Suramin interferes with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo.

Abstract

Neoplastic diseases are frequently associated with metabolic changes collectively known as cancer cachexia. The presence of cachexia complicates therapeutic intervention and is an important cause of death in cancer patients. At present there is no effective treatment for cachexia. Recently, the involvement of interleukin-6 (IL-6) in the wasting of colon-26 adenocarcinoma-bearing mice was demonstrated. The research presented here establishes an anticachectic role for the experimental drug suramin, since it partially blocks (up to 60%) the catabolic effects associated with the growth of this tumor in vivo. Suramin prevents the binding of IL-6 to its cell surface receptor subunits, as demonstrated by radioreceptor binding assay and affinity crosslinking experiments. Furthermore, the uptake of radioactive IL-6 by the liver is significantly reduced in suramintreated mice. On the other hand, the drug is 10-fold less potent in inhibiting the binding of tumor necrosis factor-a to indicator cell line in vitro and fails to block liver uptake of this cytokine in vivo. Collectively, these results suggest that suramin inhibits cancer-associated wasting, in part by interfering with the binding of IL-6 to its receptor. Whether suramin inhibits the action ofother factors /cytokines that may also participate in colon-26-mediated cachexia is not yet known. (J. Clin.

Cancer cachexia is regulated by selective targeting of skeletal muscle gene products

“…For experimental convenience, we chose the colon-26 (C-26) adenocarcinoma model (43)(44)(45). Although muscle wasting in this tumor model is largely accepted to be dependent on IL-6 rather than TNF or IFN (43,46), we reasoned that if MyHC were indeed a selective target of myofibrillar proteins in cachexia, this regulation would be maintained irrespective of the cachectic factor inducing the wasting state. To test this hypothesis, C-26 adenocarcinoma tumors were established in mice.…”

Targeting Protein Synthesis in a Myc/mTOR-Driven Model of Anorexia-Cachexia Syndrome Delays Its Onset and Prolongs Survival

“…(ii) As well, IL-6, a multifunctional cytokine, is strongly implicated in cachexia. Administration of IL-6 to mice is sufficient to recapitulate the muscle wasting and fat loss phenotype of ACS (41,42), IL-6 blocking agents reduce the severity of muscle wasting in the C26 model (8,24,26,27,43,44), and its overexpression is implicated in the pathogenesis of cachexia in several mouse models, including mice bearing the C26 cell line (5,26,45). One mechanism by which IL-6 has been implicated in this process is through activation of STAT3 signaling following binding to its receptor in muscle cells, leading to muscle-based production of acute phase proteins (28).…”

Mechanism-Based Therapeutic Approaches to Cachexia

“…As an example, muscle wasting, increased ubiquitin expression and proteasome enzymatic activity are induced in healthy animals by administration of TNF or IL-1 (reviewed in Tisdale, 2008). Consistently, at least in cancer cachexia, many years ago few studies demonstrated the crucial role played by cytokines in the onset of muscle wasting, showing that loss of muscle mass, protein hypercatabolism and ubiquitin hyperexpression could be prevented by treatment of tumor-bearing animals with antibodies directed against IL-6, TNF, or IFN (Matthys et al, 1991;Costelli et al, 1993;Strassmann et al, 1993). Altered cytokine homeostasis, positively correlated with disease progression and mortality rates, was reported also in cancer patients (Attard-Montalto et al, 1998;Nakashima et al, 1998).…”