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.