Indomethacin overcomes doxorubicin resistance with inhibiting multi-drug resistance protein 1 (MRP1).
Drug resistance continues to be a serious problem in cancer therapy. We investigated whether indomethacin, which inhibited cyclooxygenases, would overcome doxorubicin resistance in K562/ADR leukemia cells. Indomethacin at 10 muM increased the cytotoxicity of doxorubicin, as well as vincristine in K562/ADR. Both multi-drug resistant protein1 (MRP1) and P-glycoprotein were overexpressed in K562/ADR cells when compared with K562 parent cells (K562/P). Expression of MRP1 mRNA and protein, but not P-glycoprotein, was significantly decreased in K562/ADR cells after indomethacin treatment. Indomethacin treatment increased 5(6)-carboxyfluorescein diacetate (CFDA) efflux, as well as decreased accumulation in K562/ADR cells. The activity of the MRP1 promoter decreased after indomethacin treatment in Hela cells. These data strongly suggest that the cyclooxygenase inhibitor, indomethacin, increased the cytotoxicity of doxorubicin with decreasing expression of MRP1 through inhibition of MRP1 promoter activity.
Matsunaga
Seita
S
Department of Pediatrics, Nippon Medical School, Chiba Hokusoh Hospital, Inba-mura, Inba-gun, Japan.
Asano
Takeshi
T
Tsutsuda-Asano
Arisa
A
Fukunaga
Yoshitaka
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005452:Fluoresceins; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D020014:K562 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D020112:Rhodamine 123
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016861:Cyclooxygenase Inhibitors; D004317:Doxorubicin; D005452:Fluoresceins; D007213:Indomethacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D020112:Rhodamine 123; C084577:5-carboxyfluorescein diacetate; C421109:multidrug resistance-associated protein 1