Background:
Cancer cachexia is characterized by progressive muscle wasting and associated with poor survival, increased toxicity of chemo- and radiotherapy and impaired quality of life. Myostatin plays an important role in the development of cachexia as activin receptor IIB/activin- like kinase 4/5 (ALK4/5) heterodimer activation by myostatin results in catabolic muscle degradation. SB431542 is a potent inhibitor of ALK4/5. We assessed its potential for treatment of cancer cachexia.

Material and Methods:
24 CD2F1 mice were inoculated subcutaneously with 0.5x10 6colon26 murine adenocarcinoma cells to induce cachexia, and allocated randomly into four groups: healthy controls, tumor-bearing controls, tumor-bearing vehicle (DMSO) treated, and tumor- bearing SB431542 treated. Weight was recorded daily. Grip strength was determined weekly. Starting from day 5, allocated mice received 10 mg/kg SB431542, or vehicle, intraperitoneally until sacrifice on day 20.

Results:
All tumor-bearing mice had a reduction in body weight compared to controls (21.1±2.1g versus 30.0±1.3g; p<0.0001). No differences in body weight were found between tumor-bearing groups. Despite weight loss, SB431542 treated animals had no reduction in grip strength. DMSO only treated animals showed a reduction in grip strength. Mean weight of the tibialis anterior muscle was preserved in SB431542 treated animals versus tumor-bearing vehicle treated animals (53.8mg vs. 40.5mg; p=0.0171) and tumor-bearing untreated animals (53.8mg vs. 34.7mg; p=0.0002).

Conclusion:
Inhibition of ALK4/5 by SB431542 inhibits cancer cachexia associated muscle wasting and loss of muscle force in experimental cancer cachexia.