NF-κB Inhibition Protects against Tumor-Induced Cardiac Atrophy in Vivo

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. It occurs in approximately 80% of patients with advanced malignancy and is the cause of 200/0 to 30% of all cancer-related deaths. The mechanism by which striated muscle loss occurs is the tumor release of pro-inflammatory cytokines, such as IL-1, 11-6, and TNT-alpha. These cytokines interact with their cognate receptors on muscle cells to enhance NT-kappa B signaling, which then mediates muscle loss and significant cardiac dysfunction. Genetic inhibition of NF-kappa B signaling has demonstrated its predominant role in skeletal muscle loss. Therefore, we tested two novel drugs designed to specifically inhibit NF-kappa B by targeting the I kappa B kinase (IKK) complex: Compound A and NEMO binding domain (NBD) peptide. Using an established mouse model of cancer cachexia (C26 adenocarcinoma), we determined how these drugs affected the development of tumor-induced cardiac atrophy and function. Echo-cardiographic and histological analysis revealed that both Compound A and NBD inhibit cardiac NF-kappa B activity and prevent the development of tumor-induced systolic dysfunction and atrophy. This protection was independent of any effects of the tumor itself (Compound A) or tumor-secreted cytokines (NBD). This study identifies for the first time, to our knowledge, that drugs targeting the IKK complex are cardioprotective against cancer cachexia induced cardiac atrophy and systolic dysfunction, suggesting therapies that may help reduce cardiac-associated morbidities found in patients with advanced malignancies. (Am J Pathol 2011, 178:1059-1068; DOI: 10.1016/j.ajpath.2010.12.009)