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.
Original language | English |
---|---|
Pages (from-to) | 517-527 |
Number of pages | 11 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 64 |
Issue number | 3 |
Early online date | 27 Dec 2008 |
DOIs | |
Publication status | Published - Jul 2009 |
Bibliographical note
The original publication is available at www.springerlink.comKeywords
- muscle atrophy
- alpha trinositol
- protein kinase R
- PKR
- eukaryotic initiation factors
- eukaryotic elongation factors