title: The development of subcutaneous sarcomas in rodents exposed to peroxisome proliferators agonists: hypothetical mechanisms of action and de-risking attitude.
abstract: Peroxisome proliferator-activated receptors (PPARs) represent therapeutic targets for the management of type 2 diabetes mellitus and dyslipidemia. Rodent carcinogenicity studies have revealed a link between γ and dual γ/α PPAR agonist treatment and the increased incidence of subcutaneous (SC) liposarcomas/fibrosarcomas or hemangiosarcomas, but very little has been reported for potent and selective PPARα agonists. We present a mode of action framework for the development of SC mesenchymal tumors in rodents given PPAR agonists. (1) Tumor promotion results from pharmacologically mediated recruitment (proliferation and differentiation), thermogenesis and adipogenesis of stromovascular cells, and subsequent generation of oxidative free radicals. (2) Tumor initiation consists of chemotype-driven mitochondrial dysfunction causing uncontrolled oxidative stress and permanent DNA damage. Promotion is characterized by enhanced adipogenesis in the SC adipose tissue, where the baseline PPARγ expression and responsiveness to PPARγ ligands is the highest, and by thermogenesis through expression of the uncoupling protein 1 (UCP-1) and the PPARγ co-activator 1 α (PGC-1α), two factors more highly expressed in brown versus white adipose tissue. Initiation is supported by the demonstration of mitochondrial uncoupling and OXPHOS Complexes dysfunction (Complexes III, IV and V) by compounds associated with increased incidences of sarcomas (muraglitazar and troglitazone), but not others lacking malignant tumor effects (pioglitazone, rosiglitazone).
authors.affiliation: Pfizer Inc., Sandwich, Kent, UK. Ingrid.Pruimboom@Novartis.com
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Pruimboom-Brees
authors.forename: Omar
authors.initials: O
authors.lastname: Francone
authors.forename: John C
authors.initials: JC
authors.lastname: Pettersen
authors.forename: Roy L
authors.initials: RL
authors.lastname: Kerlin
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
authors.forename: David E
authors.initials: DE
authors.lastname: Amacher
authors.forename: Germaine G
authors.initials: GG
authors.lastname: Boucher
authors.forename: Daniel
authors.initials: D
authors.lastname: Morton
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002839:Chromans / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology / Q000628:therapy; D005998:Glycine / Q000031:analogs & derivatives / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010080:Oxazoles / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077205:Pioglitazone; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012377:Rodentia / Q000378:metabolism; D000077154:Rosiglitazone; D012509:Sarcoma / Q000139:chemically induced* / Q000473:pathology; D022722:Thermogenesis / Q000187:drug effects; D045162:Thiazolidinediones / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077288:Troglitazone; D000071256:Uncoupling Protein 1
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D045162:Thiazolidinediones; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D000077154:Rosiglitazone; D000077288:Troglitazone; D005998:Glycine; C500085:muraglitazar; D000077205:Pioglitazone