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bcl-2 Protein Inhibits Etoposide-induced Apoptosis through Its Effects on Events Subsequent to Topoisomerase II-induced DNA Strand Breaks and Their Repair¹

Department of Pathology [S. K., H. K., J. C.] and Radiation Medicine [T. J. J.], Georgetown University School of Medicine, Washington, D.C. 20007, and Laboratory of Molecular Pharmacology [A. T., Y. P.], Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Previous studies have shown that bcl-2 overexpression can inhibit apoptosis induced by DNA-damaging agents widely used in cancer chemotherapy, including X-irradiation, alkylating agents (hydroperoxycyclophosphamide, etc.), and topoisomerase II inhibitors (etoposide, etc.). However, little is known about the mechanism by which bcl-2 overexpression inhibits apoptosis triggered by these agents. In this study, we examined whether bcl-2 overexpression could have effects on etoposide-induced DNA damage and its repair. For these experiments, we developed CH31 clones (mouse B-cells) stably transfected with human bcl-2 sense plasmids and compared these clones with a parental CH31 clone or CH31 clones with antisense plasmids. Overexpression of bcl-2 protein inhibited etoposide-induced apoptosis and cytotoxicity. However, there was no or little difference in the production and repair of DNa-protein cross-links, DNA single-strand breaks, and double-strand breaks among a parental CH31 clone and CH31 clones with human bcl-2 sense or antisense plasmids. These findings indicate that (a) apoptosis or cytotoxicity induced by etoposide can be separated into early events (formation of double-strand breaks, DNA single-strand breaks, and double-strand breaks) and later events (secondary DNA fragmentation or cell death) and (b) bcl-2 inhibits apoptosis and cytotoxicity induced by etoposide at some steps between these events.

¹ This work was supported by grants to J. C. (ACS-PDT428) and T. J. J. (CA-48716).

² To whom requests for reprints should be addressed, at Department of Pathology, Georgetown University School of Medicine, 3900 Reservoir Road, N.W., Washington, DC 20007.

Received 3/ 8/93. Accepted 7/12/93.

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