Abstract
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.
Highlights
Cyclooxygenases (COX) are the key enzymes that catalyze the conversion of arachidonic acid to prostaglandins and other eicosanoids
Celecoxib Effect on MRP1Expression When we assayed four lung cancer cell lines for expression of COX-2 and MDR-associated protein 1 (MRP1) protein by immunoblotting, we found that expression of COX-2 protein was much higher in human A549 lung cancer cells than in the other cell lines (Fig. 1)
When we assayed the intracellular accumulation of doxorubicin, an MRP1 substrate drug, with or without celecoxib pretreatment, we observed that 50 and 100 Amol/L celecoxib increased the intracellular accumulation of doxorubicin by 1.8- and 2.0-fold (P < 0.05), respectively (Fig. 3A)
Summary
Cyclooxygenases (COX) are the key enzymes that catalyze the conversion of arachidonic acid to prostaglandins and other eicosanoids. Epidemiologic and experimental studies have shown that COX-2 inhibitors are effective chemopreventive agents, reducing the risks of many types of tumors, including colon, lung, prostate, and gastric cancers. COX-2 inhibitors have gained attention, either alone or in combination with other chemotherapeutic agents and/or radiation therapy, in the treatment of cancer [1]. A COX-2-selective inhibitor celecoxib exerted synergistic antitumor effects when combined with gemcitaine or 5-fluorouracil in patients with advanced pancreatic cancer [2], and it enhanced the response to paclitaxel and carboplatin in early-stage non – small cell lung cancer [3]. The mechanism underlying the antitumor activity of COX-2 inhibitors is thought to involve inhibition of COX-2 enzyme activity and induction of apoptosis, but it is unclear whether COX-2 inhibition is required to induce apoptosis [4]
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