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 Willis

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 - Jan 1 2011
Externally publishedYes

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Heart Neoplasms
Atrophy
Neoplasms
Cachexia
Cytokines
Wasting Syndrome
Striated Muscle
Drug Delivery Systems
Interleukin-1
Pharmaceutical Preparations
Muscle Cells
Interleukin-6
Skeletal Muscle
Adenocarcinoma
Phosphotransferases
Inflammation
Morbidity
Muscles

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. / Wysong, Ashley; Couch, Marion; Shadfar, Scott; Li, Lugi; Rodriguez, Jessica E.; Asher, Scott; Yin, Xiaoying; Gore, Mitchell; Baldwin, Al; Patterson, Cam; Willis, Monte.

In: American Journal of Pathology, Vol. 178, No. 3, 01.01.2011, p. 1059-1068.

Research output: Contribution to journalArticle

Wysong, A, Couch, M, Shadfar, S, Li, L, Rodriguez, JE, Asher, S, Yin, X, Gore, M, Baldwin, A, Patterson, C & Willis, M 2011, 'NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo', American Journal of Pathology, vol. 178, no. 3, pp. 1059-1068. https://doi.org/10.1016/j.ajpath.2010.12.009
Wysong A, Couch M, Shadfar S, Li L, Rodriguez JE, Asher S et al. NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. American Journal of Pathology. 2011 Jan 1;178(3):1059-1068. https://doi.org/10.1016/j.ajpath.2010.12.009
Wysong, Ashley ; Couch, Marion ; Shadfar, Scott ; Li, Lugi ; Rodriguez, Jessica E. ; Asher, Scott ; Yin, Xiaoying ; Gore, Mitchell ; Baldwin, Al ; Patterson, Cam ; Willis, Monte. / NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. In: American Journal of Pathology. 2011 ; Vol. 178, No. 3. pp. 1059-1068.
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