PXD001888

PXD001888 is an original dataset announced via ProteomeXchange.

Title	Mouse heart toxicity
Description	Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.
HostingRepository	PRIDE
AnnounceDate	2017-01-03
AnnouncementXML	Submission_2017-01-31_02:10:19.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Axel Ducret
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2015-03-09 02:12:13	ID requested
1	2017-01-03 00:24:09	announced
⏵ 2	2017-01-31 02:10:21	announced	Updated publication reference for PubMed record(s): 28129334.

O'Farrell AC, Evans R, Silvola JM, Miller IS, Conroy E, Hector S, Cary M, Murray DW, Jarzabek MA, Maratha A, Alamanou M, Udupi GM, Shiels L, Pallaud C, Saraste A, Liljenb, ä, ck H, Jauhiainen M, Oikonen V, Ducret A, Cutler P, McAuliffe FM, Rousseau JA, Lecomte R, Gascon S, Arany Z, Ky B, Force T, Knuuti J, Gallagher WM, Roivainen A, Byrne AT, A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. PLoS One, 12(1):e0169964(2017) [pubmed]

curator keyword: Biological

submitter keyword: Mouse, heart tissue, LC-MS/MS

Axel Ducret
contact affiliation	Pharmaceutical Sciences - TTB Roche Pharma Research and Early Development Roche Innovation Center Basel F. Hoffmann-La Roche Ltd Building/Room 93/4.44 Grenzacherstrasse 124 CH-4070 Basel, Switzerland
contact email	axel.ducret@roche.com
lab head
Axel Ducret
contact affiliation	F. Hoffmann-La Roche Ltd
contact email	axel.ducret@roche.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD001888
     1. Label: PRIDE project
     2. Name: Mouse heart toxicity