Inhibition of P-glycoprotein-dependent multidrug resistance by an isoquinolinesulfonamide compound H-87 in rat ascites hepatoma AH66 cells.
The effects of an isoquinolinesulfonamide compound, H-87, on naturally acquired multidrug-resistance (MDR) in rat hepatoma AH66 cells were examined. AH66 cells were highly resistant to vinblastine, SN-38, an active camptothecin analog, adriamycin, and etoposide, compared with the sensitive variant AH66F cells. Although H-87 hardly affected the sensitivities to antitumor agents of AH66F cells, this compound completely inhibited the resistance to vinblastine, moderately inhibited the resistance to SN-38 and adriamycin and had little effect on etoposide, mitomycin C, cisplatin, and 5-fluorouracil. H-87 significantly decreased the efflux of vinblastine from the resistant cells and increased the drug accumulation. SN-38 and adriamycin also exhibited a weak but significant increase in vinblastine accumulation in AH66 cells. H-87 inhibited [3H]azidopine-photolabeling to 160 kDa P-glycoprotein in the plasma membrane of AH66 cells, as reported in acquired MDR leukemic cells. Consequently, the MDR-overcoming effect of H-87 seems to be due to its direct inhibition of the binding of antitumor agents on P-glycoprotein in the plasma membrane.
Nakamura
S
S
Fujiyakuhin Co., Ltd., Ohmiya, Japan.
Minamino
T
T
Nomura
M
M
Wakusawa
S
S
Miyamoto
K
K
Hidaka
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000345:Affinity Labels; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001386:Azides / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D000077146:Irinotecan; D007546:Isoquinolines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D051381:Rats; D013449:Sulfonamides; D014316:Tritium; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014316:Tritium; D014747:Vinblastine; C041130:azidopine; D005047:Etoposide; D000077146:Irinotecan; D004317:Doxorubicin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002166:Camptothecin