Cyclooxygenase-independent down-regulation of multidrug resistance–associated protein-1 expression by celecoxib in human lung cancer cells

• Published in: Molecular cancer therapeutics Vol. 4; no. 9; pp. 1358 - 1363
• Main Authors: Kang, He-Kyung, Lee, Eunmyong, Pyo, Hongryull, Lim, Soo-Jeong
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.09.2005
• Subjects: Bronchi; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Celecoxib; Cyclooxygenase; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Dinoprostone - pharmacology; Dose-Response Relationship, Drug; Down-Regulation; doxorubicin; Doxorubicin - metabolism; Doxorubicin - pharmacology; drug resistance; Epithelial Cells - cytology; Epithelial Cells - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; MRP1; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Pyrazoles - pharmacology; Sulfonamides - pharmacology; Tumor Cells, Cultured
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-05-0139

The recent finding of a link between cyclooxygenase-2 (COX-2) and p-glycoprotein expression suggests that COX-2 is involved in the development of the multidrug resistance (MDR) phenotype. MDR-associated protein 1 (MRP1) is another major MDR-related protein that is frequently overexpressed in cancer patients, including those with lung cancer. Based on our observation that among four human epithelial lung cell lines both MRP1 and COX-2 protein were highly expressed only in A549 cells, we have investigated whether COX-2 regulates the expression of MRP1. The COX-2 inhibitor celecoxib down-regulated the expression of MRP1 protein in A549 cells, which was accompanied by increased accumulation and enhanced cytotoxicity of doxorubicin, an MRP1 substrate. However, enforced expression of COX-2 in human H460 lung carcinoma cell lines, which express minimal level of COX-2, did not cause enhancement in MRP1 expression. Celecoxib down-regulation of MRP1 was observed independent of COX-2 expression. Moreover, in COX-2-overexpressing cell lines, celecoxib down-regulation of MRP1 was observed only at a concentration far exceeding that required for inhibiting COX activity, and exogenous addition of prostaglandin E 2 did not restore MRP1 expression. These results suggest that celecoxib down-regulates MRP1 expression in human lung cancer cells in a COX-independent manner. The use of celecoxib for adjuvant therapy in lung cancer patients may contribute to their decreased resistance to chemotherapeutic drugs transported by MRP1.