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

Oncotarget. 2015 Feb 20;6(5):3043-54. doi: 10.18632/oncotarget.2812.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cachexia / diagnostic imaging
  • Cachexia / metabolism
  • Cachexia / pathology
  • Cachexia / prevention & control*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Indoles / pharmacology*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Nude
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / diagnostic imaging
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / ultrastructure
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / pharmacology*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Sunitinib
  • Time Factors
  • Tripartite Motif Proteins
  • Tumor Burden / drug effects
  • Ubiquitin-Protein Ligases / metabolism*
  • Weight Loss / drug effects
  • X-Ray Microtomography
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Indoles
  • Muscle Proteins
  • Protein Kinase Inhibitors
  • Pyrroles
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tripartite Motif Proteins
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Sunitinib