A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.
Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac ener...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5271313?pdf=render |
| _version_ | 1818519948509577216 |
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| author | Alice C O'Farrell Rhys Evans Johanna M U Silvola Ian S Miller Emer Conroy Suzanne Hector Maurice Cary David W Murray Monika A Jarzabek Ashwini Maratha Marina Alamanou Girish Mallya Udupi Liam Shiels Celine Pallaud Antti Saraste Heidi Liljenbäck Matti Jauhiainen Vesa Oikonen Axel Ducret Paul Cutler Fionnuala M McAuliffe Jacques A Rousseau Roger Lecomte Suzanne Gascon Zoltan Arany Bonnie Ky Thomas Force Juhani Knuuti William M Gallagher Anne Roivainen Annette T Byrne |
| author_facet | Alice C O'Farrell Rhys Evans Johanna M U Silvola Ian S Miller Emer Conroy Suzanne Hector Maurice Cary David W Murray Monika A Jarzabek Ashwini Maratha Marina Alamanou Girish Mallya Udupi Liam Shiels Celine Pallaud Antti Saraste Heidi Liljenbäck Matti Jauhiainen Vesa Oikonen Axel Ducret Paul Cutler Fionnuala M McAuliffe Jacques A Rousseau Roger Lecomte Suzanne Gascon Zoltan Arany Bonnie Ky Thomas Force Juhani Knuuti William M Gallagher Anne Roivainen Annette T Byrne |
| author_sort | Alice C O'Farrell |
| collection | DOAJ |
| description | Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment. |
| first_indexed | 2024-12-11T01:30:52Z |
| format | Article |
| id | doaj.art-a50b8f08c3d74280a693b5b4bb9f1718 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T01:30:52Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a50b8f08c3d74280a693b5b4bb9f17182022-12-22T01:25:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e016996410.1371/journal.pone.0169964A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.Alice C O'FarrellRhys EvansJohanna M U SilvolaIan S MillerEmer ConroySuzanne HectorMaurice CaryDavid W MurrayMonika A JarzabekAshwini MarathaMarina AlamanouGirish Mallya UdupiLiam ShielsCeline PallaudAntti SarasteHeidi LiljenbäckMatti JauhiainenVesa OikonenAxel DucretPaul CutlerFionnuala M McAuliffeJacques A RousseauRoger LecomteSuzanne GasconZoltan AranyBonnie KyThomas ForceJuhani KnuutiWilliam M GallagherAnne RoivainenAnnette T ByrneSunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.http://europepmc.org/articles/PMC5271313?pdf=render |
| spellingShingle | Alice C O'Farrell Rhys Evans Johanna M U Silvola Ian S Miller Emer Conroy Suzanne Hector Maurice Cary David W Murray Monika A Jarzabek Ashwini Maratha Marina Alamanou Girish Mallya Udupi Liam Shiels Celine Pallaud Antti Saraste Heidi Liljenbäck Matti Jauhiainen Vesa Oikonen Axel Ducret Paul Cutler Fionnuala M McAuliffe Jacques A Rousseau Roger Lecomte Suzanne Gascon Zoltan Arany Bonnie Ky Thomas Force Juhani Knuuti William M Gallagher Anne Roivainen Annette T Byrne A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. PLoS ONE |
| title | A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. |
| title_full | A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. |
| title_fullStr | A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. |
| title_full_unstemmed | A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. |
| title_short | A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. |
| title_sort | novel positron emission tomography pet approach to monitor cardiac metabolic pathway remodeling in response to sunitinib malate |
| url | http://europepmc.org/articles/PMC5271313?pdf=render |
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