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-8–5 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.
Footnotes
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Send reprint requests to: Dr. Shin-ichi Akiyama, Institute for Cancer Research, Kagoshima University, 8–35-1 Sakuragaoka, Kagoshima 890, Japan. E-mail:akiyamas{at}khosp2.kufm.kagoshima-u.ac.jp
- Abbreviations:
- MDR
- multidrug resistance (or resistant)
- P-Gp
- P-glycoprotein
- LTC4
- leukotriene C4
- LTD4
- leukotriene D4
- MRP
- multidrug resistance-associated protein
- GS-X pump
- ATP-dependent glutathioneS-conjugate export pump
- ADM
- doxorubicin
- HRP
- horseradish peroxidase
- PVDF
- polyvinylidene difluoride
- VCR
- vincristine
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- PBS
- phosphate-buffered saline
- SSC
- standard saline citrate
- SDS
- sodium dodecyl sulfate
- Received May 21, 1996.
- Accepted October 23, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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