Lenvatinib 是一种口服酪氨酸激酶抑制剂，作用于参与血管生成的多种受体。Lenvatinib 是治疗多种晚期癌症的标准药物，但常常会引起与肌肉有关的不良反应。我们之前的研究发现，lenvatinib 治疗会降低大鼠骨骼肌肉肉毒碱含量和肉毒碱相关和氧化磷酸化（OXPHOS）蛋白质的表达。因此，本研究旨在评估 L-肉碱对 lenvatinib 肌肉毒性和抗血管生成作用的影响。在 lenvatinib 治疗的大鼠中联合给予 L-肉碱治疗 2 周，完全预防了骨骼肌肉肉毒碱含量和肉毒碱相关和 OXPHOS 蛋白质（包括肉毒碱/有机阳离子转运蛋白2）的表达水平下降。此外，L-肉碱抵消了 C2C12 肌细胞中 lenvatinib 引起的蛋白质合成抑制、线粒体功能障碍和细胞毒性。相反，L-肉碱对于 lenvatinib 诱导的人脐静脉内皮细胞血管内皮生长因子受体2磷酸化抑制，以及内皮细胞管形成和小鼠主动脉环形成方面均没有影响。这些结果表明，L-肉碱补充可以预防 lenvatinib 引起的肌肉毒性，而不会降低其抗肿瘤活性，尽管还需要进一步的临床研究来验证这些结果。版权所有©2023 Jing, Iba, Naito, Xu, Morishige, Nagata, Okubo and Ando。

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.Copyright © 2023 Jing, Iba, Naito, Xu, Morishige, Nagata, Okubo and Ando.