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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3043-3054
Number of pages12
JournalOncotarget
Volume6
Issue number5
Publication statusPublished - 2015

Fingerprint

Cachexia
Kidney Neoplasms
Muscles
Angiogenesis Inhibitors
Renal Cell Carcinoma
Weight Loss
Neoplasms
Body Weight
Carcinoma
Kidney
Premature Mortality
Survival
Muscle Proteins
Heterografts
Nude Mice
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Colon
Fats
Phenotype

Keywords

  • Cancer cachexia
  • Muscle wasting
  • Renal carcinoma
  • STAT3
  • Sunitinib
  • Xenograft model

ASJC Scopus subject areas

  • Oncology

Cite this

Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle. / Pretto, Francesca; Ghilardi, Carmen; Moschetta, Michele; Bassi, Andrea; Rovida, Alessandra; Scarlato, Valentina; Talamini, Laura; Fiordaliso, Fabio; Bisighini, Cinzia; Damia, Giovanna; Bani, Maria Rosa; Piccirillo, Rosanna; Giavazzi, Raffaella.

In: Oncotarget, Vol. 6, No. 5, 2015, p. 3043-3054.

Research output: Contribution to journalArticle

Pretto, Francesca ; Ghilardi, Carmen ; Moschetta, Michele ; Bassi, Andrea ; Rovida, Alessandra ; Scarlato, Valentina ; Talamini, Laura ; Fiordaliso, Fabio ; Bisighini, Cinzia ; Damia, Giovanna ; Bani, Maria Rosa ; Piccirillo, Rosanna ; Giavazzi, Raffaella. / Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle. In: Oncotarget. 2015 ; Vol. 6, No. 5. pp. 3043-3054.
@article{cc4a3723e9c741ffa45be9f06912a24e,
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.",
keywords = "Cancer cachexia, Muscle wasting, Renal carcinoma, STAT3, Sunitinib, Xenograft model",
author = "Francesca Pretto and Carmen Ghilardi and Michele Moschetta and Andrea Bassi and Alessandra Rovida and Valentina Scarlato and Laura Talamini and Fabio Fiordaliso and Cinzia Bisighini and Giovanna Damia and Bani, {Maria Rosa} and Rosanna Piccirillo and Raffaella Giavazzi",
year = "2015",
language = "English",
volume = "6",
pages = "3043--3054",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "5",

}

TY - JOUR

T1 - Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle

AU - Pretto, Francesca

AU - Ghilardi, Carmen

AU - Moschetta, Michele

AU - Bassi, Andrea

AU - Rovida, Alessandra

AU - Scarlato, Valentina

AU - Talamini, Laura

AU - Fiordaliso, Fabio

AU - Bisighini, Cinzia

AU - Damia, Giovanna

AU - Bani, Maria Rosa

AU - Piccirillo, Rosanna

AU - Giavazzi, Raffaella

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Cancer cachexia

KW - Muscle wasting

KW - Renal carcinoma

KW - STAT3

KW - Sunitinib

KW - Xenograft model

UR - http://www.scopus.com/inward/record.url?scp=84923289520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923289520&partnerID=8YFLogxK

M3 - Article

VL - 6

SP - 3043

EP - 3054

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 5

ER -