Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1

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Bhagavathi A Narayanan1, Bandaru S Reddy, Maarten C Bosland

  • 1Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA. bhagavathi@env.med.nyu.edu

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 3, 2007
PubMed
Abstract

Insights

Combining low-dose celecoxib and exisulind effectively prevents prostate cancer by reducing tumor incidence and enhancing apoptosis. This combination therapy alters key molecular pathways involved in cancer growth.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) show anticancer potential via cyclooxygenase-2 (COX-2) dependent and independent pathways.
  • High doses of single NSAID agents raise toxicity concerns.
  • Investigating combination therapy with low-dose agents is crucial for effective and safe cancer treatment.

Purpose of the Study:

  • To determine the combined effect of celecoxib (a COX-2 inhibitor) and exisulind at low doses in prostate cancer.
  • To evaluate the efficacy of this combination in preventing prostate carcinogenesis.
  • To analyze the molecular mechanisms underlying the observed effects.

Main Methods:

  • Prostate cancer was induced in Wistar-Unilever rats using N-methyl-N-nitrosourea and testosterone.
  • Rats received low doses of celecoxib, exisulind, or their combination in the diet for 52 weeks.
  • Key molecular markers including COX-2, EGFR, Akt, androgen receptor, cyclin D1, and inflammatory markers were assessed.

Main Results:

  • The combination of low-dose celecoxib and exisulind significantly reduced prostatic intraepithelial neoplasia and adenocarcinomas.
  • Enhanced apoptosis and inhibition of tumor cell proliferation were observed.
  • Reduced expression of COX-2, EGFR, Akt, androgen receptor, and cyclin D1, along with decreased inflammatory markers, indicated therapeutic efficacy.

Conclusions:

  • The combination of celecoxib and exisulind at low doses demonstrates a preventative effect on prostate carcinogenesis.
  • This combination therapy acts by modulating critical molecular events involved in cancer development.
  • This study provides the first evidence for the potential of this low-dose combination therapy in prostate cancer prevention.

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