ved maximum velocity in the LLC model. Concerning the distance travelled, the treatment improved this parameter in all the models tested, independently from the distinct effect exerted on tumour burden. In order to explain the mechanisms accounting for the tumour-independent sorafenib effects, we determined the circulating concentrations of IL-6, a cytokine that has been reported to be affected by sorafenib, which reduces its release. Interestingly, in both C26 and LLC-bearing mice, where the levels of IL-6 are high as a consequence of tumour growth, sorafenib did not lower the cytokine concentration, suggesting that sorafenib effects do not directly rely on IL-6 11 / 16 Cancer Cachexia in Sorafenib-Treated Tumour-Bearing Mice inhibition. It has to be pointed out that muscle IL-6 concentration could be altered by the treatment; differences in receptor content are another possibility. Unfortunately, we have not assessed these possibilities. However, it is interesting to point out that the anti-tumour effect of sorafenib was stronger when IL-6 circulating levels were low, as in the B16-bearing mice, existing a good correlation between the degree of tumour reduction and the concentration of IL-6 in the different models tested. It seems, therefore, that sorafenib antitumour action is more effective in low IL-6 conditions. In order to further investigate the mechanisms by which sorafenib exerts its effects, we determined the intramuscular concentration and activation state of several proteins that might be involved in the sorafenib action. As far as we are concerned, there are no reports suggesting a direct kinase-inhibiting action of sorafenib in the skeletal muscle. For this part of the study we only used the C26 model, since in this setting, despite the absence of drug effects on tumour burden, sorafenib improved both muscle weight and activity parameters. The results depicted in 12 / 16 Cancer Cachexia in Sorafenib-Treated Tumour-Bearing Mice atrogin-1, sorafenib administration was able to reduce 
the atrogin-1 protein accumulation in C26 mice, likely limiting the catabolic stimulus. Such effect seems independent PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19683642 from the activation of the transcription factor FoxO3a, as the nuclear levels of the protein did not change in C26 mice and slightly PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19682619 decreased in sorafenib-treated C26 animals, confirming that the Akt/FoxO pathway is not involved in the onset of muscle wasting, at least in this experimental setting. These results suggest that sorafenib exerts its anti-cachectic action directly on the muscle by inhibiting either the STAT3 or ERK pathways, independently from IL-6 serum levels. Recent observations point out the suppressive role MedChemExpress 480-44-4 played by STAT3 in satellite cell-mediated muscle regeneration and, consistently, the anti-cachectic action exerted by sorafenib is stronger in the experimental model of cachexia where muscle regeneration is more affected. In conclusion, the results presented here reinforce the idea that sorafenib is an efficient drug for the treatment of tumours in addition to being a candidate for anti-cachectic therapy. This is based on the fact that any reduction in tumour mass results in a reduction in cachexia and also in the fact that, even without affecting the tumour, it does behave as an anti-cachectic molecule, as observed in the C26 tumour model. Yet, previous studies actually conclude that sorafenib per se induces wasting; therefore further studies in this field are needed and might lead to a new promising drug c