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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaα)–dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochromecrelease, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-κB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-κB, were both inhibited by RES. The patterns for NF-κB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-κB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-κB and calpain protease activity. Therefore, Bcl-2 and NF-κB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. © 2005 Wiley-Liss, Inc.