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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Body Weight / drug effects
-
Cachexia / drug therapy*
-
Cachexia / etiology
-
Carrier Proteins / drug effects
-
Carrier Proteins / metabolism
-
Caspase 3 / drug effects
-
Caspase 3 / metabolism
-
Caspase 8 / drug effects
-
Caspase 8 / metabolism
-
Cell Cycle Proteins
-
Eukaryotic Initiation Factor-2 / drug effects
-
Eukaryotic Initiation Factor-2 / metabolism
-
Eukaryotic Initiation Factors
-
Inositol Phosphates / chemistry
-
Inositol Phosphates / pharmacology*
-
Male
-
Mice
-
Mice, Inbred Strains
-
Muscle Fibers, Skeletal / drug effects*
-
Muscle Fibers, Skeletal / pathology
-
Muscle Proteins / drug effects
-
Muscle Proteins / metabolism
-
Muscular Atrophy / drug therapy*
-
Muscular Atrophy / etiology
-
Neoplasms, Experimental / physiopathology*
-
Phosphoproteins / drug effects
-
Phosphoproteins / metabolism
-
Phosphorylation / drug effects
-
Proteasome Endopeptidase Complex / metabolism
-
Protein Kinases / drug effects
-
Protein Kinases / metabolism
-
RNA, Double-Stranded / metabolism
-
Ubiquitin / metabolism
Substances
-
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