Repurposing of Antibiotic Sulfisoxazole Inhibits Lipolysis in Pre-Clinical Model of Cancer-Associated Cachexia

SIMPLE SUMMARY: A large number of advanced cancer patients suffer from a gradual weight loss manifested as muscle and fat loss. This condition is known as cancer-associated cachexia. Cachexia limits tolerance of anti-cancer treatments, surgeries, and quality of life of individual who have cancer. Unfortunately, there are no potential agents available to treat cancer-induced cachexia. Here, we investigated the efficacy of the drug Sulfisoxazole in both cell and animal-based experiments. Our results demonstrated that upon treatment with Sulfisoxazole there was partial reduction of fat loss and improved overall well-being of the mice with cancer cachexia. Furthermore, cell-based analysis revealed that Sulfisoxazole reduces the loss of fat cells size and number. Thus, oral administration of Sulfisoxazole could be a promising means for the treatment of cancer-associated cachexia if it is combined with agents that could potentially inhibit muscle loss and/or anti-cancer agents. ABSTRACT: Clinical management of cancer-associated cachexia, a multi-organ wasting syndrome, has been challenging without effective treatment strategies. An effective treatment that directly targets cancer-induced wasting is desperately needed to improve the quality of life and the survival of cancer patients. Recently, an antibiotic SFX was shown to have anti-tumour and anti-metastatic effects in mouse models of breast cancer. Hence, in this study, we examined the efficacy of SFX in the treatment of cancer-induced cachexia. C26 cachexic mice models were administered with SFX, and the tumour volume and body weight were regularly measured. Blood glucose, skeletal muscles, and adipose tissue were examined at the endpoint. Contrary to a previous study, SFX did not reduce the tumour volume in mice bearing C26 cells. Administration of SFX neither revealed any survival benefit nor rescued C26 cachectic mice from muscle wasting. Interestingly, SFX administration partially rescued (~10%) tumour-induced weight loss by preserving both the subcutaneous and intestinal fat mass. Together, these results suggest that the administration of SFX could partially rescue cancer-induced weight loss by inhibiting lipolysis. As anti-cachexia therapies are scarce, the results could facilitate the design of combinatorial therapies involving SFX, standard-of-care chemotherapeutics, and drugs that inhibit muscle atrophy for the treatment of cancer cachexia.