The present study was performed to evaluate the ability of KR-30026 and
KR-30031 to overcome multidrug resistance (MDR) by measuring the cytotoxicity of
paclitaxel and the rate of
rhodamine accumulation, which were then compared with
verapamil. KR-30026 potentiated the
paclitaxel-induced cytotoxicity of HCT15 to over 60 fold greater than that of
verapamil, and
KR-30031 was equipotent with
verapamil (EC50: 0.00066, 0.04 and 0.05 nM at 4.0 micrograms/ml, respectively). KR-30026 and
KR-30031 were without effect on
paclitaxel-induced cytotoxicity to SK-OV-3 cells, as well as on
tamoxifen-induced cytotoxicity to HCT15, HCT15/CL02 and SK-OV-3 cells. Maximal
rhodamine accumulation by KR-30026,
KR-30031 and
verapamil were similar in HCT15 cells, while KR-30026 was more potent than
verapamil in HCT15/CL02 cells (721 and 440%, respectively). To evaluate the
cardiac toxicity of KR-30026 and
KR-30031, the changes of tension in isolated rat aorta and left ventricular pressure (LVP) in guinea pig heart were determined; KR-30026 and
KR-30031 were 15-40 and 25-70 fold less potent than
verapamil, respectively. These results suggest that KR-30026 and
KR-30031 are active modulators of MDR with potentially minimal cardiovascular toxicity.