Novel multidrug-resistance modulators, KR-30026 and KR-30031, in cancer cells.

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.