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

Karnati R Roy1, Gorla V Reddy, Leela Maitreyi

  • 1Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.

Cancer Chemotherapy and Pharmacology
|August 18, 2009
PubMed

Insights

This study shows that inhibiting COX-2 with celecoxib can overcome doxorubicin resistance in liver cancer cells (HepG2). This is achieved by reducing the expression of MDR1, a protein that causes drug resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Hepatocellular carcinoma (HCC) is a major global health concern.
  • Multidrug resistance (MDR) significantly limits the efficacy of chemotherapy in HCC treatment.
  • P-glycoprotein (MDR1) is a key factor contributing to doxorubicin resistance in HepG2 cells.

Purpose of the Study:

  • To investigate the role of cyclooxygenase-2 (COX-2) in regulating MDR1 expression in HepG2 cells.
  • To evaluate the potential of COX-2 inhibition in overcoming doxorubicin resistance in HCC.

Main Methods:

  • Utilized HepG2 cell line for in vitro studies.
  • Administered celecoxib (a selective COX-2 inhibitor) and observed its effects on doxorubicin accumulation and sensitivity.
  • Performed COX-2 knockdown experiments.
  • Investigated the involvement of AP-1 and signal transduction pathways (ERK, JNK, p38) using in silico predictions and experimental validation.

Main Results:

  • Celecoxib (25 microM) significantly increased doxorubicin accumulation in HepG2 cells.
  • Celecoxib enhanced cellular sensitivity to doxorubicin by tenfold.
  • Prostaglandin E2 (PGE2) induced MDR1 expression, while celecoxib and COX-2 knockdown downregulated it.
  • AP-1 was implicated in the celecoxib-mediated downregulation of MDR1.
  • In silico analysis suggested inactivation of ERK, JNK, and p38 pathways.

Conclusions:

  • COX-2 plays a crucial role in regulating MDR1 expression in HepG2 cells.
  • Targeting COX-2 with celecoxib is a promising strategy to overcome doxorubicin resistance in hepatocellular carcinoma.
  • The mechanism involves the downregulation of MDR1 expression via a COX-2-dependent pathway, potentially involving AP-1 and inactivation of specific signal transduction pathways.

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