Resveratrol downregulates the constitutional activation of nuclear factor-κB in multiple myeloma cells, leading to suppression of proliferation and invasion, arrest of cell cycle, and induction of apoptosis

Resveratrol has been proposed to act as a chemopreventive agent ill numerous epidemiologic studies and has been shown to inhibit proliferation of various tumor Cells in vitro. In the present study, we investigated the antitumor effects of resveratrol on multiple myeloma (MM) cells and the mechanisms involved. Our findings indicated that resveratrol inhibited proliferation of tumor cells in a dose- and time-dependent manner by 3-(4,5-dimethylthiazol-2yl)-5-diphenyltetrazolium bromide (MT-17) assay and [H-3]thymidine incorporation assay. Resveratrol also enhanced the inhibitory effect of dexamethasone on the growth of MM cells by MTT assay. Flow cytometric analysis demonstrated that resveratrol at-rested the cells at the G, and S phases of the cell cycle. Because nuclear factor-kappa B (NF-kappa B) plays a key role in cell Survival and proliferation of human MM cells, we tested the effect of resveratrol on NF-kappa B expression by Western blot analysis and immunofluorescence. NF-kappa B was constitutively active in all human MM cell lines examined, and resveratrol down-regulated NF-kappa B expression in all cell lines. Resveratrol also down-regulated the expression of NF-kappa B-regulated gene products by Western blot analysis, gelatin zymography, and enzyme-linked immunosorbent assay, including interleukin-6, Bcl-2, Bcl-xL, XIAP, c-IAP. vascular endothelial growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9), which modulates all array of signals controlling cellular survival and proliferation and tumor promotion. Indeed, annexin V-fluoroisothyocyanate and Transwell invasion analyses revealed that incubation of MM cells with resveratrol resulted in apoptotic cell death and inhibition of invasion. In conclusion, these data suggest that resveratrol is an effective in vitro inhibitor of NF-kappa B in human MM cells. Resveratrol plays a role ill suppressing the proliferation of MM cells and induces apoptosis, thus providing the molecular basis for the treatment of MM patients with this compound. (c) 2006 Elsevier Inc. All rights reserved.