BAD PARTLY REVERSES PACLITAXEL RESISTANCE IN HUMAN OVARIAN-CANCER CELLS

Although paclitaxel is an important chemotherapy agent for the treatme nt of patients with epithelial ovarian cancer, its utility is signific antly limited by the frequent development of drug resistance, Recent e vidence suggests that resistance to chemotherapy may be partly related to defects in the apoptotic pathway. In this study me have investigat ed whether enhancement of apoptotic pathway function through stable ex pression of the BAD protein is capable of sensitizing human epithelial ovarian cancer cells to the effects of chemotherapy. Expression of HA -BAD in sis separate clonal transfectants from two different ovarian c ancer cell lines was found to significantly enhance the cytotoxic effe cts of paclitaxel, vincristine, and, to a lesser extent, etoposide, En hancement of paclitaxel-induced apoptosis in HA-BAD-expressing clones was demonstrated by trypan blue exclusion, clonogenic cell assay, and flow cytometric evaluation. Importantly, this effect was associated wi th binding of HA-BAD to BCL-x(L) and concomitant disruption of BAX:BCL -x(L) interaction. Taken together, these data suggest that the develop ment of small molecules which mimic the effects of BAD may represent a new class of drugs capable of preventing or reversing resistance to c hemotherapy agents such as paclitaxel.