Potentiation of doxorubicin cytotoxicity by the calcium antagonist bepridil in anthracycline-resistant and-sensitive cell lines - A comparison with verapamil

The ability of the calcium channel blocker bepridil (Bp) to potentiate doxorubicin (Dx) cytotoxicity and enhance its accumulation in anthracycline-sensitive and resistant human ovarian carcinoma cells (A2780 and 2780^AD) and Chinese hamster ovarian (CHO) cells (AUXB1 and CH^RC5) was compared with that of verapamil (Vp). A continuous exposure (48-72 h) to Bp as well as Vp potentiated Dx cytotoxicity in 2780^AD cells. In shortterm incubations (2 h Dx and 4 h calcium channel blocker) the same effects were observed: 4 μM Bp (4Bp) and Vp (4Vp) were equipotent, but at concentrations of 1 and 2 μM, Vp was more active (4Vp=4Bp>2Vp>2Bp>1Vp>1Bp). In CH^RC5 cells the corresponding sequence was: 4Vp>4Bp>2Vp>2Bp>1Vp>1Bp. At high (marginally inhibitory) concentrations, Bp and Vp reversed Dx resistance completely in CH^RC5 cells and partly in 2780^AD cells. No significant potentiation of Dx cytotoxicity by Bp or Vp was found in A2780 cells, but both were active in AUXB1 cells. In studies with radiolabelled Dx (2 μM), Bp and Vp (16.5 μM) stimulated accumulation in CH^RC5 cells almost up to the level in AUXB1 cells. Dx accumulation in 2780^AD cells (52 pmol/10⁶ cells) could be stimulated to a maximum of about 90 pmol/10⁶ cells (drug level in A2780 cells was 153 pmol/10⁶ cells). Also, Bp- and Vp-induced stimulation of Dx accumulation was observed in AUXB1, but not in A2780 cells. Bp effected a dose-dependent inhibition of Dx efflux from preloaded 2780^AD cells, but not from A2780 cells. We conclude that Bp is more effective than Vp in reversing resistance when both compounds are used in vitro at concentrations which are clinically achievable in plasma.