TY - JOUR T1 - Enhancement of Doxorubicin Cytotoxicity on Human Esophageal Squamous Cell Carcinoma Cells by Indomethacin and 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1<em>H</em>-pyrazol-1-yl]benzenesulfonamide (SC236) via Inhibiting P-Glycoprotein Activity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1364 LP - 1373 DO - 10.1124/mol.108.053546 VL - 75 IS - 6 AU - Le Yu AU - William Ka Kei Wu AU - Zhi Jie Li AU - Qi Cai Liu AU - Hai Tao Li AU - Ya Chun Wu AU - Chi Hin Cho Y1 - 2009/06/01 UR - http://molpharm.aspetjournals.org/content/75/6/1364.abstract N2 - 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 E2 (PGE2) 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 PGE2. 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 PGE2-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. The American Society for Pharmacology and Experimental Therapeutics ER -