O'Farrell Alice C, Evans Rhys, Silvola Johanna M U, Miller Ian S, Conroy Emer, Hector Suzanne, Cary Maurice, Murray David W, Jarzabek Monika A, Maratha Ashwini, Alamanou Marina, Udupi Girish Mallya, Shiels Liam, Pallaud Celine, Saraste Antti, Liljenbäck Heidi, Jauhiainen Matti, Oikonen Vesa, Ducret Axel, Cutler Paul, McAuliffe Fionnuala M, Rousseau Jacques A, Lecomte Roger, Gascon Suzanne, Arany Zoltan, Ky Bonnie, Force Thomas, Knuuti Juhani, Gallagher William M, Roivainen Anne, Byrne Annette T
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.
PLoS One. 2017 Jan 27;12(1):e0169964. doi: 10.1371/journal.pone.0169964. eCollection 2017.
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.
舒尼替尼是一种被批准用于治疗多种实体瘤的酪氨酸激酶抑制剂。然而，心脏毒性越来越受到关注，需要开发基于合理机制的方法来早期检测心脏功能障碍。我们试图探究舒尼替尼治疗期间心脏能量底物使用情况的变化，假设这些变化可能代表一种早期检测心脏毒性的策略。将Balb/CJ小鼠或Sprague-Dawley大鼠每日口服40或20 mg/kg的舒尼替尼，持续4周。采用心脏正电子发射断层扫描（PET）来研究心肌葡萄糖和氧化代谢的变化。治疗后，血压升高，左心室射血分数降低。心脏[18F] - 氟脱氧葡萄糖（FDG）-PET显示48小时后葡萄糖摄取增加。[11C]乙酸盐-PET显示治疗后心肌灌注减少。电子显微镜检查显示心肌中有大量脂质蓄积。蛋白质组学分析表明，氧化代谢、脂肪酸β氧化和线粒体功能障碍是受干扰的主要心肌信号通路。舒尼替尼治疗导致对糖酵解的依赖性增加、心肌脂质沉积增加以及线粒体功能紊乱，这表明存在根本性的能量危机，导致心肌能量代谢和功能受损。我们的研究结果表明，心脏PET策略可能代表一种合理的方法，用于无创监测舒尼替尼治疗后代谢途径的重塑。
