title: NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo.
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.
authors.affiliation: Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Wysong
authors.forename: Marion
authors.initials: M
authors.lastname: Couch
authors.forename: Scott
authors.initials: S
authors.lastname: Shadfar
authors.forename: Luge
authors.initials: L
authors.lastname: Li
authors.forename: Lugi
authors.initials: L
authors.lastname: Li
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Rodriguez
authors.forename: Scott
authors.initials: S
authors.lastname: Asher
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Yin
authors.forename: Mitchell
authors.initials: M
authors.lastname: Gore
authors.forename: Al
authors.initials: A
authors.lastname: Baldwin
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D001284:Atrophy; D002100:Cachexia / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D016207:Cytokines; D009124:Muscle Proteins; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases