Alteration in p53 pathway and defect in apoptosis contribute independently to cisplatin-resistance

Cell Death Differ. 1998 May;5(5):390-400. doi: 10.1038/sj.cdd.4400357.


The accumulation of molecular genetic defects selected during the adaptation process in the development of cisplatin-resistance was studied using progressive cisplatin-resistant variants (L1210/DDP2, L1210/DDP5, L1210/DDP10) derived from a murine leukemia cell line (L1210/0). Of these cell lines, only the most resistant L1210/DDP10 was cross-resistant to etoposide and deficient in apoptosis induced by these two drugs, indicating that resistance to DNA-damaging agents correlates with a defect in apoptosis. This defect was tightly associated with the loss of a Ca2+/Mg2+-dependent nuclear endonuclease activity present in the less cisplatin-resistant cells. Evidence is presented that p53-dependent function (a) is lost not only in the apoptosis defective L1210/DDP10 cells, but also in the apoptosis susceptible L1210/DDP5 cells; (b) is unrelated to drug-induced cell cycle perturbations. These results suggest that deficiency in the p53 pathway and resistance to DNA-damaging agents due to a defect in apoptosis are independent events.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cisplatin / pharmacology*
  • Cyclin B / metabolism
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • DNA Fragmentation / drug effects
  • Drug Resistance / genetics*
  • Endonucleases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Etoposide / pharmacology
  • Fluorescein-5-isothiocyanate
  • Gene Expression Regulation, Neoplastic
  • Mice
  • Nuclear Proteins / metabolism
  • Staurosporine / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics*


  • Annexin A5
  • Ccnb1 protein, mouse
  • Cdkn1a protein, mouse
  • Cyclin B
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • Etoposide
  • Endonucleases
  • Staurosporine
  • Fluorescein-5-isothiocyanate
  • Cisplatin