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Division of Hematology/Medical Oncology [D. D., Y. X. X., X. G., N. J., R. A. C., S. C. G.], and William T. Gossett Neurology Laboratories [H. J.], Department of Neurology, Henry Ford Health System, Detroit, Michigan 48202

2 To whom requests for reprints should be addressed, at Oncology Research Laboratory, 4D, Henry Ford Health System, One Ford Place, Detroit, MI 48202. Phone: (313) 874-6998; Fax: (313) 874-3770; E-mail: sgotam{at}msn.com

The role of natural food products in prevention of prostate cancer has been confirmed in recent epidemiological studies; however, the mechanism of chemoprevention by the dietary constituents largely remains unknown. Curcumin, the yellow pigment and active component of turmeric (Curcuma longa), exhibits chemopreventive and growth inhibitory activity against several tumor cell lines. The androgen-sensitive human prostate cancer cell line LNCaP is only slightly susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family of cell death-inducing ligands. In this study, we investigated whether curcumin and TRAIL cooperatively interact to promote death of LNCaP cells. At low concentrations (10 µM curcumin and 20 ng/ml TRAIL), neither of the two agents alone produced significant cytotoxicity (curcumin, <10%; TRAIL, 15%) in LNCaP cells, as measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium dye reduction assay. On the other hand, cell death was markedly enhanced (2–3-fold) if tumor cells were treated with curcumin and TRAIL together. The combined curcumin and TRAIL treatment increased the number of hypodiploid cells and induced DNA fragmentation in LNCaP cells. The combined treatment induced cleavage of procaspase-3, procaspase-8, and procaspase-9, truncation of Bid, and release of cytochrome c from the mitochondria, indicating that both the extrinsic (receptor-mediated) and intrinsic (chemical-induced) pathways of apoptosis are triggered in prostate cancer cells treated with a combination of curcumin and TRAIL. These results define a potential use of curcumin to sensitize prostate cancer cells for TRAIL-mediated immunotherapy.

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