Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR𝛼+𝛾 Agonists

Figure 3

Current mode-of-action hypothesis for the carcinogenic effect of dual-acting PPARα+γ agonists in the rat urothelium. To explain the carcinogenicity of dual-acting PPARα+γ agonists in the rat urothelium, we favor a multifactorial mode-of-action (MOA) hypothesis, compatible with the observation that PPAR agonists can cause diametrally opposite biological effects (mitogenesis as well as cytotoxicity in vitro, carcinogenicity as well as tumour inhibition in vivo) depending on context (species, PPAR activation profile of agonist, agonist dose, cell type as well as PPAR expression, etc.) [2, 4–6, 8, 33–36, 62, 106, 107]. (The shown MOA hypothesis is based on previously published ragaglitazar data [18, 28–30, 61], but may be applicable to other dual-acting agonists (Table 1) [8, 31]. The shown MOA hypothesis is applicable to rats only due to the known profound species differences in PPAR function [26, 32]. Bladder cancer was seen in SD, Wistar, and Fischer rats of both sexes [8, 29], but the shown MOA hypothesis may nevertheless be rat strain dependent due to rodent strain differences in PPAR function [10]. The shown MOA hypothesis is compatible with gender differences, due to gender differences in PPAR expression and function [108–113], and does not assume urinary excretion of the PPAR agonist [39].)