Hot off the Press
NF-κB Inhibition Protects against Tumor-Induced Cardiac Atrophy in Vivo
Ashley Wysong,* Marion Couch,†‡ Scott Shadfar,† Lugi Li,§ Jessica E. Rodriguez,§ Scott Asher,† Xiaoying Yin,†‡ Mitchell Gore,† Al Baldwin, ‡¶|| Cam Patterson,** Monte S. Willis,§**
From the Duke University School of Medicine,* Durham; the
Department of Otolaryngology–Head and Neck Surgery,†
University of North Carolina, School of Medicine, Chapel Hill; the
Lineberger Comprehensive Cancer Center,‡ the Department of
Pathology Laboratory Medicine,§ the Curriculum in Genetics and
Molecular Biology,¶ Department of Biology, and the McAllister
Heart Institute,** University of North Carolina, Chapel Hill; and
Theralogics, Inc.,|| Chapel Hill, North Carolina
The American Journal of Pathology, Vol. 178, Issue 3, Pages 1059-1068, March 2011, DOI:10.1016/j.ajpath.2010.12.009
Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. In fact, the word Cachexia comes the from the Greek kakos hexis, which literally means 'bad condition'. Cachexia is one of the most frequent effects of malignancy, with up to one-half of untreated cancer patients losing some weight as a result cachexia also accounts for about 20% of cancer deaths. As there are essentially no antitumor therapies that aid in the prevention of the affects of cancer cachexia, the Willis group has attempted to investigate novel compounds that prevent the cardiac sequelae of cancer cachexia.
The Willis group selected to use the well-characterized murine model of cancer cachexia (C26 adenocarcinoma model) to test the hypothesis that Compound A and NEMO binding domain (NBD) peptides, two novel specific NF-κB inhibitors targeting the IκB kinase (IKK) complex, can prevent C26 adenocarcinoma–induced cardiac atrophy and dysfunction. This hypothesis is supported by over three decades of studies that have revealed the mechanism of cancer cachexia using the C26 adenocarcinoma model and showing that tumors formed in these mice secrete proinflammatory cytokines. In particular, IL-6, TNF-α and IL-1 are secreted which activate the transcription factor NF-κB though the interaction of their receptors on muscle. NF-κB activation up-regulates the ubiquitin-dependent degradation of the sarcomere, which is central to the pathophysiology of striated muscle atrophy. To date, therapeutic interventions reveal that specific targeted changes in the activity of NF-κB could be useful experimentally in cardiac ischemia reperfusion injury and in reversing cardiac hypertrophy in vivo.
In the present study, the Willis group identified that Compound A inhibited cardiac atrophy without affecting tumor growth and NBD peptide inhibits cardiac atrophy without affecting circulating levels of tumor-derived cytokines. These inhibitors were able to inhibit cardiac NF-κB activation in the heart, to potently prevent cancer-induced dysfunction and atrophy. These data complement earlier findings showing that the use of cell-permeable NBD peptides has efficacy in inhibiting disease in models of pancreatitis, synovitis, and inflammatory colitis.
Overall the Willis group has presented strong evidence to suggest that NF-κB inhibition targeting the IκB complex is able to protect against cancer-associated cardiac atrophy and dysfunction by inhibiting the cytokine-induced NF-κB activity in the heart. This highlights the therapeutic potential of these drugs in treating the associated cardiac morbidity related to cancer-associated cachexia.