L-carnitine Prevents Lenvatinib-induced Muscle Toxicity Without Impairment of the Anti-angiogenic Efficacy

Overview

Journal Front Pharmacol

Date 2023 Apr 24

PMID 37089945

Authors

Zheng Jing

Tomohiro Iba

Hisamichi Naito

Pingping Xu

Jun-Ichi Morishige

Naoto Nagata

Hironao Okubo

Hitoshi Ando

Affiliations

Soon will be listed here.

Abstract

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.

References

Rajasekar P, Viswanathan P, Anuradha C . Renoprotective action of L-carnitine in fructose-induced metabolic syndrome. Diabetes Obes Metab. 2007; 10(2):171-80. DOI: 10.1111/j.1463-1326.2007.00825.x. View

Bartlett K, Eaton S . Mitochondrial beta-oxidation. Eur J Biochem. 2004; 271(3):462-9. DOI: 10.1046/j.1432-1033.2003.03947.x. View

Sauzay C, Louandre C, Bodeau S, Anglade F, Godin C, Saidak Z . Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells. Oncotarget. 2018; 9(9):8400-8414. PMC: 5823558. DOI: 10.18632/oncotarget.23843. View

Arnaoutova I, Kleinman H . In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract. Nat Protoc. 2010; 5(4):628-35. DOI: 10.1038/nprot.2010.6. View

Okubo H, Ando H, Ishizuka K, Kitagawa R, Okubo S, Saito H . Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma. PLoS One. 2020; 15(3):e0229772. PMC: 7053710. DOI: 10.1371/journal.pone.0229772. View

Rinninella E, Cintoni M, Raoul P, Pozzo C, Strippoli A, Ponziani F . Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges. Nutrients. 2020; 12(10). PMC: 7601327. DOI: 10.3390/nu12103101. View

Aboubakr M, Elsayd F, Soliman A, Fadl S, El-Shafey A, Abdelhiee E . L-Carnitine and vitamin E ameliorate cardiotoxicity induced by tilmicosin in rats. Environ Sci Pollut Res Int. 2020; 27(18):23026-23034. DOI: 10.1007/s11356-020-08919-6. View

Rosenberg L, Yoon C, Sharma G, Bertagnolli M, Cho N . Sorafenib inhibits proliferation and invasion in desmoid-derived cells by targeting Ras/MEK/ERK and PI3K/Akt/mTOR pathways. Carcinogenesis. 2018; 39(5):681-688. DOI: 10.1093/carcin/bgy038. View

Baker M, Robinson S, Lechertier T, Barber P, Tavora B, DAmico G . Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc. 2011; 7(1):89-104. DOI: 10.1038/nprot.2011.435. View

10.

Longo N, Frigeni M, Pasquali M . Carnitine transport and fatty acid oxidation. Biochim Biophys Acta. 2016; 1863(10):2422-35. PMC: 4967041. DOI: 10.1016/j.bbamcr.2016.01.023. View

11.

Gramignano G, Lusso M, Madeddu C, Massa E, Serpe R, Deiana L . Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition. 2006; 22(2):136-45. DOI: 10.1016/j.nut.2005.06.003. View

12.

Tamai I . Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos. 2012; 34(1):29-44. DOI: 10.1002/bdd.1816. View

13.

Madsen J, Seoni E, Kreuzer M, Silacci P, Bee G . Influence of l-carnitine and l-arginine on protein synthesis and maturation of the semitendinosus muscle of lightweight piglets. J Anim Physiol Anim Nutr (Berl). 2017; 102(2):440-451. DOI: 10.1111/jpn.12765. View

14.

Heo Y, Kang C, Cha Y . L-Carnitine changes the levels of insulin-like growth factors (IGFs) and IGF binding proteins in streptozotocin-induced diabetic rat. J Nutr Sci Vitaminol (Tokyo). 2002; 47(5):329-34. DOI: 10.3177/jnsv.47.329. View

15.

Hiramatsu A, Aikata H, Uchikawa S, Ohya K, Kodama K, Nishida Y . Levocarnitine Use Is Associated With Improvement in Sarcopenia in Patients With Liver Cirrhosis. Hepatol Commun. 2019; 3(3):348-355. PMC: 6396356. DOI: 10.1002/hep4.1309. View

16.

Shah A, Kamal M, Akhtar S . Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions. Curr Drug Metab. 2020; 22(1):50-59. DOI: 10.2174/1389200221666201019143252. View

17.

Liu G, Chen T, Ding Z, Wang Y, Wei Y, Wei X . Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment. Cell Prolif. 2021; 54(4):e13009. PMC: 8016646. DOI: 10.1111/cpr.13009. View

18.

Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996; 86(3):353-64. DOI: 10.1016/s0092-8674(00)80108-7. View

19.

Okubo H, Ando H, Ishizuka K, Morishige J, Ikejima K, Shiina S . Impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of lenvatinib in patients with hepatocellular carcinoma. J Pharmacol Sci. 2021; 148(1):6-13. DOI: 10.1016/j.jphs.2021.08.011. View

20.

Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T . E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2007; 122(3):664-71. DOI: 10.1002/ijc.23131. View