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


CONCLUSIONS
These results show that AT is a novel therapeutic agent with the potential to alleviate muscle wasting in cancer patients.
Russell
S T
ST
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, UK.
Siren
P M A
PM
Siren
M J
MJ
Tisdale
M J
MJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D053181:Caspase 8 / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D007295:Inositol Phosphates / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000473:pathology; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000209:etiology; D009374:Neoplasms, Experimental / Q000503:physiopathology*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D039642:Eukaryotic Initiation Factors; D007295:Inositol Phosphates; D009124:Muscle Proteins; D010750:Phosphoproteins; D012330:RNA, Double-Stranded; D025801:Ubiquitin; D011494:Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex; C059368:atrinositol