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.
Aoki
S
S
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Chen
Z S
ZS
Higasiyama
K
K
Setiawan
A
A
Akiyama
S
S
Kobayashi
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007624:KB Cells / Q000187:drug effects* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate; D013261:Sterols / Q000138:chemical synthesis / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D003078:Colchicine; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012967:Sodium Dodecyl Sulfate; D013261:Sterols; D014750:Vincristine; C420962:4-deacetoxyagosterol; C429345:agosterol A; C421109:multidrug resistance-associated protein 1