PMID- 22504321
OWN - NLM
STAT- MEDLINE
DCOM- 20121119
LR  - 20181201
IS  - 1533-1601 (Electronic)
IS  - 0192-6233 (Linking)
VI  - 40
IP  - 5
DP  - 2012 Jul
TI  - The development of subcutaneous sarcomas in rodents exposed to peroxisome 
      proliferators agonists: hypothetical mechanisms of action and de-risking 
      attitude.
PG  - 810-8
LID - 10.1177/0192623312441406 [doi]
AB  - 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 gamma and dual gamma/alpha PPAR agonist 
      treatment and the increased incidence of subcutaneous (SC) 
      liposarcomas/fibrosarcomas or hemangiosarcomas, but very little has been reported 
      for potent and selective PPARalpha 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 PPARgamma expression and responsiveness to PPARgamma ligands is the highest, and 
      by thermogenesis through expression of the uncoupling protein 1 (UCP-1) and the 
      PPARgamma co-activator 1 alpha (PGC-1alpha), 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).
FAU - Pruimboom-Brees, Ingrid M
AU  - Pruimboom-Brees IM
AD  - Pfizer Inc., Sandwich, Kent, UK. Ingrid.Pruimboom@Novartis.com
FAU - Francone, Omar
AU  - Francone O
FAU - Pettersen, John C
AU  - Pettersen JC
FAU - Kerlin, Roy L
AU  - Kerlin RL
FAU - Will, Yvonne
AU  - Will Y
FAU - Amacher, David E
AU  - Amacher DE
FAU - Boucher, Germaine G
AU  - Boucher GG
FAU - Morton, Daniel
AU  - Morton D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120413
PL  - United States
TA  - Toxicol Pathol
JT  - Toxicologic pathology
JID - 7905907
RN  - 0 (Chromans)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Ion Channels)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Oxazoles)
RN  - 0 (PPAR alpha)
RN  - 0 (PPAR gamma)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, rat)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Transcription Factors)
RN  - 0 (Ucp1 protein, mouse)
RN  - 0 (Ucp1 protein, rat)
RN  - 0 (Uncoupling Protein 1)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - I66ZZ0ZN0E (Troglitazone)
RN  - TE7660XO1C (Glycine)
RN  - W1MKM70WQI (muraglitazar)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - Adipogenesis/drug effects
MH  - Adipose Tissue, Brown/drug effects/metabolism
MH  - Adipose Tissue, White/drug effects/metabolism
MH  - Animals
MH  - Cell Differentiation
MH  - Chromans/toxicity
MH  - DNA Damage/drug effects
MH  - Diabetes Mellitus, Type 2/physiopathology/therapy
MH  - Glycine/analogs & derivatives/toxicity
MH  - Hypoglycemic Agents/*toxicity
MH  - Ion Channels/genetics/metabolism
MH  - Mice
MH  - Mitochondria/drug effects/metabolism
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Oxazoles/toxicity
MH  - Oxidative Stress/drug effects
MH  - PPAR alpha/*agonists/genetics/metabolism
MH  - PPAR gamma/*agonists/genetics/metabolism
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Pioglitazone
MH  - RNA-Binding Proteins/genetics/metabolism
MH  - Rats
MH  - Rodentia/metabolism
MH  - Rosiglitazone
MH  - Sarcoma/*chemically induced/pathology
MH  - Thermogenesis/drug effects
MH  - Thiazolidinediones/toxicity
MH  - Transcription Factors/genetics/metabolism
MH  - Troglitazone
MH  - Uncoupling Protein 1
EDAT- 2012/04/17 06:00
MHDA- 2012/12/10 06:00
CRDT- 2012/04/17 06:00
PHST- 2012/04/17 06:00 [entrez]
PHST- 2012/04/17 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - 0192623312441406 [pii]
AID - 10.1177/0192623312441406 [doi]
PST - ppublish
SO  - Toxicol Pathol. 2012 Jul;40(5):810-8. doi: 10.1177/0192623312441406. Epub 2012 
      Apr 13.