title: ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P.
abstract: Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29. 6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance, MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 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) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 microM PAK-104P increased the accumulation of CPT-11 and SN-38 in C-A120 and KB/MRP cells to a level similar to that found in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from C-A120 and KB/MRP cells was inhibited by PAK-104P. DNA topoisomerase I expression, activity, and sensitivity to SN-38 were similar in the three cell lines. Furthermore, the conversion of CPT-11 to SN-38 in KB-3-1 and C-A120 cell lines was similar. These findings suggest that MRP transports CPT-11 and SN-38 and is involved in resistance to CPT-11 and SN-38 and that PAK-104P reverses the resistance to CPT-11 and SN-38 in tumors that overexpress MRP.
authors.affiliation: Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Z S
authors.initials: ZS
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Furukawa
authors.forename: T
authors.initials: T
authors.lastname: Sumizawa
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: K
authors.initials: K
authors.lastname: Ueda
authors.forename: K
authors.initials: K
authors.lastname: Seto
authors.forename: S I
authors.initials: SI
authors.lastname: Akiyama
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000502:physiology; D027321:Anion Transport Proteins; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000378:metabolism; D003498:Cyclic P-Oxides / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000032:analysis; D018432:Drug Resistance, Multiple / Q000502:physiology; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000032:analysis; D006801:Humans; D000077146:Irinotecan; D007527:Isoenzymes / Q000032:analysis; D007624:KB Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D027321:Anion Transport Proteins; D000972:Antineoplastic Agents, Phytogenic; D019328:Buthionine Sulfoximine; D002166:Camptothecin; D002352:Carrier Proteins; D003470:Culture Media; D003498:Cyclic P-Oxides; D004264:DNA Topoisomerases, Type I; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D000077146:Irinotecan; D007527:Isoenzymes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids; D011422:Propionates; D011804:Quinolines; C103821:PAK 104P; C059141:verlukast; C496556:GSTP1 protein, human