title: Expression of bcl-xL can confer a multidrug resistance phenotype.
abstract: 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-XL expression affects the sensitivity of tumor cells to chemotherapy, we have created stable cell lines overexpressing bcl-XL and have tested these cells for resistance to cell death induced by metabolic inhibitors and chemotherapeutic agents. Bcl-XL expression dramatically reduces the cytotoxicity of bleomycin, cisplatin, etoposide, vincristine, hygromycin B, and mycophenolic acid for up to 4 days in culture. Bcl-XL 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-XL expressing cells treated with chemotherapeutic drugs retain their proliferative ability after the drugs are removed. Interestingly, vincristine-treated cells expressing bcl-XL become polyploid after drug removal. These data show that bcl-XL 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-XL 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-XL in tumor cells is likely to be an important indicator of chemotherapeutic efficacy.
authors.affiliation: Gwen Knapp Center for Lupus and Immunology Research, Department of Medicine, University of Chicago, IL 60637-5420, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Minn
authors.forename: C M
authors.initials: CM
authors.lastname: Rudin
authors.forename: L H
authors.initials: LH
authors.lastname: Boise
authors.forename: C B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D051379:Mice; D005810:Multigene Family; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein