Evaluation of 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)- hexanamide (NPC 15437), a protein kinase C inhibitor, as a modulator of P-glycoprotein-mediated resistance in vitro.

摘要: We assessed the effect of protein kinase C inhibitor 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl] methyl)hexanamide (NPC 15437) on action anthracyclines, epipodophyllotoxins and vinca alkaloids in P-glycoprotein (Pgp)-expressing CHRC5 hamster ovary MCF-7/AdriaR human breast cancer cells. Flow microfluorimetry revealed that treatment cells with 75 μM NPC 15437 for 1 h resulted a 6- to 10-fold increase nuclear accumulation daunorubicin. Colony forming assays was associated 4-fold decrease LD90 etoposide 2.5-fold LD50 vincristine. At higher concentrations 15437, greater modulation anthracycline observed; but itself inhibited subsequent colony formation. Similar effects drug cytotoxicity were observed Experiments designed investigate mechanism by which exerts these activator phorbol-12-myristate 12-acetate partially reversed suggesting exerting an through C. Photoaffinity labeling experiments also binding [3H]-azidopine Pgp isolated membrane vesicles. These results identify as prototype new class potential modulators indicate this agent modulator are potentially limited its cytotoxicity.