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

Abstract

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-, 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.

Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity

“…The previous biological studies suggested that the COX inhibitory effect of the NSAIDs, including indomethacin 1a, may be related to the MDR of cancer cells. 3,4,6 Accordingly, these results, demonstrating that the MDR-modulating effect of the NSAID indomethacin would not be associated with its COX-inhibitory activity, are of significant importance.…”

“…5 Cho showed a mechanism by which COX inhibitors exerted an enhancing effect on the cytotoxic effect of doxorubicin via direct inhibition of P-gpATPase activity in human esophageal squamous cell carcinoma cell lines. 6 However, it is less certain whether COX-1 and/or COX-2 activity is directly related to the MDR property of cancer cells. 2 Indomethacin (1a, Figure 1) is a clinically useful NSAID with an indole structure, which inhibits both COX-1 and COX-2.…”

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

“…The mechanisms that lead to enhanced resistance to doxorubicin require further investigation. The use of doxorubicin 55,56 and taxane-based drugs 57 for the treatment of esophageal cancer has been described; the potential use of Pea3 as a biomarker to predict drug efficacy may warrant further investigation. Inhibition of PI3K-Akt-mTORC1-sensitized EC109 cells to doxorubicin treatment suggests that this pathway may be important in governing doxorubicin resistance.…”

Mechanism of P-glycoprotein Expression in the SGC7901 Human Gastric Adenocarcinoma Cell Line Induced by Cyclooxygenase-2

“…At the same time hydrolysis of ATP happens and gets energy, pump out drug inverse concentration gradient from the cell, drugs concentration in cell is declining constantly, making the toxic injury of drugs for cell weaken until it disappears and finally dug resistance appears. In recent years, many studies (Yu et al, 2009) find that there exits correlation between MDR and COX-2, COX-2 may participate in the production of MDR through P-gp. Vitro Studies (Zhang et al, 2009) suggest that when paclitaxel induces gastric cancer cell lines COX-2 to express highly, P-gp also increases, inhibit COX-2 expression, P-gp expression also decreases.…”