Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase, H-87.
A newly synthesized compound, H-87, N-[2-(p-bromo cinnamylmethylamino)ethyl]-5-isoquinolinesulfonamide was found to be a potent and selective inhibitor of cyclic AMP-dependent protein kinase. The effects of H-87 on in vitro sensitivities of various P388 murine leukemia cell lines resistant to several antitumor agents were examined. H-87 significantly potentiated the cytotoxic effects of Adriamycin (ADR), daunorubicin (DAU), vincristine (VCR) and vinblastine (VBL) on P388 cells resistant to these antitumor agents but hardly influenced the effects of mitomycin C (MMC), 5-fluorouracil (5-FU) and cisplatin (CDDP) on ADR-resistant P388 cells (P388/ADR) and P388 phenotypes resistant to the corresponding antitumor agents. H-87 promoted the accumulation of VBL much more in P388/ADR cells than in the sensitive cells by inhibiting the energy-dependent extrusion of the antitumor agent from the cells. These results suggest that this novel isoquinoline-sulfonamide derivative, H-87, overcomes the multidrug resistance by inhibiting the phosphorylation of an outward drug transport system through cyclic AMP-dependent protein kinase.
Miyamoto
K
K
Research Laboratory for Development of Medicine, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Wakusawa
S
S
Nakamura
S
S
Koshiura
R
R
Otsuka
K
K
Naito
K
K
Hagiwara
M
M
Hidaka
H
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001692:Biological Transport / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D007941:Leukemia P388 / Q000188:drug therapy* / Q000235:genetics; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014747:Vinblastine; D004317:Doxorubicin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide