DataSheet1_L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy.docx

Lenvatinib is an oral tyrosine kinase inhibitor that acts on multiple receptors involved in angiogenesis. Lenvatinib is a standard agent for the treatment of several types of advanced cancers; however, it frequently causes muscle-related adverse reactions. Our previous study revealed that lenvatinib treatment reduced carnitine content and the expression of carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle of rats. Therefore, this study aimed to evaluate the effects of L-carnitine on myotoxic and anti-angiogenic actions of lenvatinib. Co-administration of L-carnitine in rats treated with lenvatinib for 2 weeks completely prevented the decrease in carnitine content and expression levels of carnitine-related and OXPHOS proteins, including carnitine/organic cation transporter 2, in the skeletal muscle. Moreover, L-carnitine counteracted lenvatinib-induced protein synthesis inhibition, mitochondrial dysfunction, and cell toxicity in C2C12 myocytes. In contrast, L-carnitine had no influence on either lenvatinib-induced inhibition of vascular endothelial growth factor receptor 2 phosphorylation in human umbilical vein endothelial cells or angiogenesis in endothelial tube formation and mouse aortic ring assays. These results suggest that L-carnitine supplementation could prevent lenvatinib-induced muscle toxicity without diminishing its antineoplastic activity, although further clinical studies are needed to validate these findings.

仑伐替尼（Lenvatinib）是一种口服酪氨酸激酶抑制剂（tyrosine kinase inhibitor），可作用于参与血管生成（angiogenesis）的多种受体。仑伐替尼是治疗多种晚期癌症的标准用药，但常引发肌肉相关不良反应。我们既往的研究显示，仑伐替尼给药可降低大鼠骨骼肌内的肉碱含量，以及肉碱相关蛋白与氧化磷酸化（oxidative phosphorylation，OXPHOS）蛋白的表达水平。因此本研究旨在评估L-肉碱（L-carnitine）对仑伐替尼的肌毒性与抗血管生成活性的影响。在接受仑伐替尼给药2周的大鼠中，联合给予L-肉碱可完全阻止骨骼肌内肉碱含量、肉碱/有机阳离子转运体2（carnitine/organic cation transporter 2）等肉碱相关蛋白及OXPHOS蛋白表达水平的下降。此外，L-肉碱可抵消C2C12肌细胞中仑伐替尼诱导的蛋白质合成抑制、线粒体功能障碍与细胞毒性。与之相反，L-肉碱对人脐静脉内皮细胞（human umbilical vein endothelial cells）中仑伐替尼诱导的血管内皮生长因子受体2（vascular endothelial growth factor receptor 2）磷酸化抑制，以及内皮细胞管形成实验与小鼠主动脉环实验中的血管生成均无影响。上述结果表明，补充L-肉碱可预防仑伐替尼诱导的肌肉毒性，且不会削弱其抗肿瘤活性，不过仍需开展进一步的临床研究以验证上述发现。