Expression of Bcl-xL Can Confer a Multidrug Resistance Phenotype

It has been suggested that genes that regulate apoptotic cell death may play an important role in determining the sensitivity of tumor cells to chemotherapy. We have recently cloned a member of the bcl-2 family, bcl-x. To test whether bcl-x_L expression affects the sensitivity of tumor cells to chemotherapy, we have created stable cell lines overexpressing bcl-x_L and have tested these cells for resistance to cell death induced by metabolic inhibitors and chemotherapeutic agents. Bcl-x_L expression dramatically reduces the cytotoxicity of bleomycin, cisplatin, etoposide, vincristine, hygromycin B, and mycophenolic acid for up to 4 days in culture. Bcl-x_L does not prevent cells from undergoing cell cycle arrest in response to these drugs, but rather prevents treated cells from undergoing apoptosis. Cell-cycle analysis on cells treated with the chemotherapeutic agents bleomycin, cisplatin, etoposide, and vincristine, show that the drugs cause growth arrest in different positions within the cell cycle. Bcl-x_L expressing cells treated with chemotherapeutic drugs retain their proliferative ability after the drugs are removed. Interestingly, vincristine-treated cells expressing bcl-x_L become polyploid after drug removal. These data show that bcl-x_L protects cells from a wide variety of apoptotic stimuli, acts in multiple positions within the cell cycle, and confers a multidrug resistance phenotype. The ability of bcl-x_L to prevent apoptotic cell death in response to chemotherapy-induced DNA damage and cell-cycle arrest may contribute to the accumulation of chromosomal aberrations within tumors. The expression of bcl-x_L in tumor cells is likely to be an important indicator of chemotherapeutic efficacy.