Long-lasting accumulation of vinblastine in inostamycin-treated multidrug-resistant KB cells

Inostamycin, a novel polyether compound, reverses multidrug resistance in KB cells. The mechanism of its action was studied by use of radioactively labeled vinblastine. Inostamycin dose-dependently increased the accumulation of [3H]vinblastine in multidrug-resistant KB-C4 cells at 0.5-2 micrograms/ml, while it did not enhance accumulation in the drug-sensitive KB-3-1 cells. At a concentration of 1 microgram/ml inostamycin inhibited active [3H]vinblastine efflux from KB-C4 cells, but not from KB-3-1 cells, and inhibited [3H]vinblastine binding to KB-C4 membranes with an IC50 of 0.94 microgram/ml (1.3 microM). Furthermore, [3H]vinblastine accumulated by treatment with 1 microgram/ml of inostamycin was resistant to efflux from KB-C4 cells, even after the removal of inostamycin.