Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 5, pp 903–911 | Cite as

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

  • Karnati R. Roy
  • Gorla V. Reddy
  • Leela Maitreyi
  • Smita Agarwal
  • Chandrani Achari
  • Shireen Vali
  • Pallu Reddanna
Original Article

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 

Notes

Acknowledgments

This work was supported by research grants from Council of Scientific and Industrial Research (CSIR) (Grant # 37(1221)/05/EMR-II) and from Department of Science and Technology (DST) (Grant # VII-PRDSF/50/05-06/TDT), Govt. of India. We duly acknowledge CSIR, Govt. of India for providing Senior Research Fellowship to Dr. Karnati R. Roy and Dr. Smita Agarwal; University Grants Commission (UGC), New Delhi for providing Dr. D. S. Kothari-Postdoctoral Fellowship (PDF) to Dr. Gorla V. Reddy; DBT, Govt. of India for providing UOH-CREBB-Junior Research Fellowship (JRF) to Chandrani Achari. We thank Mr. Ch. Shiva Kumar, technical assistant, for his help during the manuscript preparation.

Supplementary material

280_2009_1097_MOESM1_ESM.doc (30 kb)
Supplementary material 1 (DOC 30 kb)

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Karnati R. Roy
    • 1
  • Gorla V. Reddy
    • 1
  • Leela Maitreyi
    • 2
  • Smita Agarwal
    • 1
  • Chandrani Achari
    • 1
  • Shireen Vali
    • 2
  • Pallu Reddanna
    • 1
  1. 1.Department of Animal Sciences, School of Life SciencesUniversity of HyderabadHyderabadIndia
  2. 2.Cellworks Group Inc.CaliforniaUSA

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