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Cyclooxygenase-2 gene induction causes CDDP resistance in colon cancer cell line, HCT-15

Yoshiro Saikawa1, Tsudoi Sugiura, Fumiki Toriumi

  • 1Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. saiky@sc.itc.keio.ac.jp

Anticancer Research
|November 3, 2004
PubMed

Insights

Cyclooxygenase-2 (COX-2) overexpression in colon cancer cells increases resistance to cisplatin (CDDP) by upregulating multidrug resistance-associated protein 1 (MRP-1). A COX-2 inhibitor, JTE-522, restored sensitivity to CDDP, offering a potential strategy to overcome drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Drug resistance to cisplatin (CDDP) is a significant challenge in cancer therapy.
  • Adenosine triphosphate (ATP) binding cassette (ABC) transporters, like P-glycoprotein (MDR-1) and multidrug resistance-associated proteins (MRPs), are implicated in multidrug resistance.
  • Cyclooxygenase-2 (COX-2) is a potential mediator of chemoresistance.

Purpose of the Study:

  • To investigate the relationship between cyclooxygenase-2 (COX-2) expression and chemosensitivity to cisplatin (CDDP).
  • To determine if COX-2 overexpression influences the expression of drug resistance genes.
  • To evaluate the efficacy of a COX-2 selective inhibitor in overcoming CDDP resistance.

Main Methods:

  • Established a COX-2 overexpressed colon cancer cell line (TR-5) from HCT-15 cells.
  • Quantified mRNA expression of MRP-1 and MDR-1 using real-time PCR.
  • Assessed chemosensitivity to CDDP by measuring cell survival rates and IC50 values.
  • Investigated the effect of the COX-2 selective inhibitor JTE-522 on CDDP chemosensitivity.

Main Results:

  • COX-2 overexpression in TR-5 cells led to significantly increased expression of MRP-1 and MDR-1 mRNA compared to HCT-15 cells.
  • TR-5 cells exhibited approximately triple the resistance to CDDP compared to HCT-15 cells, indicated by higher IC50 values.
  • Pretreatment with the COX-2 selective inhibitor JTE-522 markedly decreased the IC50 of CDDP in TR-5 cells, restoring chemosensitivity.

Conclusions:

  • COX-2 overexpression induces increased MRP-1 expression in colon cancer cells, contributing to cisplatin (CDDP) chemoresistance.
  • The COX-2 selective inhibitor JTE-522 demonstrates efficacy in re-sensitizing resistant colon cancer cells to CDDP.
  • Targeting COX-2 presents a promising therapeutic strategy for overcoming cisplatin resistance in cancer treatment.

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