Lenvatinib causes reduced expression of carnitine/organic cation transporter 2 and carnitine deficiency in the skeletal muscle of rats

Jing, Zheng; Okubo, Hironao; Morishige, Jun‐ichi; Xu, Pingping; Nazmul, Hasan; Nagata, Naoto; Ando, Hitoshi

doi:10.1016/j.toxlet.2022.06.012

Cited by 7 publications

(9 citation statements)

References 30 publications

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“…These treatments did not obviously alter the food intake or body weight of the rats throughout the treatment period ( Figure 1 ). Consistent with our previous results ( Jing et al, 2022 ), lenvatinib significantly reduced L-carnitine content ( Figure 2 ) and downregulated the expression of carnitine-related ( Figure 3A ) and OXPHOS proteins ( Figure 3B ) in the skeletal muscle on day 15 of treatment initiation. These effects of lenvatinib were completely offset by co-administration of high-dose L-carnitine.…”

Section: Resultssupporting

confidence: 92%

“…41, Tsukuba, Japan) and maintained in Dulbecco’s modified Eagle’s medium (DMEM; Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (Biowest, Nuaille, France), 100 μg/mL streptomycin, and 100 U/mL penicillin (Thermo Fisher Scientific) at 37°C in a humidified atmosphere containing 5% CO 2 . Differentiation of the cells to myocytes was induced by incubating the cells in a standard differentiation medium consisting of DMEM with 2% horse serum (Thermo Fisher Scientific) for 6 days, and was confirmed by upregulation of mRNA expression of Myod1 and Myog ( Jing et al, 2022 ). Thereafter, myocytes were treated for 24 h with 1 µM lenvatinib or vehicle (0.1% dimethyl sulfoxide) in combination with varying concentrations (0, 1.6, 6.4, or 25.6 mM) of L-carnitine.…”

Section: Methodsmentioning

confidence: 99%

“…After 1-week acclimation period, the rats were divided into four groups: control (n = 5), lenvatinib (n = 5), lenvatinib + low-dose L-carnitine (n = 5), and lenvatinib + high-dose L-carnitine (n = 6). Similar to our previous study (Jing et al, 2022), all groups received oncedaily oral dose of lenvatinib mesylate (2 mg/kg; Carbosynth, Berkshire, UK) or vehicle (0.5% w/v methyl cellulose 400 solution; Fujifilm Wako Pure Chemical, Osaka, Japan) at a volume of 1 mL/kg for 14 days. Additionally, L-carnitine (150 or 300 mg/kg; Fujifilm Wako Pure Chemical) or vehicle (distilled water) was co-administered in a volume of 2 mL/kg once daily for 14 days to all rats.…”

Section: Rats and Treatmentsmentioning

confidence: 99%

“…Our previous study demonstrated that a 14-day daily administration of lenvatinib to rats reduced OCTN2 protein levels in the skeletal muscle and intestine, but not in the kidney, and consequently decreased L-carnitine content in the skeletal muscle ( Jing et al, 2022 ). Lenvatinib administration also reduced mitochondrial carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

“…Lenvatinib administration also reduced mitochondrial carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle. Moreover, lenvatinib inhibited protein synthesis and mitochondrial function in cultured C2C12 myocytes in a dose-dependent manner ( Jing et al, 2022 ). In patients with HCC, we found that the plasma acylcarnitine to free carnitine ratio, a marker of carnitine insufficiency, was significantly increased on day 14 of lenvatinib therapy initiation, and that the increase was apparently correlated with the change in fatigue severity on day 28 ( Okubo et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy

et al. 2023

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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.

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Rats and Treatmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy

et al. 2023

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Real world data of cabozantinib in patients with hepatocellular carcinoma: Focusing on dose setting and modification

Okubo,

Ando,

Nakamura

et al. 2024

Cancer Medicine

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AimTo investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification.MethodsWe retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients.ResultsSixteen patients received ≥40 mg (high‐dose group), and 18 patients received 20 mg (low‐dose group). Dose escalations were performed in 27.8% of the patients in the low‐dose group. Although median duration of the first dose reduction or interruption in the low‐dose group was twice that in the high‐dose group (28 vs. 14 days, p < 0.001), there were no significant differences in the relative dose intensity (RDI) during 6 weeks, progression free survival (PFS), and overall survival (p = 0.162, p = 0.950, p = 0.817, respectively) between the two groups. Patients who received RDI during 6 weeks ≥33.4% showed a trend toward longer median PFS (p = 0.054). Each serum aldolase value during the 6 weeks was significantly correlated with the Ctrough at any point (r = 0.500, p < 0.001). In multivariate analyses, aldolase ≥8.7 U/L within 2 weeks was significantly associated with the very early dose reduction or interruption (odds ratio 20.0, p = 0.002).ConclusionsAn initial dose of 20 mg cabozantinib could be a safe option in Japanese patients. The serum aldolase value could be useful for making appropriate dose modifications of cabozantinib.

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Effects of Lenvatinib on Skeletal Muscle Volume and Cardiac Function in Patients with Hepatocellular Carcinoma

Nagai¹,

Amaki²,

Mukozu³

et al. 2023

Oncology

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Introduction: previously, we reported that the tyrosine kinase inhibitor (TKI) sorafenib decreases serum levels of carnitine and reduce skeletal muscle volume. Moreover, others were reported that TKIs might lead to cardiomyopathy or heart failure. Therefore, this study aimed to evaluated the effects of lenvatinib (LEN) on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma (HCC). Methods: This retrospective study included 58 adult Japanese patients with chronic liver diseases and HCC treated with LEN. Blood samples were collected before and after 4 weeks of treatment, and serum carnitine fraction and myostatin levels were measured. Before and after 4 to 6 weeks of treatment, the skeletal muscle index (SMI) was evaluated from computed tomography images and cardiac function was assessed by ultrasound cardiography. Results: After treatment, SMI, serum levels of total carnitine, and global longitudinal strain were significantly lower, but serum levels of myostatin were significantly higher. Left ventiricular ejection fraction showed no significant change. Conclusion: In patients with HCC, LEN decreases serum levels of carnitine, skeletal muscle volume, and worsens cardiac function.

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Lenvatinib causes reduced expression of carnitine/organic cation transporter 2 and carnitine deficiency in the skeletal muscle of rats

Cited by 7 publications

References 30 publications

L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy

L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy

Real world data of cabozantinib in patients with hepatocellular carcinoma: Focusing on dose setting and modification

Effects of Lenvatinib on Skeletal Muscle Volume and Cardiac Function in Patients with Hepatocellular Carcinoma

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