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A new therapeuthical approach to block cancer cachexia: focusing inhibition of STAT3
Author(s) -
Silva Kleiton Augusto Santos,
Dong Yanlan,
Dong Yanjun,
Tweardy David J.,
Mitch William E.,
Zhang Liping
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.793.4
Subject(s) - myogenesis , cachexia , muscle atrophy , stat3 , atrophy , c2c12 , lewis lung carcinoma , myocyte , phosphorylation , medicine , endocrinology , skeletal muscle , cancer research , cancer , knockout mouse , wasting , biology , microbiology and biotechnology , receptor , metastasis
Cachexia is a devastating complication of cancer. The mechanisms by which cancers cause cachexia are unclear and there are few successful therapeutic options. In muscles from mouse models of cancer cachexia, we found increased STAT3 phosphorylation associated with muscle atrophy. In muscle cells (C2C12 myotubes) incubated with media from cultured Lewis lung carcinoma (LLC) or Colon 26 (C26) tumor cells, we found rapid phosphorylation of STAT3 and progressive myotube atrophy. We created mice with muscle‐specific STAT3 knockout (KO) with implanted tumor cells. We found a prevention of body and muscle weight loss in KO mice compared to control mice injected with LLC tumors. We treated C2C12 cells and mice with a small molecule inhibitor of STAT3 (C188–9). C2C12 myotubes were incubated with C188–9 and conditioned media from C26 colon tumors and after 24 hours, the STAT3 phosphorylation was suppressed and the wasting of myotubes was blocked. In CD2F1 mice bearing C26 xenografts, daily i.p. administration of C188–9 (6.25mg/kg) over 14 days significantly reduced loss of body weight and muscle mass compared to tumor‐bearing mice injected with the diluent. The increase in muscle mass of C188–9‐treated mice was due to increased protein synthesis and decreased protein degradation. Thus, small‐molecule inhibition of STAT3 represents a novel therapeutic strategy for preventing cachexia‐induced muscle atrophy.