Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists

Martin B. Oleksiewicz, Jennifer Southgate, Lars Iversen, Frederikke L. Egerod

Research output: Contribution to journalArticlepeer-review

Abstract

Despite clinical promise, dual-acting activators of PPAR alpha and gamma (here termed PPAR alpha+gamma agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPAR alpha is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPAR gamma can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPAR alpha as well as PPAR gamma, making it plausible that the urothelial carcinogenicity of PPAR alpha+gamma agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPAR alpha+gamma agonist ragaglitazar, and the available literature about the role of PPAR alpha and gamma in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPAR alpha+gamma agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds. Copyright (C) 2008 Martin B. Oleksiewicz et al.

Original languageEnglish
Article number103167
Pages (from-to)-
Number of pages14
JournalPPAR research
Volume2008
DOIs
Publication statusPublished - 2008

Keywords

  • ACTIVATED-RECEPTOR-GAMMA
  • HUMAN UROTHELIAL CELLS
  • EARLY GROWTH RESPONSE-1
  • PEROXISOME-PROLIFERATOR
  • GENE-EXPRESSION
  • IN-VITRO
  • ALPHA/GAMMA AGONIST
  • CELLULAR ACIDOSIS
  • MESSENGER-RNA
  • TRANSCRIPTIONAL REGULATION

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