RT Journal Article
SR Electronic
T1 Reversal of Multidrug Resistance-Associated Protein-Mediated Drug Resistance by the Pyridine Analog PAK-104P
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 399
OP 405
VO 51
IS 3
A1 Sumizawa, Tomoyuki
A1 Chen, Zhe-Sheng
A1 Chuman, Yutaka
A1 Seto, Kiyotomo
A1 Furukawa, Tatsuhiko
A1 Haraguchi, Misako
A1 Tani, Ayako
A1 Shudo, Norimasa
A1 Akiyama, Shin-Ichi
YR 1997
UL http://molpharm.aspetjournals.org/content/51/3/399.abstract
AB 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-pyridinecarboxylate 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 μm 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. The American Society for Pharmacology and Experimental Therapeutics