Combined treatment of carfilzomib and z-VAD-fmk inhibits skeletal proteolysis and apoptosis and ameliorates cancer cachexia

The purpose of the study was to evaluate the therapeutic benefit of treatments with carfilzomib (CFZ) and z-VAD-fmk in a mouse model of cancer-induced cachexia. The model of cancer-associated cachexia was generated by injecting murine C26 adenocarcinoma cells into BALB/C mice. CFZ and z-VAD-fmk were administered individually or in combination at 5 and 12 days after inoculation. Changes in body weight, gastrocnemius muscle mass, tumor burden, spontaneous activity, survival, and metabolic profiles were noted. Also evaluated were the circulatory levels of renin and angiotensin II, and levels of apoptotic, proteolytic, and renin-angiotensin system-associated markers and transcription factor 2 (ATF2) in gastrocnemius muscle. The CFZ and z-VAD-fmk treatments were associated with less muscle wasting, reduced tumor burden, modulated metabolism, higher levels of glucose, albumin, and total proteins, and lower levels of triglyceride fatty acids, more spontaneous physical activity, and longer survival in C26-inoculated mice compared with PBS-treated cachectic mice. CFZ and z-VAD-fmk treatments resulted in higher levels of caspase-3 and BAX and lower level of BCL-XL in gastrocnemius muscles and altered the level of proteins in the renin-angiotensin system. The combined treatment administered 5 days after C26 inoculation was more effective than other regimens. Combined treatment with CFZ and z-VAD-fmk early in the development of cachexia was associated with signs of less proteolysis and apoptosis and less severe cachexia in a mouse model of cancer-induced cachexia.