Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia

Stefan D. Anker
,
Jochen Springer
,
Anika Tschirner
,
Kai Hartman
,
Sandra Palus
,
Eva K. Wirth

University of Bedfordshire
,
University of East Anglia
,
Charité – Universitätsmedizin Berlin
,
University of Barcelona
,
Leipzig University

Research Output: Contribution to journal Article Peer-review

Sustainable Development Goals

SDG 3 Good Health and Well

Abstract

Cachexia is a common co-morbidity in cancer occurring in up to 80% of patients depending on the type of cancer. Uric acid (UA), the end-product of the purine metabolism, is elevated in cachexia due to tissue wasting and upregulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO-dependent production of oxygen free radicals (reactive oxygen species; ROS) and correlate with metabolic illness and poor survival. We hypothesized that XO-inhibition might reduce inflammatory signals accounting for tissue wasting and improve survival in experimental cancer cachexia. Animals were inoculated intraperitoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol [Allo, low (LD) and high dose (HD) 4 and 40 mg/kg/d] and its more effective active metabolite oxypurinol (Oxy, 4 and 40 mg/kg/d) or placebo for 15 days. Weight loss and tissue wasting of both fat and lean tissue (assessed by NMR-scanning) was reduced by both LD and HD Allo and LD-Oxy, but not by HD-Oxy. A robust induction of XO-activity for generation of reactive oxygen species was seen in the placebo group (assessed by electron paramagnetic spectroscopy), which was reduced by XO-inhibition. Increased ROS induced cytokine signaling, proteolytic activity and tissue degradation were all attenuated by XO inhibition. Survival was significantly and dose dependently improved. Food intake and spontaneous locomotor activity were higher, indicating a higher quality of life. Inhibition of XO can reduce tissue wasting and improve survival in cancer cachexia and clearly clinical studies are needed.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 2187-2196

Journal (Volume, Issue Number)

International Journal of Cancer (Volume 131, Issue 9)

Publication milestones

Published - 01/11/2012

Publication status

Published - 01/11/2012

ISSN

0020-7136

External Publication IDs

handle.net: 10547/593452
Scopus: 84865533185

Access to documents

10.1002/ijc.27494

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