Bcl-2 and Bcl-XL can differentially block chemotherapy-induced cell death.
Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors and their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and gamma-irradiation. In the present report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if these survival proteins could provide equivalent protection when challenged with chemotherapy or gamma-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposide-induced cell death. In addition, Bcl-XL provided significantly greater cell viability than Bcl-2 against methotrexate, fluorouracil, and hydroxyurea, three S-phase specific agents. In apoptosis induced by gamma-irradiation and cisplatin, two antitumor treatments that are cell-cycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against gamma-irradiation, but Bcl-XL provided better protection than Bcl-2 against cisplatin. These results indicate that Bcl-XL and Bcl-2 confer a differential ability to protect against chemotherapy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase specificity.
Simonian
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PL
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor 48109, USA.
Grillot
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DA
Nuñez
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D002999:Clone Cells / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D019254:Genes, bcl-2; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016196:S Phase / Q000187:drug effects; D013713:Teniposide / Q000494:pharmacology; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D014750:Vincristine; D005047:Etoposide; D013713:Teniposide; D005472:Fluorouracil; D006918:Hydroxyurea; D008727:Methotrexate