Febuxostat improves outcome in a rat model of cancer cachexia

Journal of Cachexia, Sarcopenia and Muscle

Masaaki Konishi¹  Loes Pelgrim³  Anika Tschirner³  Anna Baumgarten³  Stephan von Haehling¹  Sandra Palus¹  Wolfram Doehner²  Stefan D. Anker¹ 

[1] Division of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany;Center for Stroke Research Berlin, Charité Medical School, Berlin, Germany;Applied Cachexia Research, Center for Cardiovascular Research, Charité Medical School, Berlin, Germany

关键词: Cancer cachexia;    Yoshida hepatoma animal model;    Weight loss;    Wasting;    Survival;   

DOI  :  10.1002/jcsm.12017

来源: Wiley

【 摘 要 】

Abstract

Background

Activity of xanthine oxidase is induced in cancer cachexia, and its inhibition by allopurinol or oxypurinol improves survival and reduces wasting in the Yoshida hepatoma cancer cachexia model. Here, we tested the effects of the second-generation xanthine oxidase inhibitor febuxostat compared with placebo in the same model as used previously by our group.

Methods

Wistar rats (~200 g) were treated daily with febuxostat at 5 mg/kg/day or placebo via gavage for a maximum of 17 days. Weight change, quality of life, and body composition were analysed. After sacrifice, proteasome activity in the gastrocnemius muscle was measured. Muscle-specific proteins involved in metabolism were analysed by western blotting.

Results

Treatment of the tumour-bearing rats with febuxostat led to a significantly improved survival compared with placebo (hazard ratio: 0.45, 95% confidence interval: 0.22–0.93, P = 0.03). Loss of body weight was reduced (−26.3 ± 12.4 g) compared with placebo (−50.2 ± 2.1 g, P < 0.01). Wasting of lean mass was attenuated (−12.7 ± 10.8 g) vs. placebo (−31.9 ± 2.1 g, P < 0.05). While we did not see an effect of febuxostat on proteasome activity at the end of the study, the pAkt/Akt ratio was improved by febuxostat (0.94 ± 0.09) vs. placebo (0.41 ± 0.05, P < 0.01), suggesting an increase in protein synthesis.

Conclusions

Febuxostat attenuated cachexia progression and improved survival of tumour-bearing rats.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society of Sarcopenia, Cachexia and Wasting Disorders

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.