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

2.50
Hdl Handle:
http://hdl.handle.net/10547/593452
Title:
Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia
Authors:
Springer, Jochen; Tschirner, Anika; Hartman, Kai; Palus, Sandra; Wirth, Eva K.; Ruis, Silvia Busquets; Möller, Nadine; von Haehling, Stephan; Argiles, Josep M.; Köhrle, Josef; Adams, Volker; Anker, Stefan D.; Doehner, Wolfram
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.
Affiliation:
Charité Medical School; Universitat de Barcelona; University of Leipzig; IRCCS San Raffaele, Rome
Citation:
Springer, J., et al (2012) 'Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia' Int. J. Cancer 131 (9):2187-96
Publisher:
Wiley
Journal:
International journal of cancer
Issue Date:
1-Nov-2012
URI:
http://hdl.handle.net/10547/593452
DOI:
10.1002/ijc.27494
PubMed ID:
22336965
Additional Links:
http://onlinelibrary.wiley.com/doi/10.1002/ijc.27494/full
Type:
Article
Language:
en
ISSN:
1097-0215
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorSpringer, Jochenen
dc.contributor.authorTschirner, Anikaen
dc.contributor.authorHartman, Kaien
dc.contributor.authorPalus, Sandraen
dc.contributor.authorWirth, Eva K.en
dc.contributor.authorRuis, Silvia Busquetsen
dc.contributor.authorMöller, Nadineen
dc.contributor.authorvon Haehling, Stephanen
dc.contributor.authorArgiles, Josep M.en
dc.contributor.authorKöhrle, Josefen
dc.contributor.authorAdams, Volkeren
dc.contributor.authorAnker, Stefan D.en
dc.contributor.authorDoehner, Wolframen
dc.date.accessioned2016-01-14T12:51:53Zen
dc.date.available2016-01-14T12:51:53Zen
dc.date.issued2012-11-01en
dc.identifier.citationSpringer, J., et al (2012) 'Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia' Int. J. Cancer 131 (9):2187-96en
dc.identifier.issn1097-0215en
dc.identifier.pmid22336965en
dc.identifier.doi10.1002/ijc.27494en
dc.identifier.urihttp://hdl.handle.net/10547/593452en
dc.description.abstractCachexia 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.en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1002/ijc.27494/fullen
dc.rightsArchived with thanks to International journal of cancer. Journal international du canceren
dc.subjectcancer cachexiaen
dc.subjectskeletal muscleen
dc.subjectoxidative stressen
dc.subjectsurvivalen
dc.subjectxanthine oxidaseen
dc.subject.meshAllopurinolen
dc.subject.meshAnimalsen
dc.subject.meshBody Compositionen
dc.subject.meshBody Weighten
dc.subject.meshCachexiaen
dc.subject.meshCaspase 3en
dc.subject.meshEnzyme Inhibitorsen
dc.subject.meshMaleen
dc.subject.meshNeoplasmsen
dc.subject.meshOxidative Stressen
dc.subject.meshOxypurinolen
dc.subject.meshRandom Allocationen
dc.subject.meshRatsen
dc.subject.meshRats, Wistaren
dc.subject.meshReactive Oxygen Speciesen
dc.subject.meshTreatment Outcomeen
dc.subject.meshUric Aciden
dc.subject.meshXanthine Oxidaseen
dc.titleInhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexiaen
dc.typeArticleen
dc.contributor.departmentCharité Medical Schoolen
dc.contributor.departmentUniversitat de Barcelonaen
dc.contributor.departmentUniversity of Leipzigen
dc.contributor.departmentIRCCS San Raffaele, Romeen
dc.identifier.journalInternational journal of canceren

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