Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

Duchenne Muscular Dystrophy (DMD) is an incurable inherited disease ofchildhood, characterized by progressive muscle degeneration and weakness. Our previousfindings supported the idea that dystrophin and associated proteins, absent or greatlyreduced in DMD, are degraded in dystrophin-deficient muscl...

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Vydáno v:Cell cycle (Georgetown, Tex.) Ročník 6; číslo 10; s. 1242 - 1248
Hlavní autoři: Bonuccelli, Gloria, Sotgia, Federica, Capozza, Franco, Gazzerro, Elisabetta, Minetti, Carlo, Lisanti, Michael P.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Taylor & Francis 15.05.2007
Témata:
Animals
Binding
Biology
Bioscience
Boronic Acids - pharmacology
Bortezomib
Calcium
Cancer
Cell
Cycle
Dipeptides - pharmacology
Dystrophin - metabolism
Dystrophin-Associated Proteins - metabolism
Landes
Male
Mice
Mice, Inbred mdx
Microscopy, Fluorescence
Muscle, Skeletal - metabolism
Muscular Dystrophy, Duchenne - drug therapy
Muscular Dystrophy, Duchenne - metabolism
NF-kappa B - metabolism
Organogenesis
Protease Inhibitors - pharmacology
Proteins
Pyrazines - pharmacology
ISSN:1538-4101, 1551-4005, 1551-4005
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Shrnutí:Duchenne Muscular Dystrophy (DMD) is an incurable inherited disease ofchildhood, characterized by progressive muscle degeneration and weakness. Our previousfindings supported the idea that dystrophin and associated proteins, absent or greatlyreduced in DMD, are degraded in dystrophin-deficient muscle by the proteasomaldependentpathway. Indeed, treatment with the proteasome inhibitor MG-132 of skeletalmuscles from mdx mice --a spontaneous mouse model of DMD-- as well as from DMDpatients, effectively rescued the expression and correct cellular localization of dystrophinand associated proteins. These promising results led us to further explore the use ofproteasome inhibitors as a therapy for DMD. Therefore, we directed our attentiontowards two new dipeptide boronic acid inhibitors blocking the proteasomal-dependentdegradation pathway: Velcade (bortezomib or PS-341) and MLN273 (PS-273). Theexciting aspect of this development is that these drugs have already progressed to preclinicaland clinical trials, in different fields than muscular dystrophy. Indeed, Velcadehas been already FDA-approved for treatment of multiple myeloma and its side effectshad been already explored and managed. Promisingly, MLN273 is currently in thepreclinical trial phase. Here, we test the effectiveness of Velcade and MLN273 by localinjection into the gastrocnemius muscle of mdx mice. We show the rescue of expressionand membrane localization of -dystroglycan, -dystroglycan, -sarcoglycan, anddystrophin after Velcade and MLN273 localized treatment, versus untreated (PBS only)mdx mice. Intriguingly, we also show that localized treatment with Velcade and MLN273reduces the activation of Nuclear Factor-kappaB (NF-kB). Because NF-kB pathway hasbeen shown to be involved in inflammation responses in myopathies and DMD, ourcurrent results may have important clinical implications. Clearly, more investigations areneeded, but our results emphasize the effectiveness of the pharmacological approach as apotential treatment for Duchenne muscular dystrophy.
Bibliografie:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ISSN:1538-4101
1551-4005
1551-4005
DOI:10.4161/cc.6.10.4182