Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival.
Summary of "Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival."
Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.
Affiliation
Departments of Metabolic Disorders and Protein Science, Amgen Research, Thousand Oaks, CA 91320, USA.
Journal Details
This article was published in the following journal.
Name: Cell
ISSN: 1097-4172
Pages: 531-543
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20723755
- DOI: http://dx.doi.org/10.1016/j.cell.2010.07.011
Medical and Biotech [MESH] Definitions
Metabolic Detoxication, Phase I
Functionalization of exogenous substances to prepare them for conjugation in PHASE II DETOXIFICATION. Phase I enzymes include CYTOCHROME P450 enzymes and some OXIDOREDUCTASES. Excess induction of phase I over phase II detoxification leads to higher levels of FREE RADICALS that can induce CANCER and other cell damage. Induction or antagonism of phase I detoxication is the basis of a number of DRUG INTERACTIONS.
Hiv Wasting Syndrome
Involuntary weight loss of greater than 10 percent associated with intermittent or constant fever and chronic diarrhea or fatigue for more than 30 days in the absence of a defined cause other than HIV infection. A constant feature is major muscle wasting with scattered myofiber degeneration. A variety of etiologies, which vary among patients, contributes to this syndrome. (From Harrison's Principles of Internal Medicine, 13th ed, p1611).
Muscular Dystrophies
A heterogeneous group of inherited MYOPATHIES, characterized by wasting and weakness of the SKELETAL MUSCLE. They are categorized by the sites of MUSCLE WEAKNESS; AGE OF ONSET; and INHERITANCE PATTERNS.
Muscle Neoplasms
Tumors or cancer located in muscle tissue or specific muscles. They are differentiated from NEOPLASMS, MUSCLE TISSUE which are neoplasms composed of skeletal, cardiac, or smooth muscle tissue, such as MYOSARCOMA or LEIOMYOMA.
Sterilization Reversal
Procedures to reverse the effect of REPRODUCTIVE STERILIZATION and to regain fertility. Reversal procedures include those used to restore the flow in the FALLOPIAN TUBE or the VAS DEFERENS.
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