title: Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines.
abstract: Chemotherapeutic drugs eliminate cancer cells by induction of apoptosis. Resistance to chemotherapy is partly due to a decreased apoptosis rate. Here we investigated resistance to anticancer drugs in 9 small cell lung cancer (SCLC) cell lines. Apoptosis was induced by cisplatin, doxorubicin and etoposide and was found to be independent of caspase-8 expression. Since caspase-8 is essential for signal transduction of death receptor-mediated apoptosis, all known death receptor systems are thus not required for drug-induced apoptosis in SCLC. Furthermore, we found that anticancer drugs could activate the mitochondrial pathway of apoptosis without involvement of upstream caspases. Finally, by culturing 3 sensitive cell lines in subtherapeutic concentrations of etoposide, resistant cells were generated that exhibit cross-resistance to cisplatin and doxorubicin. Drug resistance was paralleled by strong upregulation of Bcl-2, which diminished apoptosis by inhibiting the loss of the mitochondrial transmembrane potential and the release of cytochrome c. The role of bcl-2 in these processes was supported by bcl-2 transfection and antisense inhibition. These results indicate that Bcl-2 contributes to drug resistance in SCLC, a finding that has profound therapeutic implications.
authors.affiliation: Tumor Immunology Program, Division of Immunogenetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Ute A
authors.initials: UA
authors.lastname: Sartorius
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000032:analysis; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D005047:Etoposide; D004317:Doxorubicin; D020169:Caspases; D002945:Cisplatin