Dual modes of death induced by etoposide in human epithelial tumor cells allow Bcl-2 to inhibit apoptosis without affecting clonogenic survival.
The Bcl-2 oncoprotein, which is expressed in a variety of human malignancies, blocks apoptosis induced by chemotherapeutic drugs, including the topoisomerase II inhibitor, etoposide. To determine the significance of Bcl-2 in etoposide-induced death of human epithelial tumor cells, HeLa S3 cells were transfected with human bcl-2 cDNA in the pSFFV expression vector, and stable Bcl-2-expressing clones established. In agreement with previous studies, Bcl-2 inhibited loss of cell viability (by trypan blue exclusion), the appearance of morphologically apoptotic cells, and the amount of low molecular weight DNA extracted after etoposide exposure (25 microns, 4 h). The degree of inhibition, compared to wild-type and vector control-transfected clones, differed according to the level of Bcl-2 protein expressed in the two clones studied. However, when cell survival was assessed by colony-forming assays, no significant differences were detected at any of the etoposide concentrations used. Although Bcl-2 inhibited etoposide-induced apoptosis, it had no effect on the formation of giant, multinucleated cells characteristic of mitotic catastrophe. Consequently, the ability of Bcl-2 to prevent apoptosis caused by chemotherapeutic drugs may not necessarily translate into increased survival of cells that express Bcl-2.
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Henry Vogt Cancer Research Institute, J. Graham Brown Cancer Center, Department of Medicine, University of Louisville, Kentucky 40292, USA.
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D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005047:Etoposide / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005047:Etoposide