Urothelial Carcinogenesis in the Urinary Bladder of Rats Treated with Naveglitazar, a γ-dominant PPAR α/γ Agonist: Lack of Evidence for Urolithiasis as an Inciting Event

Abstract

Naveglitazar, a γ-dominant peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogenesis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated.

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

“…A similar carcinogenic effect has been reported with naveglitazar, without urolithiasis as an inciting event [8,9]. Urothelial cells coexpress PPARα and PPARγ, and an interaction study with rosiglitazone (PPARγ agonist) and fenofibrate (PPARα agonist), alone or in combination, showed synergy in inducing Egr-1 transcription factor [10], which was suggested as a candidate biomarker for the carcinogenic effect of dual-acting PPAR agonists [11].…”

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

“…A similar carcinogenic effect has been reported with naveglitazar, without urolithiasis as an inciting event [8,9]. Urothelial cells coexpress PPARα and PPARγ, and an interaction study with rosiglitazone (PPARγ agonist) and fenofibrate (PPARα agonist), alone or in combination, showed synergy in inducing Egr-1 transcription factor [10], which was suggested as a candidate biomarker for the carcinogenic effect of dual-acting PPAR agonists [11].…”

Naturally Occurring Compounds Targeting Peroxisome Proliferator Receptors: Potential Molecular Mechanisms and Future Perspectives for Promoting Human Health

“…Nevertheless, their clinical use has been determined to be unsafe because of side effects like edema, hyperplasia, cardiac and kidney disorders, and increased body weight (e.g., glitazone and ragaglitazar) [99]. Indicatively, naveglitazar, a γ-dominant PPAR-α/γ dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothelium; however, no alterations in the urinary parameters were found [100].…”

“…Indicatively, naveglitazar, a γ-dominant PPAR-α/γ dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothelium; however, no alterations in the urinary parameters were found [100]. Accordingly, muraglitazar, another PPAR-α/γ ligand, promoted, in a dose-dependent manner, urinary bladder cancer in male Harlan Sprague-Dawley rats at concentrations of 5, 30, or 50 mg/kg/day for almost two years [101].…”

Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta‐analysis

“…However, whilst muraglitazar‐induced rat bladder carcinogenesis was ascribed to the seemingly rat‐specific ‘crystalluria’ mechanism, other glitazars (e.g. aleglitazar) have not been associated with rodent bladder tumours and, similar to pioglitazone, a bladder carcinogenic effect has been reported in rats administered naveglitazar without urolithiasis as an inciting event . Therefore, although the dual PPARα/γ receptor agonism of pioglitazone may be contributory, the underlying mechanism of pioglitazone bladder carcinogenicity in humans is likely to be more complex.…”

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

“…A similar carcinogenic effect has been reported with naveglitazar, without urolithiasis as an inciting event [8,9]. Urothelial cells coexpress PPARα and PPARγ, and an interaction study with rosiglitazone (PPARγ agonist) and fenofibrate (PPARα agonist), alone or in combination, showed synergy in inducing Egr-1 transcription factor [10], which was suggested as a candidate biomarker for the carcinogenic effect of dual-acting PPAR agonists [11].…”

Naturally Occurring Compounds Targeting Peroxisome Proliferator Receptors: Potential Molecular Mechanisms and Future Perspectives for Promoting Human Health

“…Nevertheless, their clinical use has been determined to be unsafe because of side effects like edema, hyperplasia, cardiac and kidney disorders, and increased body weight (e.g., glitazone and ragaglitazar) [99]. Indicatively, naveglitazar, a γ-dominant PPAR-α/γ dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothelium; however, no alterations in the urinary parameters were found [100].…”

“…Indicatively, naveglitazar, a γ-dominant PPAR-α/γ dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothelium; however, no alterations in the urinary parameters were found [100]. Accordingly, muraglitazar, another PPAR-α/γ ligand, promoted, in a dose-dependent manner, urinary bladder cancer in male Harlan Sprague-Dawley rats at concentrations of 5, 30, or 50 mg/kg/day for almost two years [101].…”

Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta‐analysis

“…However, whilst muraglitazar‐induced rat bladder carcinogenesis was ascribed to the seemingly rat‐specific ‘crystalluria’ mechanism, other glitazars (e.g. aleglitazar) have not been associated with rodent bladder tumours and, similar to pioglitazone, a bladder carcinogenic effect has been reported in rats administered naveglitazar without urolithiasis as an inciting event . Therefore, although the dual PPARα/γ receptor agonism of pioglitazone may be contributory, the underlying mechanism of pioglitazone bladder carcinogenicity in humans is likely to be more complex.…”

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

“…A similar carcinogenic effect has been reported with naveglitazar, without urolithiasis as an inciting event [8,9]. Urothelial cells coexpress PPARα and PPARγ, and an interaction study with rosiglitazone (PPARγ agonist) and fenofibrate (PPARα agonist), alone or in combination, showed synergy in inducing Egr-1 transcription factor [10], which was suggested as a candidate biomarker for the carcinogenic effect of dual-acting PPAR agonists [11].…”

Naturally Occurring Compounds Targeting Peroxisome Proliferator Receptors: Potential Molecular Mechanisms and Future Perspectives for Promoting Human Health

“…Nevertheless, their clinical use has been determined to be unsafe because of side effects like edema, hyperplasia, cardiac and kidney disorders, and increased body weight (e.g., glitazone and ragaglitazar) [99]. Indicatively, naveglitazar, a γ-dominant PPAR-α/γ dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothelium; however, no alterations in the urinary parameters were found [100].…”

“…Indicatively, naveglitazar, a γ-dominant PPAR-α/γ dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothelium; however, no alterations in the urinary parameters were found [100]. Accordingly, muraglitazar, another PPAR-α/γ ligand, promoted, in a dose-dependent manner, urinary bladder cancer in male Harlan Sprague-Dawley rats at concentrations of 5, 30, or 50 mg/kg/day for almost two years [101].…”

Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta‐analysis

“…However, whilst muraglitazar‐induced rat bladder carcinogenesis was ascribed to the seemingly rat‐specific ‘crystalluria’ mechanism, other glitazars (e.g. aleglitazar) have not been associated with rodent bladder tumours and, similar to pioglitazone, a bladder carcinogenic effect has been reported in rats administered naveglitazar without urolithiasis as an inciting event . Therefore, although the dual PPARα/γ receptor agonism of pioglitazone may be contributory, the underlying mechanism of pioglitazone bladder carcinogenicity in humans is likely to be more complex.…”