Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines

Int J Cancer. 2002 Feb 10;97(5):584-92. doi: 10.1002/ijc.10096.


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.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Carcinoma, Small Cell / chemistry
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / metabolism*
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm*
  • Etoposide / pharmacology
  • Fas Ligand Protein
  • Humans
  • Lung Neoplasms / chemistry
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Membrane Glycoproteins / analysis
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neoplasms, Experimental / chemistry
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism*
  • Oligonucleotides, Antisense / pharmacology
  • Phenotype
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation*
  • fas Receptor / analysis


  • Antineoplastic Agents
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • fas Receptor
  • Etoposide
  • Doxorubicin
  • Caspases
  • Cisplatin