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.
We assessed the effect of the protein kinase C inhibitor 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)hexanami de (NPC 15437) on the action of anthracyclines, epipodophyllotoxins and vinca alkaloids in P-glycoprotein (Pgp)-expressing CH(R)C5 hamster ovary and MCF-7/Adria(R) human breast cancer cells. Flow microfluorimetry revealed that treatment of CH(R)C5 cells with 75 microM NPC 15437 for 1 h resulted in a 6- to 10-fold increase in the nuclear accumulation of daunorubicin. Colony forming assays revealed that treatment with 75 microM NPC 15437 was associated with a 4-fold decrease in the LD90 for etoposide and a 2.5-fold decrease in the LD50 for vincristine. At higher concentrations of NPC 15437, greater modulation of anthracycline accumulation was observed; but NPC 15437 itself inhibited subsequent colony formation. Similar effects on drug accumulation and cytotoxicity were observed in MCF-7/Adria(R) cells. Experiments designed to investigate the mechanism by which NPC 15437 exerts these effects revealed that treatment with the protein kinase C activator phorbol-12-myristate 12-acetate partially reversed the effect of NPC 15437, suggesting that NPC 15437 was exerting an effect through protein kinase C. Photoaffinity labeling experiments revealed that NPC 15437 also inhibited the binding of [3H]-azidopine to Pgp in isolated membrane vesicles. These results identify NPC 15437 [correction of NPC15437] as the prototype of a new class of potential Pgp modulators but indicate that the effects of this agent as a modulator are potentially limited by its cytotoxicity.
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Johns Hopkins Oncology Center and Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
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Kaufmann
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D010880:Piperidines; C069701:NPC 15437; D011493:Protein Kinase C