Enhancement of doxorubicin cytotoxicity on human esophageal squamous cell carcinoma cells by indomethacin and 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC236) via inhibiting P-glycoprotein activity.
Doxorubicin is a chemotherapeutic drug widely used for the treatment of advanced esophageal squamous cell carcinoma. However, its efficacy is usually limited by the development of multidrug resistance (MDR), which has been linked to the up-regulation of P-glycoprotein (P-gp) in cancer cells. Conventional nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 (COX-2)-selective inhibitors have been demonstrated to overcome MDR in some cancer cells. Here we sought to elucidate the effect of COX inhibitors on doxorubicin-induced cytotoxicity in relation to P-gp function in human esophageal squamous cell carcinoma cells. Among the five tested COX inhibitors [indomethacin, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide (SC236), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluorom-ethylpyrazole (SC560), nimesulide, and N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS398)], all of which substantially suppressed prostaglandin E(2) (PGE(2)) production to a similar extent, only the nonselective COX inhibitor indomethacin and the COX-2-selective inhibitor SC236 enhanced cytotoxic effects of doxorubicin on HKESC-1 and HKESC-2 cells. Moreover, these effects could not be reversed by the addition of PGE(2). Knockdown of COX-2 by small interference RNA also failed to mimic the enhancing effects of indomethacin or SC236, implicating that their action is COX- and PGE(2)-independent. To this end, we observed that indomethacin and SC236 directly functioned as noncompetitive inhibitors of P-gp, which were manifested as a reduction of P-gp ATPase activity. Collectively, these findings suggest that the direct inhibitory effects of indomethacin and SC236 on P-gp may contribute to their ability to increase the intracellular retention of doxorubicin and thus enhance its cytotoxicity. The combination of indomethacin or SC236 with doxorubicin may have significant potential clinical application, especially in the circumvention of P-gp-mediated MDR in cancer cells.
Yu
Le
L
Department of Pharmacology, The Chinese University of Hong Kong, China.
Wu
William Ka Kei
WK
Li
Zhi Jie
ZJ
Liu
Qi Cai
QC
Li
Hai Tao
HT
Wu
Ya Chun
YC
Cho
Chi Hin
CH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004938:Esophageal Neoplasms; D055785:Gene Knockdown Techniques; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D004317:Doxorubicin; D007213:Indomethacin; D016328:NF-kappa B; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides