Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

Steve T. Russell, P.M.A. Siren, M.J. Siren, Michael J. Tisdale

Research output: Contribution to journalArticle

Abstract

PURPOSE: To determine the effectiveness of the polyanionic, metal binding agent D-myo-inositol-1,2,6-triphosphate (alpha trinositol, AT), and its hexanoyl ester (HAT), in tissue wasting in cancer cachexia. METHODS: The anti-cachexic effect was evaluated in the MAC16 tumour model. RESULTS: Both AT and HAT attenuated the loss of body weight through an increase in the nonfat carcass mass due to an increase in protein synthesis and a decrease in protein degradation in skeletal muscle. The decrease in protein degradation was associated with a decrease in activity of the ubiquitin-proteasome proteolytic pathway and caspase-3 and -8. Protein synthesis was increased due to attenuation of the elevated autophosphorylation of double-stranded RNA-dependent protein kinase, and of eukaryotic initiation factor 2alpha together with hyperphosphorylation of eIF4E-binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2. In vitro, AT completely attenuated the protein degradation in murine myotubes induced by both proteolysis-inducing factor and angiotensin II. CONCLUSION: These results show that AT is a novel therapeutic agent with the potential to alleviate muscle wasting in cancer patients.
LanguageEnglish
Pages517-527
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume64
Issue number3
Early online date27 Dec 2008
DOIs
Publication statusPublished - Jul 2009

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Cachexia
Muscular Atrophy
Muscle
Skeletal Muscle
Proteolysis
Neoplasms
Proteins
Degradation
Esters
Peptide Elongation Factor 2
eIF-2 Kinase
Eukaryotic Initiation Factors
Phosphorylation
Double-Stranded RNA
Caspase 8
Skeletal Muscle Fibers
Proteasome Endopeptidase Complex
Ubiquitin
Caspase 3
Angiotensin II

Bibliographical note

The original publication is available at www.springerlink.com

Keywords

  • muscle atrophy
  • alpha trinositol
  • protein kinase R
  • PKR
  • eukaryotic initiation factors
  • eukaryotic elongation factors

Cite this

Russell, Steve T. ; Siren, P.M.A. ; Siren, M.J. ; Tisdale, Michael J. / Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate. In: Cancer Chemotherapy and Pharmacology. 2009 ; Vol. 64, No. 3. pp. 517-527.
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Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate. / Russell, Steve T.; Siren, P.M.A.; Siren, M.J.; Tisdale, Michael J.

In: Cancer Chemotherapy and Pharmacology, Vol. 64, No. 3, 07.2009, p. 517-527.

Research output: Contribution to journalArticle

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