Pro-apoptotic treatment with an adenovirus encoding Bax enhances the effect of chemotherapy in ovarian cancer

Background: Tumor cell heterogeneity and resistance to chemotherapy-mediated cell death are major obstacles in cancer therapy. It has been reported that expression of the pro-apoptotic molecule Bax can induce cell death or sensitize tumor cells to chemotherapy in stable cell clones derived from tumor cells. However, these studies are limited in that they cannot represent the heterogeneity of cancer cells observed in vivo. In this study, we have further explored the therapeutic potential of Bax. Methods: Using an inducible recombinant Bax adenovirus, we screened a panel of ovarian cancer cell lines and primary patient-derived ovarian tumor cells for their sensitivity to Bax-mediated cytotoxicity. Apoptotic cell death was evaluated qualitatively with Hoechst staining and quantitatively with MTS and Annexin V-based assays. Endogenous levels of both Bcl-2 and Bax protein and p53 status were evaluated. The potential of bax to sensitize ovarian cancer lines to chemotherapy was also tested. Dose-response curves were generated to evaluate cell death. Results: Overexpression of Bax directly induced apoptosis in both ovarian cancer cell lines and the patient-derived primary cancer cells. However, the sensitivity of these cells to Bax varied and appeared to be independent of both the status of p53 and the endogenous levels of bcl-2 or Bax, critical molecules in the apoptotic pathway. Importantly, overexpression of Bax significantly enhanced chemotherapy-induced cytotoxicity in both established cell lines and primary ovarian carcinoma cells. Conclusions: These studies suggest that overexpression of Bax alone or in combination with chemotherapy may provide a means to overcome the problems imposed by the heterogeneous nature of tumors, ultimately augmenting the efficacy of chemotherapy in patients suffering from ovarian cancer. Copyright (C) 2000 John Wiley & Sons, Ltd.