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p38 Inhibitor SB203580 sensitizes the resveratrol‐induced apoptosis in human lung adenocarcinoma (A549) cells

Based on our recent findings that resveratrol, a natural plant polyphenol found in red grape skins as well as other food products, induces apoptosis via a caspase‐independent intrinsic pathway in human lung adenocarcinoma cells, this study is designed to explore whether SB203580, a p38 inhibitor, potentiates the resveratrol‐induced apoptosis of human lung adenocarcinoma (A549) cells. We found that pretreatment with SB203580 enhanced the resveratrol‐induced apoptosis by accelerating the intrinsic apoptotic pathway including Bax activation, loss of mitochondrial membrane potential, and activation of both caspase‐9 and −3. Although treatment with resveratrol alone did not induce caspase‐8 activation, cotreatment with both SB203580 and resveratrol not only enhanced FasL cleavage but also activated caspase‐8, indicating that the extrinsic apoptotic pathway may be involved in the synergistic effect. Collectively, we for the first time demonstrate that SB203580 synergistically enhances the resveratrol‐induced apoptosis by accelerating Bax‐mediated intrinsic pathway and initiating extrinsic pathway, suggesting a possible alternative therapeutic strategy for human lung cancer. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:251–257, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21413