Reversal effects of several Ca(2+)-entry blockers, neuroleptics and local anaesthetics on P-glycoprotein-mediated vincristine resistance of L1210/VCR mouse leukaemic cell line

Drugs Exp Clin Res. 1994;20(1):13-8.

Abstract

The ability of several Ca(2+)-entry blockers, neuroleptics and local anaesthetics to depress the P-glycoprotein-mediated resistance to vincristine was studied in vitro using the L1210/VCR cell line. This cell line was obtained by long-term adaptation of the L1210 mouse leukaemic cell line on vincristine and showed an overexpression of P-glycoprotein and accompanying multidrug resistance (MDR) which was defined as a cell resistance to several cytostatics such as vincristine, vinblastine and actinomycin D. Efficiency of the drugs applied to reverse this resistance was as follows: for Ca(2+)-entry blockers: verapamil (VER) > or = galopamil (GAL) > flunarizine (FLU) >> diltiazem (DIL) > nimodipine (NIM) > or = nifedipine (NIM); for neuroleptics: trifluoperazine (TFP) > chlorpromazine (CHP) > thioridazine (TRD) > perphenazine (PER); for local anaesthetics: carbanilate-Ca7 > cinchocaine (CIN) >> carbanilate-Ca3 > articaine (ART) > carbanilate CAO > lidocaine (LID). Quaternary cabanilate derivatives (Ca7Q and Ca3Q) with permanent positive charge were found to be unable to reverse the vincristine resistance of L1210/VCR cells. No reasonable correlation between the ability of calcium-entry blockers (DIL, VER, GAL, NIF, NIM and FLU) to reduce the viability of L1210/VCR cells growing in the medium supplemented with vincristine and their reported affinity to the L-type of calcium channel was observed. On the other hand, significant positive correlations were observed between both the inhibitory action of local anaesthetics on propagation of action potential in rat sciatic nerve and the ability of drugs to interact with calmodulin and the ability of the respective drug to reverse the resistance of L1210 cells to vincristine.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Action Potentials / drug effects
  • Anesthetics, Local / pharmacokinetics
  • Anesthetics, Local / pharmacology*
  • Animals
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology*
  • Calcium Channel Blockers / pharmacokinetics
  • Calcium Channel Blockers / pharmacology*
  • Calmodulin / metabolism
  • Cell Line
  • Drug Resistance
  • Leukemia L1210 / drug therapy*
  • Mice
  • Neoplasm Proteins / physiology*
  • Protein Binding
  • Sciatic Nerve / drug effects
  • Vincristine / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anesthetics, Local
  • Antipsychotic Agents
  • Calcium Channel Blockers
  • Calmodulin
  • Neoplasm Proteins
  • Vincristine