Febuxostat reduces muscle wasting in tumor-bearing mice with LM8 osteosarcoma cells via inhibition of reactive oxygen species generation

摘要

Abstract Cachexic condition due to malignant tumors has been a challenging problem. The aim of this study is to analyze effects of febuxostat on both in?vitro and in?vivo models of the wasting of skeletal muscles, due to LM8 osteosarcoma cells. C2C12 myotubes were incubated in the conditioned medium of LM8. Febuxostat was added at a concentration of 3?μM and 30?μM, and ROS, diameter of myotubes, and expression of atrogin-1 were analyzed. Furthermore, an in?vivo study was performed by subcutaneous injection of LM8 on C3H mice. Febuxostat was administered in the drinking water at 5?μg/ml, and 25?μg/ml. In addition, tumor-bearing mice without febuxostat (group TB) and control mice (group C) were established. At 4?weeks, body weight, wet weights of the gastrocnemius muscles, XO activity, 8-OHdG, and expression of TNF-α and IL-6 were evaluated. ROS generation, atrophy of myotubes, and upregulation of atrogin-1 were clearly observed in C2C12 myotubes following incubation in the conditioned medium. These pathological conditions were significantly inhibited by febuxostat administration. Furthermore, mice in group TB showed significant loss of body weight and muscle weight in which XO activity, 8-OHdG, and expression of IL-6 were significantly increased compared to those in group C. Febuxostat administration not only significantly improved the body weight and muscleweight, but also reduced markers of oxidative stress and pro-inflammatory cytokines. Febuxostat did not show anti-tumor effects. Febuxostat, which is clinically used for treatment of hyperuricemia, is effective against the wasting of the skeletal muscles induced by LM8 osteosarcoma cells.