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 (MRPl)‐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 μM concentration. Agosterol A at 3 μM 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.