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

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 COXindependent manner. The use of celecoxib for adjuvant therapy in lung cancer patients may contribute to their decreased resistance to chemotherapeutic drugs transported by MRP1. [Mol Cancer Ther 2005;4(9):1358 -63]

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

“…Therefore, we also developed a NCI-H460 cell line constitutively overexpressing COX-2 (H460-COX-2; refs. 21,22) and did the same comparison. EGFR expression in H460-COX-2 cells was also found to be down-regulated compared with mock cells much as it was in the HCT-116-COX-2 cells (Fig.…”

“…MOR-P lung cancer cells were kindly provided by Dr. Zhu (University of Sheffield, Sheffield, United Kingdom). COX-2-overexpressing HCT-116 and H460 stable cell lines (HCT-116-COX-2 and H460-COX-2) and their mock-transfected control cells (HCT-116-Mock and H460-Mock) were developed as described previously (22), and then the differences of mock versus COX-2 were compared within these stable cells. All tested cells were cultured in RPMI 1640 (Hyclone) containing 10% fetal bovine serum (Life Technologies), 50 units/mL penicillin (Life Technologies), 50 μg/mL streptomycin (Life Technologies), and 2 mmol/L L-glutamine (Life Technologies) at 37°C in an atmosphere of 5% CO 2 and 95% air.…”

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

“…52,53 As mentioned these genes can lead to chemotherapy resistance. This fact should be taken into consideration when assessing prognosis and treatment issues.…”

MCF-7 Breast Cancer Cell Line, a Model for the Study of the Association Between Inflammation and ABCG2-Mediated Multi Drug Resistance

“…Several preclinical and clinical trials have shown that nonsteroidal anti-inflammatory drugs (NSAIDs), used as classical COX inhibitors, could reduce the incidence of cancers (Cha et al, 2007;Kang et al, 2005;Lin et al, 2005). Although the exact anticancer mechanisms of NSAIDs are not fully understood, it seems to be related closely to their suppression of COX enzyme and subsequent reduction in prostaglandin production (Kismet et al, 2004;Zatelli et al, 2005).…”