Reversing effect of agosterol A, a spongean sterol acetate, on multidrug resistance in human carcinoma cells.

The effect of agosterol A, a novel polyhydroxylated sterol acetate isolated from a marine sponge, on P-glycoprotein (P-gp)-mediated multidrug-resistant cells (KB-C2) and the multidrug resistance associated protein (MRP1)-mediated multidrug-resistant cells (KB-CV60) was examined. Agosterol A reversed the resistance to colchicine in KB-C2 cells and also the resistance to vincristine in KB-CV60 cells at 3 to 10 microM concentration. Agosterol A at 3 mM increased the vincristine concentration in both KB-C2 cells and KB-CV60 cells to the level in parental KB-3-1 cells. Agosterol A also decreased the efflux of vincristine from both KB-C2 cells and KB-CV60 cells to the level seen in KB-3-1 cells. Agosterol A inhibited the [(3)H]azidopine-photolabeling of P-gp and also inhibited the uptake of [(3)H]S-(2,4-dinitrophenyl)glutathione (DNP-SG) in inside-out membrane vesicles prepared from KB-CV60 cells. We conclude that agosterol A directly inhibited drug efflux through P-gp and/or MRP1.