Cyclooxygenase-independent down-regulation of multidrug resistance-associated protein-1 expression by celecoxib in human lung cancer cells.
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.
Kang
He-Kyung
HK
Research Institute, National Cancer Center, Ilsan-gu, Goyang, Gyeonggi, Korea.
Lee
Eunmyong
E
Pyo
Hongryull
H
Lim
Soo-Jeong
SJ
D001980:Bronchi; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011720:Pyrazoles; D013449:Sulfonamides; C421109:multidrug resistance-associated protein 1