Febuxostat improves outcome in a rat model of cancer cachexia

Masaaki Konishi, Loes Pelgrim, Anika Tschirner, Anna Baumgarten, Stephan von Haehling, Sandra Palus, Wolfram Doehner, Stefan D. Anker, Jochen Springer

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)174-180
Number of pages7
JournalJournal of Cachexia, Sarcopenia and Muscle
DOIs
Publication statusPublished - 2015

Fingerprint

Cachexia
Placebos
Neoplasms
Xanthine Oxidase
Proteasome Endopeptidase Complex
Oxypurinol
Cohort Effect
Allopurinol
Muscle Proteins
Body Composition
Febuxostat
Wistar Rats
Hepatocellular Carcinoma
Skeletal Muscle
Western Blotting
Body Weight
Quality of Life
Confidence Intervals
Weights and Measures
Proteins

Keywords

  • Cancer cachexia
  • Survival
  • Wasting
  • Weight loss
  • Yoshida hepatoma animal model

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

Konishi, M., Pelgrim, L., Tschirner, A., Baumgarten, A., von Haehling, S., Palus, S., ... Springer, J. (2015). Febuxostat improves outcome in a rat model of cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 174-180. https://doi.org/10.1002/jcsm.12017

Febuxostat improves outcome in a rat model of cancer cachexia. / Konishi, Masaaki; Pelgrim, Loes; Tschirner, Anika; Baumgarten, Anna; von Haehling, Stephan; Palus, Sandra; Doehner, Wolfram; Anker, Stefan D.; Springer, Jochen.

In: Journal of Cachexia, Sarcopenia and Muscle, 2015, p. 174-180.

Research output: Contribution to journalArticle

Konishi, M, Pelgrim, L, Tschirner, A, Baumgarten, A, von Haehling, S, Palus, S, Doehner, W, Anker, SD & Springer, J 2015, 'Febuxostat improves outcome in a rat model of cancer cachexia', Journal of Cachexia, Sarcopenia and Muscle, pp. 174-180. https://doi.org/10.1002/jcsm.12017
Konishi M, Pelgrim L, Tschirner A, Baumgarten A, von Haehling S, Palus S et al. Febuxostat improves outcome in a rat model of cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle. 2015;174-180. https://doi.org/10.1002/jcsm.12017
Konishi, Masaaki ; Pelgrim, Loes ; Tschirner, Anika ; Baumgarten, Anna ; von Haehling, Stephan ; Palus, Sandra ; Doehner, Wolfram ; Anker, Stefan D. ; Springer, Jochen. / Febuxostat improves outcome in a rat model of cancer cachexia. In: Journal of Cachexia, Sarcopenia and Muscle. 2015 ; pp. 174-180.
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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.",
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