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 drugs. Recently, oxygen radical species have been implicated in the process of apoptosis, and Bcl-2 has been proposed to exert its protective effect by altering the redox state of the cell. Unlike most other chemotherapeutic agents, naturally occurring enediynes are rendered more cytotoxic in the presence of a higher reducing potential, because as prodrugs, they require reduction for activation. We demonstrate herein that induction of Bcl-2 expression in PC12 cells potentiates the induction of apoptosis and differentiation by the enediyne neocarzinostatin. In contradistinction, Bcl-2 abrogates the induction of apoptosis and differentiation by the autoactivating enediyne, enediyne-5, and the non-enediyne chemotherapeutic agent, cisplatin. We further demonstrate that 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 cancers, the resistance of which is related to up-regulation of Bcl-2.