Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P.
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.
Sumizawa
T
T
Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Japan.
Chen
Z S
ZS
Chuman
Y
Y
Seto
K
K
Furukawa
T
T
Haraguchi
M
M
Tani
A
A
Shudo
N
N
Akiyama
S I
SI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000470:Alkaloids / Q000494:pharmacology; D044182:Benzylisoquinolines; D003498:Cyclic P-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D052117:Benzodioxoles
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000470:Alkaloids; D044182:Benzylisoquinolines; D003498:Cyclic P-Oxides; D004250:DNA Topoisomerases, Type II; D004317:Doxorubicin; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids; D012333:RNA, Messenger; D014700:Verapamil; D014750:Vincristine; C103821:PAK 104P; C006947:cepharanthine; D052117:Benzodioxoles