Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P.

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Sumizawa T, Chen ZS, Chuman Y, Seto K, Furukawa T, Haraguchi M, Tani A, Shudo N, Akiyama SI

Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P.

Mol Pharmacol. 1997 Mar;51(3):399-405.

PubMed ID

9058594 [ View in PubMed

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Abstract

Three agents, verapamil, cepharanthine, and 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1, 3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-py ridinecarboxylate P-oxide (PAK-104P), that reverse drug resistance in P-glycoprotein (P-Gp)-mediated multidrug-resistant cells were examined for their activity to reverse drug resistance in multidrug resistance-associated protein (MRP)-mediated multidrug-resistant C-A120 cells. Agents other than PAK-104P could not reverse the resistance to doxorubicin in C-A120 cells. PAK-104P moderately reversed the doxorubicin resistance. In contrast, PAK-104P almost completely reversed the resistance to vincristine (VCR) in C-A120 cells as well as in KB-8-5 cells, and other agents moderately reversed the VCR resistance in C-A120 cells. PAK-104P at 10 microM enhanced the accumulation of VCR in C-A120 cells to the level of that in KB-3-1 cells without the agent. PAK-104P competitively inhibited the ATP-dependent [3H]leukotriene C4 uptake in membrane vesicles isolated from C-A120 cells. These findings demonstrate that PAK-104P can completely reverse the resistance to VCR in both P-Gp- and MRP-mediated multidrug-resistant cells and that PAK-104P directly interacts with MRP and inhibits the transporting activity of MRP.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Vincristine	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details