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

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.

• Authors: S T Russell, P M A Siren, M J Siren, M J Tisdale
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 64 Issue 3 Pg. 517-27 (Aug 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19112551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cell Cycle Proteins
• Eif4ebp1 protein, mouse
• Eukaryotic Initiation Factor-2
• Eukaryotic Initiation Factors
• Inositol Phosphates
• Muscle Proteins
• Phosphoproteins
• RNA, Double-Stranded
• Ubiquitin
• Protein Kinases
• Caspase 3
• Caspase 8
• Proteasome Endopeptidase Complex
• atrinositol

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Body Weight (drug effects)
• Cachexia (drug therapy, etiology)
• Carrier Proteins (drug effects, metabolism)
• Caspase 3 (drug effects, metabolism)
• Caspase 8 (drug effects, metabolism)
• Cell Cycle Proteins
• Eukaryotic Initiation Factor-2 (drug effects, metabolism)
• Eukaryotic Initiation Factors
• Inositol Phosphates (chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred Strains
• Muscle Fibers, Skeletal (drug effects, pathology)
• Muscle Proteins (drug effects, metabolism)
• Muscular Atrophy (drug therapy, etiology)
• Neoplasms, Experimental (physiopathology)
• Phosphoproteins (drug effects, metabolism)
• Phosphorylation (drug effects)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Kinases (drug effects, metabolism)
• RNA, Double-Stranded (metabolism)
• Ubiquitin (metabolism)