[Aim] Lenvatinib (LEN), an oral tyrosine kinase inhibitor, is widely used to treat several types of advanced cancers but often causes muscular adverse reactions. Our previous study revealed that LEN reduces L-carnitine (L-CAR) content, expression of carnitine-related genes, and mitochondrial function in the skeletal muscle. Therefore, the present study aimed to investigate whether L-CAR supplementation prevents LEN-induced muscle impairment without affecting its anti-angiogenesis effect.
[Methods] Eight-week-old male Wistar rats were divided into four groups and administrated orally once daily for 2 weeks with vehicle, LEN (2 mg/kg/day), LEN + L-CAR (150 mg/kg/day), or LEN + L-CAR (300 mg/kg). In the in vitro studies, differentiated C2C12 myocytes, HUVECs, and mouse aorta were treated with LEN (0.1 and/or 1 μM) and L-CAR (1.6, 6.4, and 25.6 mM).
[Results] L-CAR supplementation significantly attenuated LEN-induced deleterious effects on L-CAR content, expression of carnitine-related (OCTN2, CPT1, CACT, and CPT2) and OXPHOS genes in the skeletal muscle of rats. In addition, L-CAR prevented LEN-induced reductions in mitochondrial function (ATP content and membrane potential) in C2C12 myocytes. Furthermore, L-CAR did not affect the anti-angiogenesis action of LEN assessed by the tube formation and ring assays.
[Conclusion] These results suggest that L-CAR supplementation can alleviate the adverse reactions of LEN in the skeletal muscle without reducing its antineoplastic effect.