Drug resistance towards etoposide and cisplatin in human melanoma cells is associated with drug-dependent apoptosis deficiency

J Invest Dermatol. 2002 Jun;118(6):923-32. doi: 10.1046/j.1523-1747.2002.01786.x.


Anticancer drugs kill susceptible cells through induction of apoptosis. Alterations of apoptotic pathways in drug-resistant tumor cells leading to apoptosis deficiency might represent a potent mechanism conferring drug resistance. We have assessed the effect of etoposide and cisplatin on the apoptotic pathways of the drug-sensitive human melanoma cell line MeWo as well as its etoposide- and cisplatin-resistant sublines (MeWo(Eto01), MeWo(Eto1), (and) MeWoCis01, MeWo(Cis1)). Etoposide and cisplatin induced apoptosis in drug-sensitive MeWo cells as indicated by dose-dependent (i) cytochrome c release, (ii) caspase activation, (iii) DNA fragmentation, and (iv) cleavage of poly(ADP-ribose)polymerase. In contrast, whereas low etoposide-resistant cells (MeWo(Eto01)) demonstrated reduced but detectable apoptotic activities, highly etoposide-resistant cells (MeWo(Eto1)) did not exhibit any of the apoptotic events observed in etoposide-induced cell death downstream of a strongly reduced cytochrome c release. Highly cisplatin-resistant cells (MeWo(Cis1)), however, demonstrated a reduced caspase 9 activity and cytochrome c release but the extent of effector caspase activation as well as DNA fragmentation was comparable to that of sensitive MeWo cells at equitoxic concentrations. In addition, poly(ADP-ribose)polymerase cleavage was strongly reduced in highly cisplatin-resistant sublines. Taken together, sensitive and drug-resistant MeWo cells utilized different apoptotic pathways upon drug exposure in a drug-dependent fashion and apoptosis deficiency was strongly associated with the drug-resistant phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Caspases / genetics
  • Caspases / immunology
  • Caspases / metabolism
  • Cisplatin / pharmacology*
  • Coumarins / metabolism
  • Coumarins / pharmacology
  • Cytochrome c Group / metabolism
  • DNA Fragmentation / drug effects*
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • Etoposide / pharmacology*
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma*
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Poly(ADP-ribose) Polymerases / metabolism
  • RNA, Messenger / analysis
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Coumarins
  • Cytochrome c Group
  • Peptide Fragments
  • RNA, Messenger
  • 7-amino-4-trifluoromethylcoumarin
  • Etoposide
  • Poly(ADP-ribose) Polymerases
  • Caspases
  • Cisplatin