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Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle

2014; Impact Journals LLC; Volume: 6; Issue: 5 Linguagem: Inglês

10.18632/oncotarget.2812

1949-2553

Francesca Pretto, Carmen Ghilardi, Michele Moschetta, Andrea Bassi, Alessandra Rovida, Valentina Scarlato, Laura Talamini, Fabio Fiordaliso, Cinzia Bisighini, Giovanna Damia, Maria Rosa Bani, Rosanna Piccirillo, Raffaella Giavazzi,

Vitamin D Research Studies

// Francesca Pretto 1,4,* , Carmen Ghilardi 1,* , Michele Moschetta 1 , Andrea Bassi 2 , Alessandra Rovida 1 , Valentina Scarlato 1 , Laura Talamini 1 , Fabio Fiordaliso 3 , Cinzia Bisighini 3 , Giovanna Damia 1 , Maria Rosa Bani 1 , Rosanna Piccirillo 1 and Raffaella Giavazzi 1 1 Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy 2 Department of Phisics, Politecnico di Milano, 20133 Milan, Italy 3 Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy 4 Present address: Philochem AG, 8112 Otelfingen, Switzerland * These authors contributed equally to this work Correspondence: Raffaella Giavazzi, email: // Rosanna Piccirillo, email: // Keywords : renal carcinoma, cancer cachexia, muscle wasting, sunitinib, STAT3, xenograft model Received : October 15, 2014 Accepted : November 14, 2014 Published : November 15, 2014 Abstract Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome. We used the RXF393 human renal carcinoma xenograft that recapitulates the characteristics of the disease, including the growth in the mouse kidney (orthotopic implantation), and the induction of cachexia with subsequent premature death. Sunitinib prevents body weight loss and muscle wasting and significantly improves the survival of RXF393-bearing nude mice. The anti-cachectic effect was not associated to direct anti-tumor activity of the drug. Most relevant is the ability of sunitinib to reverse the cachectic phenotype and rescue the animals from the loss of fat tissue. Body weight loss is prevented also in mice bearing the C26 colon carcinoma, classically reported to induce cachexia in immunocompetent mice. Among the mechanisms, we herein show that sunitinib is able to restrain the overactivation of STAT3 and MuRF-1 pathways, involved in enhanced muscle protein catabolism during cancer cachexia. We suggest that off-target effects of angiogenesis inhibitors targeting STAT3 are worth considering as a therapeutic option for patients who develop cachexia, independently of their anti-tumor activity.