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¹ William T. Gossett Neurology Laboratories, Departments of ² Surgery and ³ Otolaryngology Research, and⁴ Complementary and Integrative Medicine Program, Henry Ford Health System; ⁵ John D. Dingell VA Medical Center; and ⁶ Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan

Requests for reprints: Robert A. Levine, William T. Gossett Neurology Laboratories, Henry Ford Health System, One Ford Place, Detroit, MI 48202. Phone: 313-874-3771; Fax: 313-874-3770. E-mail: bob-levine{at}earthlink.net

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose- and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G₀/G₁ growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma.

Key Words: glioma • resveratrol • Bcl-2 • CDK • caspase-3 • Brain/central nervous system cancers • Effectors of apoptosis • bcl-2 pathways • anti- and proapoptotic • cell cycle • Caspases

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Received 3/ 1/04; revised 1/27/05; accepted 2/ 7/05.