Relationship between cytotoxicity, drug accumulation, DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933

Cancer Chemother Pharmacol. 1989;25(2):77-83. doi: 10.1007/BF00692343.

Abstract

The effect of N-(3,4-dimethoxyphenyl) N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 microM as compared with 10 microM verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium Channel Blockers / therapeutic use*
  • Calcium Channel Blockers / toxicity
  • Cell Line / drug effects
  • Cell Line / metabolism
  • Cell Line / radiation effects
  • DNA Damage*
  • DNA Repair / drug effects*
  • DNA Repair / radiation effects
  • DNA, Neoplasm / analysis
  • DNA, Neoplasm / drug effects*
  • DNA, Neoplasm / radiation effects
  • Dose-Response Relationship, Drug
  • Doxorubicin / antagonists & inhibitors
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Doxorubicin / toxicity*
  • Drug Interactions
  • Drug Resistance
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Propylamines / therapeutic use*
  • Propylamines / toxicity
  • Tiapamil Hydrochloride
  • Time Factors
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / radiation effects

Substances

  • Calcium Channel Blockers
  • DNA, Neoplasm
  • Propylamines
  • Doxorubicin
  • Tiapamil Hydrochloride