Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation.

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents.

PPAR alpha and PPAR gamma coactivation rapidly induces Egr-1 in the nuclei of the dorsal and ventral urinary bladder and kidney pelvis urothelium of rats.

To facilitate studies of the rat bladder carcinogenicity of dual-acting PPAR alpha+gamma agonists, we previously identified the Egr-1 transcription factor as a candidate carcinogenicity biomarker and developed rat models based on coadministration of commercially available specific PPAR alpha and PPAR gamma agonists. Immunohistochemistry for Egr-1 with a rabbit monoclonal antibody demonstrated that male vehicle-treated rats exhibited minimal urothelial expression and specifically, no nuclear signal. In contrast, Egr-1 was induced in the nuclei of bladder, as well as kidney pelvis, urothelia within one day (2 doses) of oral dosing of rats with a combination of 8 mg/kg rosiglitazone and 200 mg/kg fenofibrate (specific PPAR gamma and PPAR alpha agonists, respectively).

High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression.

Background: Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression.

Methods: Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer.

PPARalpha and PPARgamma are co-expressed, functional and show positive interactions in the rat urinary bladder urothelium.

Some dual-acting PPARalpha + gamma agonists cause cancer in the rat urinary bladder, in some cases overrepresented in males, by a mechanism suggested to involve chronic stimulation of PPARalpha and PPARgamma, i.e. exaggerated pharmacology.

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

Despite clinical promise, dual-acting activators of PPARalpha and gamma (here termed PPARalpha+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 PPARalpha is invariably associated with cancer in rats and mice.

Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo.

Small-molecule agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms (dual-acting PPAR agonists) can cause urothelial cancers in rodents. Rats were dosed orally for 16 days with bladder carcinogenic (ragaglitazar) as well as non-bladder carcinogenic (fenofibrate and rosiglitazone) PPAR agonists and protein changes were assayed in the urinary bladder urothelium by Western blotting. Dose levels reflected 10-20 x human exposure, and the ragaglitazar dose was in the carcinogenic range.