Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3

The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some cancer cells, includinG AGS gastric adenocarcinoma cells. However, treatment with TRAIL in combination with subtoxic concentrations of genistein sensitizes TRAIL-resistant AGS cells to TRAIL-mediated apoptosis. Combined treatment with genistein and TRAIL-induced chromatin condensation and sub-G I phase DNA content. These indicators of apoptosis are correlated with the activation of death receptors (DR5) and induction of caspase-3 activity, which results in the cleavage of poly(ADPribose)polymerase. Both the cytotoxic effect and apoptotic characteristics induced by combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role of caspase-3 in the observed cytotoxic effect. These results indicate that caspase-3 is a key regulator of apoptosis in response to combined genistein and TRAIL in human gastric adenocarcinorna AGS cells through the activation of DR5 and mitochondrial dysfunction. (C) 2007 Elsevier Ireland Ltd. All rights reserved.