title: Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle.
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.
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.|Present address: Philochem AG, 8112 Otelfingen, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pretto
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ghilardi
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: Department of Phisics, Politecnico di Milano, 20133 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bassi
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rovida
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Scarlato
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Talamini
authors.affiliation: Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bisighini
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Bani
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Piccirillo
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002100:Cachexia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015431:Weight Loss / Q000187:drug effects; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000077210:Sunitinib