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.