ArticlePPAR research2008
Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists.
Article in PPAR research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014Pooled it
- Small-Molecule Modulation of PPARs for the Treatment of Prevalent Vascular Retinal Diseases.International journal of molecular sciences · 2020Review
- The PPARPPAR research · 2020Review
- The role and function of PPARγ in bladder cancer.Journal of Cancer · 2020Review
- Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence.International journal of molecular sciences · 2019Review
- Association of Pioglitazone with Increased Risk of Prostate Cancer and Pancreatic Cancer: A Functional Network Study.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2018Article
- The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development.International journal of molecular sciences · 2018Review
- Pioglitazone Use and Risk of Bladder Cancer: anInternational journal of medical sciences · 2018Article
- Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets.eLife · 2017Article
- Deciphering the Roles of Thiazolidinediones and PPARPPAR research · 2017Review
- Pioglitazone use and risk of bladder cancer: population based cohort study.BMJ (Clinical research ed.) · 2016Article
- Fibrates and risk of cancer in tissues with high PPAR-α concentration: a nested case-control study.Drug safety · 2014Article
- Insulin therapy and cancer.Diabetes care · 2013Review
- Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!European journal of clinical pharmacology · 2012Article
- PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty.Journal of lipid research · 2012Review
- Peroxisome proliferator-activated receptors and cancer: challenges and opportunities.British journal of pharmacology · 2011Review
- Safety of PPAR agonists.Diabetes care · 2011Article
- Review
- Structurally diverse peroxisome proliferator-activated receptor agonists induce apoptosis in human uro-epithelial cells by a receptor-independent mechanism involving store-operated calcium channels.Cell proliferation · 2009Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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. Chronic pharmacological activation of PPARgamma can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARalpha as well as PPARgamma, making it plausible that the urothelial carcinogenicity of PPARalpha+gamma agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARalpha+gamma agonist ragaglitazar, and the available literature about the role of PPARalpha and gamma in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARalpha+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.
Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.