POTENTIATION OF ENEDIYNE-INDUCED APOPTOSIS AND DIFFERENTIATION BY BCL-2

Bcl-2 overexpression has been shown to be protective against apoptosis induced by a variety of mechanistically diverse chemotherapeutic drug s. Recently, oxygen radical species have been implicated in the proces s of apoptosis, and Bcl-2 has been proposed to exert its protective ef fect by altering the redox state of the cell. Unlike most other chemot herapeutic agents, naturally occurring enediynes are rendered more cyt otoxic in the presence of a higher reducing potential, because as prod rugs, they require reduction for activation. We demonstrate herein tha t induction of Bcl-2 expression in PC12 cells potentiates the inductio n of apoptosis and differentiation by the enediyne neocarzinostatin. I n contradistinction, Bcl-2 abrogates the induction of apoptosis and di fferentiation by the autoactivating enediyne, enediyne-5, and the non- enediyne chemotherapeutic agent, cisplatin. We further demonstrate tha t enediyne potentiation by Bcl-2 is related to an increase in cellular glutathione. The present studies suggest that enediynes that require reductive activation might be critically useful agents in the therapy of tumors such as neuroblastomas and estrogen-responsive breast cancer s, the resistance of which is related to up-regulation of Bcl-2.