Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO

1 Bisphenol A diglycidyl ether ( BADGE) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) antagonist, which is able to induce apoptosis in tumor cells independently of PPAR-gamma in caspase-dependent and - independent manners. Additionally, BADGE promotes TRAIL-induced apoptosis. 2 We report that BADGE activates via Bax and caspases-2 and - 8 both the intrinsic and extrinsic apoptotic pathways using Bid as a shunt. 3 BADGE stimulates the mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl ( Smac/ DIABLO). The release of cytochrome c could not be blocked by inhibitors of caspases-3, - 8 and - 9 indicating that BADGE acts upstream of caspases-3 and - 9 and does not involve caspase-8 to release cytochrome c. 4 While the caspase-independent apoptotic effect might be mediated by AIF, the sensitizing effect of BADGE against other apoptotic substances is most likely mediated by the X-linked inhibitor of apoptosis inhibitor Smac/ DIABLO. 5 Our data suggest that BADGE or BADGE derivatives could represent promising substances for the treatment of neoplasms improving the antitumoral activity of TRAIL.