Gastroenterology

Gastroenterology

Volume 120, Issue 7, June 2001, Pages 1713-1719
Gastroenterology

Alimentary Tract
Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth*,**

https://doi.org/10.1053/gast.2001.24844Get rights and content

Abstract

Background & Aims: The cyclooxygenase 2 (COX-2) and ErbB/HER pathways are important modulators of cancer cell growth. We sought to determine the effects of treatment with a specific COX-2 inhibitor and/or a monoclonal antibody against the ErbB receptor subtype HER-2/neu on carcinoma cell growth. Methods: A cell-proliferation assay was used to determine the response of HCA-7 cells to the HER-3/HER-4 ligand heregulin β-1 (HRGβ-1). Both in vitro and in vivo assays were used to determine the effects of the selective COX-2 inhibitor, celecoxib, and/or an anti–HER-2/neu monoclonal antibody (either Herceptin [Genetech Inc., S. San Francisco, CA] or 2C4) on cell growth. Results: HCA-7 cells express HER-2/neu messenger RNA and protein, and exposure of these cells to HRGβ-1 results in a significant stimulation of cell growth. Celecoxib or Herceptin inhibits HCA-7 cell growth in vitro and in vivo. Combination therapy with celecoxib plus Herceptin or celecoxib plus 2C4 resulted in additive effects that resulted in almost complete inhibition of tumor growth. Conclusions: Combined treatment with COX-2 and HER-2/neu inhibitors more effectively reduces colorectal carcinoma growth than either agent alone. Therefore, targeting of both the COX-2 and ErbB signaling pathways may represent a novel approach for the treatment and/or prevention of colorectal cancer in humans.

GASTROENTEROLOGY 2001;120:1713-1719

Section snippets

Cell culture and materials

All cell lines were purchased from the American Type Culture Collection except the HCA-7 rectal adenocarcinoma cell line, which was a kind gift of Susan Kirkland (ICRF, London, England).25 Cells were grown in Dulbecco's modified Eagle medium (DMEM) or McCoy medium (Life Technologies, Inc., Rockville, MD) supplemented with 10% fetal bovine serum (FBS; Hyclone, Logan, UT), L-glutamine (2 mmol/L), penicillin (100 U/mL), and streptomycin (100 μg/mL) in a 5% CO2 atmosphere with constant humidity.

Results

We first sought to identify a human colorectal cancer cell line that would serve as a good model system to study the biologic effects of both selective COX-2 inhibitors and anti–HER-2/neu antibodies. We have previously reported that the HCA-7 colorectal carcinoma cells express high levels of COX-2 and produce significant amounts of prostaglandins.32 Furthermore, selective COX-2 inhibitors block the growth of these cells both in vitro and in vivo. To determine whether this cell line was also a

Discussion

The impetus for a combination of therapeutic agents for cancer treatment lies in the realization that tumor cells have evolved to bypass multiple growth-control pathways.35 Thus, targeting any single pathway may not be sufficient to achieve a meaningful clinical effect. The rationale for combination targeting of the COX-2 and HER-2/neu pathways to inhibit colorectal cancer cell growth is derived from 2 major observations: (1) both the COX-2 and HER-2/neu pathways have been shown to play

References (45)

  • S Kargman et al.

    Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer

    Cancer Res

    (1995)
  • H Sano et al.

    Expression of cyclooxygenase-1 and -2 in human colorectal cancer

    Cancer Res

    (1995)
  • CS Williams et al.

    The role of cyclooxygenases in inflammation, cancer and development

    Oncogene

    (1999)
  • RA Gupta et al.

    Translational studies on COX-2 inhibitors in the prevention and treatment of colorectal cancer

    Ann N Y Acad Sci

    (2000)
  • T Kawamori et al.

    Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis

    Cancer Res

    (1998)
  • BS Reddy et al.

    Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis

    Cancer Res

    (1996)
  • RF Jacoby et al.

    Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos

    Cancer Res

    (2000)
  • G Steinbach et al.

    The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis

    N Engl J Med

    (2000)
  • LN Klapper et al.

    Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors

    Adv Cancer Res

    (2000)
  • AO Monilola et al.

    The ErbB signaling network: receptor heterodimerization in development and cancer

    EMBO J

    (2000)
  • J Albanell et al.

    The ErbB receptors as targets for breast cancer therapy

    J Mammary Gland Biol Neoplasia

    (1999)
  • S Nicholson et al.

    Epidermal growth factor receptor (EGFR); results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup

    Br J Cancer

    (1991)
  • Cited by (178)

    • Pertuzumab in breast cancer: A systematic review

      2013, Clinical Breast Cancer
      Citation Excerpt :

      Preclinical models have shown that pertuzumab inhibits tumor growth in the absence of HER2+, unlike trastuzumab, presumably by preventing ligand-stimulated HER2 heterodimer formation.7,14,15 In in vivo preclinical studies, pertuzumab has been active in various tumor types, including breast,7,10,15–17 ovary,16 non–small-cell lung carcinoma,15,17 prostate,7,18 and colon cancer,19 whereas Agus et al7 showed dose-dependent inhibition of xenograft tumor growth. In light of these promising nonclinical findings, it has been postulated that inhibition of HER2-mediated dimerization may be an effective anticancer therapy.

    • The Pharmacological Guide to Trastuzumab

      2020, The Pharmacological Guide to Trastuzumab
    • HER2-targeted therapies — a role beyond breast cancer

      2020, Nature Reviews Clinical Oncology
    View all citing articles on Scopus
    *

    Address requests for reprints to: Raymond N. DuBois, M.D., Ph.D., Department of Medicine/GI, MCN C-2104, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279. e-mail:[email protected]; fax: (615) 343-6229.

    **

    Supported in part by grants DK 47297, P01CA77839, and P30CA-68485 from the United States Public Health Services (to R.N.D.), by a Veterans Affairs Research Merit Grant (to R.N.D.), and by the T. J. Martell Foundation and the National Colorectal Cancer Research Alliance (NCCRA).

    View full text