BAD partly reverses paclitaxel resistance in human ovarian cancer cells.
Although paclitaxel is an important chemotherapy agent for the treatment of patients with epithelial ovarian cancer, its utility is significantly limited by the frequent development of drug resistance. Recent evidence suggests that resistance to chemotherapy may be partly related to defects in the apoptotic pathway. In this study we have investigated whether enhancement of apoptotic pathway function through stable expression of the BAD protein is capable of sensitizing human epithelial ovarian cancer cells to the effects of chemotherapy. Expression of HA-BAD in six separate clonal transfectants from two different ovarian cancer cell lines was found to significantly enhance the cytotoxic effects of paclitaxel, vincristine, and, to a lesser extent, etoposide. Enhancement 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 with binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction. Taken together, these data suggest that the development of small molecules which mimic the effects of BAD may represent a new class of drugs capable of preventing or reversing resistance to chemotherapy agents such as paclitaxel.
Strobel
T
T
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Tai
Y T
YT
Korsmeyer
S
S
Cannistra
S A
SA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D001202:Ascitic Fluid / Q000166:cytology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002999:Clone Cells / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000473:pathology*; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051025:bcl-Associated Death Protein
D000972:Antineoplastic Agents, Phytogenic; C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D051025:bcl-Associated Death Protein; D017239:Paclitaxel