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.

The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass

“…Finally, Sunitinib, a small molecule tyrosine kinase inhibitor, has been shown to have therapeutic efficacy in renal cell carcinoma patients who frequently develop cachexia. In RXF393 tumor-bearing mice, sunitinib was reported to prevent muscle wasting and significantly attenuate the over-expression of MuRF-1, but not MAFbx [153].…”

Signal transducer and activator of transcription 3 signaling as a potential target to treat muscle wasting diseases

“…STAT3 activation has been directly linked to the loss of muscle mass in several murine models of muscle wasting, such as streptozotocin-induced diabetes, chronic kidney disease (CKD) and cancer cachexia (32-35). In some of these studies, authors utilized the MCK-Cre STAT3 flox/flox mouse model, which abrogates STAT3 expression specifically in myofibers (32, 33).…”

“…In addition to STAT3 genetic ablation in myofibers, several reports have shown that pharmacological inhibition of STAT3 (both direct and indirect) is able to ameliorate muscle wasting in mice (32-35). Most of these studies have been done in murine models of cancer cachexia (33-35).…”

“…Most of these studies have been done in murine models of cancer cachexia (33-35). The treatment of cachectic mice with C188-9 (STAT3 inhibitor), AG490 (JAK2 inhibitor), sunitinib (tyrosine kinase inhibitor) or sorafenib (tyrosine kinase inhibitor) partially prevented loss of muscle mass (33-35). Moreover, inhibition of STAT3 with C188-9 also ameliorated muscle wasting in CKD and streptozotocin-induced diabetes (32).…”

“…Overall, available data suggest that STAT3 signaling pathway is involved in the muscle wasting observed in different human pathologies. Pharmacological inhibition of STAT3 ameliorates muscle wasting in murine models of accelerated muscle loss (9, 10, 31-35), suggesting that pharmacological manipulation of STAT3 signaling pathway in humans could be a promising approach for the treatment of muscle-wasting associated diseases. In fact, JAK-STAT inhibitors are currently being used in the clinic to treat inflammatory diseases such as rheumatoid arthritis or psoriasis.…”