RIFAMPICIN ENHANCES ANTICANCER DRUG ACCUMULATION AND ACTIVITY IN MULTIDRUG-RESISTANT CELLS

Rifampicin, a semi-synthetic antibiotic used in the treatment of tuber culosis and belonging to the chemical class of rifamycins, was examine d for its effect on anti-cancer drug accumulation and activity in mult idrug resistant cells overexpressing P-glycoprotein (P-gp). Rifampicin was shown to strongly enhance vinblastine accumulation in both rat he patoma RHC1 and human leukemia K562 R7 multidrug resistant cells, but had no effect in rat SDVI drug-sensitive liver cells. By contrast, two other rifamycins, rifamycins B and SV, had no or only minor effect on vinblastine accumulation in RHC1 cells. Efflux experiments revealed t hat rifampicin was able, like the well-known chemosensitizer agent ver apamil, to decrease export of vinblastine out of resistant cells. Rifa mpicin, when used at a concentration close to plasma concentrations ac hievable in humans (25 mu M), was able to increase sensitivity of RHC1 cells to both vinblastine and doxorubicin. Rifampicin was also demons trated to inhibit P-gp radiolabeling by the photoactivable P-gp ligand azidopine, thereby suggesting that the antituberculosis compound can interfere directly with P-gp drug binding sites. These results thus in dicate that rifampicin was able to down-modulate P-gp-associated resis tance through inhibition of P-gp function.