Journal
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 65, Issue 5, Pages 903-911Publisher
SPRINGER
DOI: 10.1007/s00280-009-1097-3
Keywords
AP-1; Celecoxib; COX-2; HepG2 cells; MDR1; Simulation
Categories
Funding
- Council of Scientific and Industrial Research (CSIR) [37(1221)/05/EMR-II]
- Department of Science and Technology (DST) [VII-PRDSF/50/05-06/TDT]
- University Grants Commission (UGC), New Delhi
- DBT, Govt. of India
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The role of COX-2 in the regulation of the expression of MDR1, a P-glycoprotein involved in hepatocellular carcinoma cell line, HepG2, was studied in the present investigation. Celecoxib, a selective inhibitor of COX-2, at 25 mu M concentration increased the accumulation of doxorubicin in HepG2 cells and enhanced the sensitivity of the cells to doxorubicin by tenfold. The induction of MDR1 expression by PGE(2) and its downregulation by celecoxib or by COX-2 knockdown suggests that the enhanced sensitivity of HepG2 cells to doxorubicin by celecoxib is mediated by the downregulation of MDR1 expression, through COX-2-dependent mechanism. Further studies revealed the involvement of AP-1 in the celecoxib-induced downregulation of MDR1 expression. These experimental studies correlated well with in silico predictions and further suggested the inactivation of the signal transduction pathways involving ERK, JNK and p38. The present study thus demonstrates the usefulness of COX-2 intervention in overcoming the drug resistance in HepG2 cells.
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