Curcumin May Enhance TRAIL-Induced Cancer Cell Death

SAN FRANCISCO—Curcumin, the active ingredient in the spice turmeric, can act together with the natural molecule TRAIL to increase apoptosis in androgen-sensitive human prostate cancer cells, researchers said at the 93rd Annual Meeting of the American Association for Cancer Research (abstract 4237).

"When added at low concentrations, neither agent alone produced significant effects. But when added together, they induced apoptosis in 70% to 80% of LNCaP prostate cancer cells," said lead researcher Subhash C. Gautam, PhD, senior staff investigator in the Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Health System, Detroit.

Curcumin has long been used as a folklore remedy and anti-inflammatory agent. Recent studies have revealed it is also an antioxidant and is chemopreven-tive against several tumor cell lines, Dr. Gautam said. In India, where it is used commonly to spice foods, there is a very low rate of gastrointestinal tumors, especially colon cancers.

LNCaP, an androgen-sensitive human prostate cell line, is moderately sensitive to the induction of apoptosis by TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL). In the study, the researchers aimed to find out whether curcumin and TRAIL cooperatively interact to increase apoptosis in this prostate cancer cell line. The researchers also sought to find the mechanism by which TRAIL and curcumin could produce apoptosis.

The researchers found that low concentrations of either agent used alone (10 µM curcumin; 20 ng/mL TRAIL) did not have enough cytotoxicity to induce significant apoptosis in the prostate cancer cell line. But when used together, these two agents enhanced cell death by two- to threefold (see Figure).

The combined treatment induced DNA fragmentation in LNCaP cells. The production of DNA fragments in treated LNCaP cells was associated with the cleavage of procaspase-3 and poly (ADP-ribose) polymerase (PARP). Cells were protected from dying in the presence of a general caspase inhibitor (zVAD-fmk) or a caspase-3 specific inhibitor (zDEVD-fmk). These data indicate that apoptosis is the major mode of tumor cell death induced by the combined curcumin and TRAIL treatment, Dr. Gautam said.

Since the AACR meeting, the researchers have observed similar apoptosis with combined curcumin and TRAIL treatment in neuroblastoma and glioma cell lines. "This opens possibilities for patients who have become resistant to other treatments," Dr. Gautam said. "Curcumin as an oral supplement might sensitize drug-resistant tumors to immunotherapy with TRAIL." Although TRAIL is effective at inducing apoptosis in tumors in vivo, it is toxic at therapeutic levels.

The next step for the researchers will be to test a combined TRAIL and curcu-min treatment in mice with human prostate cancer growths. "We would like to find out if we can stop prostate tumor progression in animals given the concentrations we use," Dr. Gautam said. "We are trying to find out at what level curcumin causes sensitization of cancer cells." If there is a beneficial therapeutic effect in animal models, Dr. Gautam hopes to test curcumin in a phase I clinical trial to evaluate its toxicity.