@article {Sumizawa399, author = {Tomoyuki Sumizawa and Zhe-Sheng Chen and Yutaka Chuman and Kiyotomo Seto and Tatsuhiko Furukawa and Misako Haraguchi and Ayako Tani and Norimasa Shudo and Shin-Ichi Akiyama}, title = {Reversal of Multidrug Resistance-Associated Protein-Mediated Drug Resistance by the Pyridine Analog PAK-104P}, volume = {51}, number = {3}, pages = {399--405}, year = {1997}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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-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{\textendash}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{\textendash}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}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/51/3/399}, eprint = {https://molpharm.aspetjournals.org/content/51/3/399.full.pdf}, journal = {Molecular Pharmacology} }