Exploiting bcl-2 Overexpression in the Chemotherapy of Breast Cancer
Final rept. 1 Jun 1997-31 May 2000
CHILDREN'S HOSPITAL OF PITTSBURGH PA
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Previous studies have demonstrated that exposure of estrogen-responsive breast cancer cells in culture to estrogen leads to overexpression of bcl-2. Contrary to the case for apoptosis induced by conventional anticancer drugs, bcl-2 overexpression potentiates apoptosis induction by neocarzinostatin in neural crest tumor cells. We therefore examined the effects of neocarzinostatin on bc-2- overexpressing breast cancer cells in culture. Unlike the case for neural crest tumor cells, overexpression of bcl-2 in MCF-7 cells did not afford potentiation of apoptosis induction by the reduction-dependent enediyne neocarzinostatin. Instead, MCF-7 cells were protected from apoptosis induced by neocarzinostatin. Two critical mechanistic differences have been discovered to relate to this finding. While bcl-2 overexpression in neural crest tumor cells leads to alteration of glutathione handling in the direction of greater reducing potential, bcl-2 overexpression in MCF-7 cells does not alter cellular redox potential or glutathione handling. Furthermore, neocarzinostatin treatment of neural crest tumor cells results in conversion of Bcl-2 protein to its pro-apoptotic cleavage products. This enzymatic cleavage is induced by caspase 3, an enzyme that is not expressed in MCF-7 cells. Predictably, only apoptosis induced by neocarzinostatin in neural crest tumor cells is inhibited by an inhibitor of caspase 3 activity.
- Anatomy and Physiology
- Medicine and Medical Research