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Chemopreventive Properties of trans-Resveratrol Are Associated with Inhibition of Activation of the IB Kinase¹

Lineberger Comprehensive Cancer Center [M. H-M., A. S. B.] and Curriculum in Genetics and Molecular Biology [A. S. B.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295

trans-Resveratrol (Res), a phytoalexin found at high levels in grapes and in grape products such as red wine, has been shown to have anti-inflammatory and antioncogenic properties. Because the transcription factor nuclear factor B (NF-B) is involved in inflammatory diseases and oncogenesis, we tested whether Res could modulate NF-B activity. Res was shown to be a potent inhibitor of both NF-B activation and NF-B-dependent gene expression through its ability to inhibit IB kinase activity, the key regulator in NF-B activation, likely by inhibiting an upstream signaling component. In addition, Res blocked the expression of mRNA-encoding monocyte chemoattractant protein-1, a NF-B-regulated gene. Relative to cancer chemopreventive properties, Res induced apoptosis in fibroblasts after the induced expression of oncogenic H-Ras. Thus, Res is likely to function by inhibiting inflammatory and oncogenic diseases, at least in part, through the inhibition of NF-B activation by blocking IB kinase activity. These data may also explain aspects of the so-called "French paradox" that is associated with reduced mortality from coronary heart disease and certain cancers and provide a molecular rationale for the role of a potent chemopreventive compound in blocking the initiation of inflammation and oncogenesis.

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