Original Article

Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 5, pp 903-911

First online:

Celecoxib inhibits MDR1 expression through COX-2-dependent mechanism in human hepatocellular carcinoma (HepG2) cell line

  • Karnati R. RoyAffiliated withDepartment of Animal Sciences, School of Life Sciences, University of Hyderabad
  • , Gorla V. ReddyAffiliated withDepartment of Animal Sciences, School of Life Sciences, University of Hyderabad
  • , Leela MaitreyiAffiliated withCellworks Group Inc.
  • , Smita AgarwalAffiliated withDepartment of Animal Sciences, School of Life Sciences, University of Hyderabad
  • , Chandrani AchariAffiliated withDepartment of Animal Sciences, School of Life Sciences, University of Hyderabad
  • , Shireen ValiAffiliated withCellworks Group Inc.
  • , Pallu ReddannaAffiliated withDepartment of Animal Sciences, School of Life Sciences, University of Hyderabad Email author 

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Abstract

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 μM 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 PGE2 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.

Keywords

AP-1 Celecoxib COX-2 HepG2 cells MDR1 Simulation