p21Waf1/Cip1 acts in synergy with bcl-2 to confer multidrug resistance in a camptothecin-selected human lung-cancer cell line

Int J Cancer. 1999 Dec 10;83(6):790-7. doi: 10.1002/(sici)1097-0215(19991210)83:6<790::aid-ijc15>3.0.co;2-6.


The realization that chemotherapeutic agents induce apoptosis raises the concern that tumors resistant to chemotherapy are unable to initiate the apoptotic program. In the present study, we examined the apoptosis-resistance mechanism of a multidrug-resistant cell line, A549/CPT, which was established from the human lung-cancer cell line A549 by in vitro selection with gradually increased camptothecin (CPT) concentrations. We found that A549/CPT cells were resistant to anti-cancer drug-induced apoptosis in which caspase-3-like protease activity was attenuated remarkably, compared with parental A549 cells. We observed 2 mechanisms associated with apoptosis resistance in A549/CPT cells: over-expression of anti-apoptotic bcl-2 and elevated expression of p21Waf1/Cip1. Transfection of either bcl-2 or p21Waf1/Cip1 cDNA into parental A549 cells resulted in resistance to apoptosis. Furthermore, the co-treatment of p21Waf1/Cip1 and bcl-2 anti-sense oligodeoxy-nucleotides restored drug susceptibility in A549/CPT cells more effectively than either one of them alone. These results indicate that co-induction of bcl-2 and p21Waf1/Cip1 in A549/CPT cells may be involved in acquired drug resistance by inhibiting caspase-mediated apoptosis. Agents aimed at preventing both bcl-2 and p21Waf1/Cip1 expression may increase the efficiency of chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Camptothecin / toxicity*
  • Caspase 3
  • Caspase Inhibitors
  • Cisplatin / toxicity
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Drug Resistance, Multiple*
  • Enzyme Inhibitors / metabolism
  • Genes, bcl-2*
  • Humans
  • Kinetics
  • Lung Neoplasms
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Proteins / metabolism
  • Transfection
  • Tumor Cells, Cultured


  • CDKN1A protein, human
  • Caspase Inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Oligodeoxyribonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • CASP3 protein, human
  • Caspase 3
  • Cisplatin
  • Camptothecin