcumin appears to potentiate the effects of a number of antibiotics. It increases the antibacterial activities of cefixime, cefotaxime, vancomycin, and tetracycline against a test strain of Staphylococcus aureus.10 Apoptosis has been shown to be induced in HPV-infected cervical cancer cells exposed to curcumin.11-13 A 2004 study in India showed that in HIV-infected cells exposed to curcumin, replication of the virus is halted. The authors hypothesize that this is due to curcumin's inhibition of normal activities of the P300 enzyme in controlling human genes, a mechanism that must remain intact for HIV to replicate.14 A Cochrane review, though, showed no therapeutic benefit or reduction in HIV viral load or CD4 counts in humans taking curcumin supplements.15 A 2008 study from Michigan State University showed that herpes simplex virus-1 replication is inhibited by curcumin, but independent of its effects on P300.16

Neuroprotective Effects

With the world's population living longer, neurodegenerative disorders have become more prevalent and the search for neuroprotective agents has become an imperative. Here too, curcumin shows great potential to curtail these disorders as it has potent antioxidant and free radical scavenger properties in neuronal tissues. A 2004 study in mice suggests that curcumin might inhibit beta amyloid accumulation in the brain, a pathophysiologic hallmark of Alzheimer's disease in humans.17 Curcumin has also been shown to be a selective MAO inhibitor, implying that this agent might have antidepressant and neuroprotective effects.18 Several studies have shown that curcumin has a positive effect on neurogenesis in the hippocampus,19-21 and since neurodegeneration is associated with stress, depression, and anxiety, the role of curcumin in these disorders should be explored. It is well known that the incidence of Alzheimer's disease in India is very low, but a link to curcumin would need to be established by well-designed epidemiological studies.

Bioavailability

Despite many animal studies demonstrating curcumin's biological effects, it has very limited bioavailability beyond the GI tract, including the liver. When taken alone, oral doses of 2-12 g result in low to undetectable serum levels.2 Research into altered forms of curcumin that might increase bioavailability is ongoing. Further, it is unclear if heat or oil solubilized forms are better absorbed or if combination with other natural substances and spices, as occurs in the culinary uses of turmeric, may increase absorption and bioavailability. Whether its metabolites might be active and more bioavailable needs urgent investigation.

Safety

Thus far, curcumin appears to have a favorable safety profile, especially in culinary doses. However, some of curcumin's biologic effects deserve consideration. Because curcumin causes gallbladder contraction, patients with known gallstones should be advised to avoid using supplements containing curcumin. Curcumin may increase stomach acid, and thus may be problematic for patients taking stomach acid-reducing medications. Curcumin has shown a blood sugar-lowering effect and might put diabetics on medication at risk for hypoglycemia. These patients should be warned and carefully monitored. It also inhibits platelet aggregation; bleeding problems may be precipitated in patients with known bleeding disorders and those on anticoagulation therapy or other platelet inhibitors such as NSAIDs or clopidogrel (Plavix®). Thus, all patients using curcumin should stop taking these supplements 2 weeks before any scheduled invasive procedure. One study reported lung tumor promotion by curcumin.22 Patients allergic to turmeric, suffering from or at risk for iron deficiency or on anticoagulation therapy, should not use curcumin supplementation. The same applies to patients with lung cancer or at substantial risk of lung cancer, and patients who are pregnant or breastfeeding. For all others, supplements up to 12 g or 200 mg/kg of body weight daily are probably safe, but research has not clearly indicated a favorable risk/benefit ratio. Though some data suggest that GI upset and diarrhea may result from higher doses, limited clinical trials of the 12 g/d dose have demonstrated only mild nausea or diarrhea and no dose-limiting toxicities.2

Recommendation

It is widely agreed by researchers and reviewers alike that more research is needed before recommendations can be made concerning the safe use of curcumin as a therapeutic or chemopreventive intervention for any specific disease. Certainly, if one finds pleasure in consumption of curries or adding turmeric spice in food preparations, this behavior can be encouraged and endorsed and may have some yet unproven health-promoting potential. Considering the multitargeting nature of turmeric and its enigmatic active ingredient, curcumin, in biological life processes, it could prove to be part of the elusive "elixir of life."

References

1. Ehrlich SD. Turmeric. University of Maryland Medicine Center web site. Available at: www.umm.edu/altmed/articles/turmeric-000277.htm. Accessed Feb. 12, 2010.

2. Hatcher H, et al. Curcumin: From ancient medicine to current clinical trials. Cell Mol Life Sci 2008;65: 1631-1652.

3. Epstein J, et al. Curcumin suppresses p38 mitogen-activated protein kinase activation, reduces IL-1beta and matrix metalloproteinase-3 and enhances IL-10 in the mucosa of children and adults with inflammatory bowel disease. Br J Nutr 2009;2:1-9.

4. Hanai H, Sugimoto K. Curcumin has bright prospects for the treatment of inflammatory bowel disease. Curr Pharm Des 2009;15:2087-2094.

5. Aggarwal B, et al, eds. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. New York, NY: Springer; 2007.

6. Jiao Y, et al. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 2009;113:462-469.

7. Rivera-Espinoza Y, Muriel P. Pharmacological actions of curcumin in liver diseases or damage. Liver Int 2009;29:1457-1466.

8. Reddy RC, et al. Curcumin for malaria therapy. Biochem Biophys Res Commun 2005;326:472-474.

9. Martins CV, et al. Curcumin as a promising antifungal of clinical interest. J Antimicrob Chemother 2009;63: 337-339.

10. Moghaddam KM, et al. The combination effect of curcumin with different antibiotics against Staphylococcus aureus. IJGP 2009;3:141-143.

11. Singh M, et al. Molecular mechanisms of curcumin induced cytotoxicity in human cervical carcinoma cells. Mol Cell Biochem 2009;325:107-119.

12. Divya CS, Pillai MR. Antitumor action of curcumin in human papillomavirus associated cells involved downregulation of viral oncogenes, prevention of NFkB and AP-1 translocation, and modulation of apoptosis. Mol Carcinog 2006;45:320-332.

13. Prusty BK, Das BC. Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. Int J Cancer 2005;113:951-960.

14. Balasubramanyam K, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/ non-histone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 2004;279:51163-51171.

15. Liu JP, et al. Herbal medicines for treating HIV infection and AIDS. Cochrane Database Syst Rev 2005;(3): CD003937.

16. Kutluay SB, et al. Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. Virology 2008;373:239-247.

17. Yang F, et al. Curcumin inhibits formation of amyloid beta oligomers, and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005;280:5892-5901.

18. Kulkarni SK, et al. Antidepressant activity of curcumin: Involvement of serotonin and dopamine system. Psychopharmacolog (Berl) 2008;201:435-442.

19. Xu Y, et al. Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 2007;1162:9-18.

20. Wu A, et al. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol 2006;197:309-317.

21. Bala K, et al. Neuroprotective and anti-ageing effects of curcumin in aged rat brain regions. Biogerontology 2006;7:81-89.

22. Dance-Barnes ST, et al. Lung tumor promotion by curcumin. Carcinogenesis 2009;30:1016-1023.