Chemotherapy, as one of the primary and indispensable treatment modalities for cancers in clinic, usually causes robust side effects, such as anorexia, weight loss, weakness and fatigue, which would induce or worsen a cachectic phenotype, especially cachectic muscle loss (Bozzetti, 2020; Hellmann et al., 2016; Pin et al., 2019; Zhang et al., 2018). In cancer patients, the prevalence of cachexia reaches nearly 80%, which directly resulted in approximately 30% of mortality (Khatib et al., 2018; Sin et al., 2021). Previous reports suggested that, after platinum-based chemotherapy, patients with oesophagogastric cancer lost 11.4 kg of body weight (Awad et al., 2012); patients with pancreatic cancer, who received neoadjuvant therapy (a combination of gemcitabine and cisplatin), were found to lose 8% of fat and 2.5% of skeletal muscle though detection of computed tomography (Cooper et al., 2015); chemoirradiation treatment made patients with head and neck cancer reduce 4.2 kg of body weight (Kubrak et al., 2013). These side effects caused by chemotherapy, particularly cachectic muscle loss, are weakening the therapeutic outcomes, reducing quality of life and even threatening patients’ lives (Meng et al., 2022; Sin et al., 2021). Unfortunately, there is no approved treatment to combat chemotherapy-induced cachexia.

Although the underlying mechanisms of chemotherapy-induced cachectic muscle loss are complex and diverse, which involve the ubiquitin-proteasome pathway (UPP), the autophagy-lysosome pathway (ALP), calcium homeostasis, mitochondrial damage, pro-inflammation pathways, etc., oxidative stress is believed to play a key role (Conte et al., 2020; Gilliam and St Clair, 2011; Hiensch et al., 2020). Most of chemotherapeutic agents can lead to DNA destruction and increase reactive oxygen species (ROS) production (Pulito et al., 2020). Growing evidence suggests that ROS, as a typical feature of oxidative stress, can decrease protein synthesis and increase proteolysis to promote muscle atrophy (Saito et al., 2019). As key mediators of cellular physiology and pathology, cellular ROS can damage mitochondrial proteins and activate the apoptosis pathway in case of overload (Saito et al., 2019; Park et al., 2017). Since oxidative damages are mostly responsible for chemotherapy-induced muscle loss, counteracting oxidative stress might protect skeletal muscle against chemotherapeutic agents.

On the basis of the skeleton of dithocarbamates (DTCs) with a wide range of biological activities (anti-inflammation, anti-oxidation and anti-tumor, etc. (Schreck et al., 1992; Zanocco et al., 1989), we have designed and synthesized novel series of compounds in our previous study. Compound Z526 (Dodecyl pyrrolidine-1-carbo (dithioperoxo)thioate, CN Patent No. ZL202011100806.X) was found to significantly alleviate muscle atrophy induced by cancer cachexia, by which Z526 intervened oxidative stress in cachectic muscle. In the present study, we explored the alleviating effects of Z526 on chemotherapy-induced cachectic muscle loss in in vitro and in vivo models in the presence and absence of tumor loads and the relevant pharmacological mechanisms, which could contribute to drug development to alleviate chemotherapy-induced muscle atrophy.