Effects of carvedilol on MDR1 ‐mediated multidrug resistance: comparison with verapamil

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Abstract
The reversing effects of carvedilol and other β‐adrenoceptor antagonists on multidrug resistance (MDR) were assessed in HeLa cells and the MDR1‐overexpressing derivative Hvr100–6 cells, established by stepwise increases of vinblastine concentration in the culture medium. The inhibitory effects on the transcellular transport and intracellular accumulation of [3H]vinblastine and [3H]daunorubicin were also assessed using LLC‐GA5‐COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC‐PK, cells. The cytotoxic effects of vinblastine, paclitaxel, doxorubicin and daunorubicin in Hvr100–6 were reversed 1.4‐ to 7.1‐fold by carvedilol at the realistic clinical concentration of 1 μM, whereas other β‐adrenoceptor antagonists had weaker or no such effects. Transport experiments using LLC‐GA5‐COL150 cell monolayers demonstrated that this effect of carvedilol was due to the inhibition of MDR1‐mediated transport of vinblastine, paclitaxel, doxorubicin and daunorubicin. These MDR1‐mediated reversing effects of carvedilol were similar to those of 1 μM verapamil, suggesting that carvedilol could be a candidate modulator of MDR in clinical use. Since other β‐adrenoceptor antagonists had no inhibitory effect on transport, the effects of carvedilol were not related to β‐adrenoceptors and might have been due to antioxidant activity. (Cancer Sci 2003; 94: 81–86)

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