Resistance to apoptosis plays an important role in tumors that are refractory to chemotherapy. We report that Bcl-xL, which functions like Bcl-2 to inhibit apoptosis, is highly expressed in MCF-7 human breast carcinoma cells. We used Bcl-xS, a dominant negative inhibitor of Bcl-2 and Bcl-xL, to demonstrate the role of these genes in modulating chemotherapy-induced apoptosis. Bcl-xS overexpressed in MCF-7 cells by stable transfection does not affect viability by itself but induces a marked increase in chemosensitivity to VP-16 or taxol. Using an ELISA assay which quantitates DNA damage, we demonstrate that this sensitization is due to apoptosis, suggesting the therapeutic utility of targeting this pathway.
This research was supported by NIH Grants CA-61777 and CA-64556, and American Cancer Society Grant BE-161C. G. N. is supported by NIH Research Career Development Award K04 CA64421-01.