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Research ArticleArticle

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

Le Yu, William Ka Kei Wu, Zhi Jie Li, Qi Cai Liu, Hai Tao Li, Ya Chun Wu and Chi Hin Cho
Molecular Pharmacology June 2009, 75 (6) 1364-1373; DOI: https://doi.org/10.1124/mol.108.053546
Le Yu
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William Ka Kei Wu
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Zhi Jie Li
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Qi Cai Liu
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Hai Tao Li
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Ya Chun Wu
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Chi Hin Cho
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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-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.

Footnotes

  • This work was supported by The Hong Kong Research Grants Council [Grant CUHK 7499/05M] and the Direct Grand from the Chinese University of Hong Kong.

  • ABBREVIATIONS: MDR, multidrug resistance; SC236, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; SC560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluorom-ethylpyrazole; NS398, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; nimesulide, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide; PGE2, prostaglandin E2; COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; siRNA, small interference RNA; P-gp, P-glycoprotein; MRP1, multidrug resistance protein 1; NF-κB, nuclear factor κB; PBS, phosphate-buffered saline.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received November 20, 2008.
    • Accepted March 5, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (6)
Molecular Pharmacology
Vol. 75, Issue 6
1 Jun 2009
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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
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Research ArticleArticle

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

Le Yu, William Ka Kei Wu, Zhi Jie Li, Qi Cai Liu, Hai Tao Li, Ya Chun Wu and Chi Hin Cho
Molecular Pharmacology June 1, 2009, 75 (6) 1364-1373; DOI: https://doi.org/10.1124/mol.108.053546

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Research ArticleArticle

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

Le Yu, William Ka Kei Wu, Zhi Jie Li, Qi Cai Liu, Hai Tao Li, Ya Chun Wu and Chi Hin Cho
Molecular Pharmacology June 1, 2009, 75 (6) 1364-1373; DOI: https://doi.org/10.1124/mol.108.053546
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