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

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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 20% 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, IL-6, and TNF-α. These cytokines interact with their cognate receptors on muscle cells to enhance NF-κB signaling, which then mediates muscle loss and significant cardiac dysfunction. Genetic inhibition of NF-κB signaling has demonstrated its predominant role in skeletal muscle loss. Therefore, we tested two novel drugs designed to specifically inhibit NF-κB by targeting the IκB 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. Echocardiographic and histological analysis revealed that both Compound A and NBD inhibit cardiac NF-κB 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.

Original languageEnglish (US)
Pages (from-to)1059-1068
Number of pages10
JournalAmerican Journal of Pathology
Volume178
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Wysong, A., Couch, M., Shadfar, S., Li, L., Rodriguez, J. E., Asher, S., Yin, X., Gore, M., Baldwin, A., Patterson, C., & Willis, M. S. (2011). NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. American Journal of Pathology, 178(3), 1059-1068. https://doi.org/10.1016/j.ajpath.2010.12.009