Almost a decade has passed since the already substantial knowledge of curcuminoids’ role in prevention and treatment of cancer was available, and the pace of research on these compounds has only accelerated. In the last three three years alone, there has been at least one pioneering IND (Investigational New Drug) study granted by the Food and Drug Administration (FDA) and other National Institutes of Health (NIH)-funded studies for the investigation of curcumin and its derivatives in treatment of patients with cancer. Some of the leading cancer research centers in the United States, including M.D. Anderson Hospital in Houston, TX, are involved in pre-clinical and clinical research of the anti-cancer mechanism and application of curcuminoids in conditions including multiple myeloma and colon cancer; breast, prostate, head and neck, and respiratory tract cancers are being considered next in line for systematic evaluation with curcuminoid therapy.

Curcuminoids inhibit several processes that contribute to the survival, proliferation, invasion and metastasis of tumor cells. These processes with which curcuminoids interfere include signaling mechanisms (critical for tumor growth), regulation of apoptosis (cell death), and tumor angiogenesis (new blood vessel formation which feeds tumors). Current research is designed to determine which of these fundamental processes in cancer development account for the clinical effects of curcumin and its derivatives.

Curcuminoids have significant immuno-modulating and anti-inflammatory effects, in part due to their inhibition of cyclooxygenase type 2 enzyme (COX-2) and their subsequent arachidonic acid metabolism. Like several other immunomodulators, curcuminoids inhibit the activation of the nuclear factor kappa-B (NF-kB) family of transcription factors, which are known to be activated in a wide variety of solid tumors and leukemias. The activation of NF-kB may shield tumor cells from apoptosis, or programmed cell death, promote tumor growth factors and those factors that facilitate invasion and metastasis of tumors. Curcuminoids block the NF-kB mediated gene expression responsible for the chain of events leading to tumor development, progression and expansion. A probable mechanism of curcuminoids seems to be blocking the phosphorylation of the inhibitors of NF-kB. In vitro, curcuminoids induce apoptosis, and thus inhibit tumor growth in a broad range of tumor cells, including cell lines from colon, breast, prostate, squamous cell, renal cell, hepatocellular carcinomas, B and T-cell lymphomas, leukemias, melanoma and sarcoma cells.
Curcuminoids also affect a signaling mechanism that involves expression and activation of certain receptors of growth factors that promote tumor growth. For example, HER-2/neu is a member of the Epidermal Growth Factor Receptor family, which is overexpressed in approximately 30% of breast cancer patients. HER-2/neu breast cancer cells, when exposed to curcuminoids, inhibited the expression of the HER-2 receptor. Interestingly, curcuminoids may have a comparable mechanism of action to the recently approved drug therapy involving Herceptin for breast cancer patients with HER-2 receptor positive cancer cells. Herceptin is an antibody against HER-2 receptors; binding, blocking and inactivating those receptors. In addition, in vitro, the growth of breast cancer cells with multi-drug resistance (MDR) characteristics is inhibited by turmeric phenolics; the stimulation of estrogen receptor (ER) positive cell lines by estrogenic pesticides is also inhibited by curcuminoids. Curcuminoids have also been found to inhibit epidermal growth factor receptor expression and/or activation in skin cancer cell lines as well as in androgen-sensitive and androgen-insensitive prostate cancer cell lines.

One of the important anti-cancer mechanisms of curcuminoids is due to constriction of vital blood supply to the rapidly growing tumor. These compounds inhibit in vitro the vessel endothelial and smooth muscle cell growth and proliferation, which is the basis for inhibition of angiogenesis (new blood vessel formation). Curcuminoids also inhibit new vessel formation induced by growth factors, such as fibroblast growth factor-2 (FGF-2).

Furthermore, curcuminoids inhibit the production of vascular endothelial growth factor (VEGF) in human melanoma cells. The anti-angiogenic effect of turmeric compounds can be explained due to the aforementioned selective COX-2 inhibition with curcuminoids. The COX-2 enzyme activity may actually contribute to tumor growth (inhibition of apoptosis) along with increased production of the new vessel growth factors (VEGF, FGF) and the formation of new blood vessels. An in vivo study showed tumor regression in response to cyclooxygenase inhibitors in experimental models of human colon, prostate, gastric, lung and certain types of head and neck tumors. In in vitro experiments cyclooxygenase inhibitors inhibited the growth of human pancreatic, liver and breast cancer cell lines.

While human trials involving curcuminoids are still limited, in animal models curcuminoids have been shown to prevent tumor formation in genetically predisposed animals, i.e. animals prone to develop precancerous multiple intestinal adenomas, a model for the human condition known as Familial Adenomatous Polyposis (FAP). Dietary enrichment with curcuminoids inhibited polyp growth in these animals by over 60%. A study with human subjects is currently under way evaluating the effects of curcuminoids on Aberrant Crypt Foci (ACF) development in the colon. Curcuminoids were also successfully tested in several other intervention trials. In one experiment mice inoculated with melanoma cells responded to dietary curcumin intervention with a reduction in the number of lung tumor nodules by 90% as compared to sham-fed controls.

In the late 1980s, a Phase I chemopreventive study of curcuminoids administered orally was performed in a selected group of patients with a high risk of developing bladder cancer, Bowen’s Disease, cervical cancer, and premalignant conditions such as oral leukoplakia (an inflammatory precancerous condition of the oral cavity) and intestinal metaplasia (premalignant transformation of tissue) of the gastric mucosa (stomach lining). The premalignant state improved in seven of the 25 patients, and no adverse effects related to curcuminoids use were observed. Several other chemoprevention trials focusing on the use of curcuminoids are currently under way.
The National Toxicology Program of the National Institute of Environmental and Health Sciences evaluated the safety of turmeric oleoresin containing concentrated and standardized levels of curcuminoids at the request of the National Cancer Institute and the FDA. No biologically significant differences in hematologic (blood parameters), clinical chemistry or urinalysis parameters were noted between the experimental and control animals in the 13-week studies. The turmeric oleoresin used was found to be non-mutagenic. The LD50 in rats was higher than 3,500 mg/kg. Monkeys given doses up to 800 mg/kg/day for three months exhibited no adverse effects on growth, behavior and biochemical parameters. The U.S. FDA includes turmeric powder and oleoresin on its list of substances generally recognized as safe (GRAS).

The well recognized and documented properties of curcuminoids in inhibiting the COX-2 enzyme, coupled with the history of safe use as food and dietary supplement qualifies these turmeric derived compounds for further clinical trials in cancer prevention and intervention. The use of anti-inflammatory compounds is of particular interest now, not only in the prevention of cancer, but also in the treatment of full-blown cancer. For example, in a 1990s study performed in Sweden, patients with advanced metastatic solid tumors benefited from NSAID anti-inflammatory therapy by a mean survival of 510 days compared to 250 days for the placebo group, and also maintained a better quality of life in the course of the disease. WF

Vladimir Badmaev, M.D., Ph.D., is vice president of scientific and medical affairs, and Muhammed Majeed, Ph.D., is the C.E.O. of Sabinsa Corporation, headquartered in Piscataway, NJ.