Abstract
Cisplatin (DDP), a widely used chemotherapeutic drug in cancer treatment, causes oxidative stress, resulting in cancer cachexia and skeletal muscle atrophy. This study investigated the effects and activity of silibinin (SLI) in reducing DDP-induced oxidative stress and skeletal muscle atrophy in vivo and in vitro. SLI alleviated weight loss, food intake, muscle wasting, adipose tissue depletion, and organ weight reduction induced by DDP and improved the reduction of grip force caused by DDP. SLI can attenuated the increase in reactive oxygen species (ROS) levels, the decrease in Nrf2 expression, the decrease in the fiber cross-sectional area, and changes in fiber type induced by DDP. SLI regulated the ERK/FoxO and JNK/FoxO pathways by downregulating the abnormal increase in ROS and Nrf2 expression in DDP-treated skeletal muscle and C2C12 myotube cells. Further, SLI inhibited the upregulation of MAFbx and Mstn, the downregulation of MyHC and MyoG, the increase in protein degradation, and the decrease of protein synthesis. The protective effects of SLI were reversed by cotreatment with JNK agonists and ERK inhibitors. These results suggest that SLI can reduce DDP-induced skeletal muscle atrophy by reducing oxidative stress and regulating ERK/FoxO and JNK/FoxO pathways.
Highlights
Chemotherapy has been used to treat cancer since the 1970s [1, 2] and several recent studies have shown that during treatment with chemotherapy drugs, patients will experience cancer cachexia [3, 4]
The aim of this study was at exploring the effects of SLI on DDP-induced cachexia and its mechanism of alleviating skeletal muscle atrophy, at providing experimental evidence supporting the antioxidant effect of SLI, and at providing a rationale for its development as a drug to alleviate cancer cachexia and skeletal muscle atrophy caused by chemotherapeutic agents such as cisplatin
The Lewis lung cancer-bearing group (LLC) + DDP group mouse showed marked leg muscle atrophy and reduction in epididymal fat compared to mice in other groups, evidencing cachexia from cancer, which was improved by treatment with SLI
Summary
Chemotherapy has been used to treat cancer since the 1970s [1, 2] and several recent studies have shown that during treatment with chemotherapy drugs, patients will experience cancer cachexia [3, 4]. Many studies have shown that drugs with antioxidant and free radical scavenging activities, such as Scutellaria baicalensis and quercetin, can prevent and treat DDP-induced oxidative damage [13, 29, 30]. These findings suggest that it is possible to treat cancer cachexia caused by DDP by improving oxidative stress. SLI can improve the distribution of fatty acids in lipid droplets, improve liver fat metabolism, and decrease the activation of nuclear factor kappa-B (NF-κB) in the liver [35,36,37] It protects the liver by improving mitochondrial oxidation and reducing oxidative stress by reducing ROS levels, lipid peroxidation levels, and catalase activity [34, 38]. The aim of this study was at exploring the effects of SLI on DDP-induced cachexia and its mechanism of alleviating skeletal muscle atrophy, at providing experimental evidence supporting the antioxidant effect of SLI, and at providing a rationale for its development as a drug to alleviate cancer cachexia and skeletal muscle atrophy caused by chemotherapeutic agents such as cisplatin
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