title: Pharmacological strategies in lung cancer-induced cachexia: effects on muscle proteolysis, autophagy, structure, and weakness.
abstract: Cachexia is a relevant comorbid condition of chronic diseases including cancer. Inflammation, oxidative stress, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) are involved in the pathophysiology of cancer cachexia. Currently available treatment is limited and data demonstrating effectiveness in in vivo models are lacking. Our objectives were to explore in respiratory and limb muscles of lung cancer (LC) cachectic mice whether proteasome, NF-κB, and MAPK inhibitors improve muscle mass and function loss through several molecular mechanisms. Body and muscle weights, limb muscle force, protein degradation and the ubiquitin-proteasome system, signaling pathways, oxidative stress and inflammation, autophagy, contractile and functional proteins, myostatin and myogenin, and muscle structure were evaluated in the diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing cachectic mice (BALB/c), with and without concomitant treatment with NF-κB (sulfasalazine), MAPK (U0126), and proteasome (bortezomib) inhibitors. Compared to control animals, in both respiratory and limb muscles of LC cachectic mice: muscle proteolysis, ubiquitinated proteins, autophagy, myostatin, protein oxidation, FoxO-1, NF-κB and MAPK signaling pathways, and muscle abnormalities were increased, while myosin, creatine kinase, myogenin, and slow- and fast-twitch muscle fiber size were decreased. Pharmacological inhibition of NF-κB and MAPK, but not the proteasome system, induced in cancer cachectic animals, a substantial restoration of muscle mass and force through a decrease in muscle protein oxidation and catabolism, myostatin, and autophagy, together with a greater content of myogenin, and contractile and functional proteins. Attenuation of MAPK and NF-κB signaling pathway effects on muscles is beneficial in cancer-induced cachexia.
authors.affiliation: Pulmonology-Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Parc de Recerca Biomèdica de Barcelona (PRBB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Chacon-Cabrera
authors.forename: Clara
authors.initials: C
authors.lastname: Fermoselle
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Urtreger
authors.forename: Mercè
authors.initials: M
authors.lastname: Mateu-Jimenez
authors.forename: Miriam J
authors.initials: MJ
authors.lastname: Diament
authors.forename: Elisa D Bal
authors.initials: ED
authors.lastname: de Kier Joffé
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.forename: Esther
authors.initials: E
authors.lastname: Barreiro
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002070:Butadienes / Q000494:pharmacology / Q000627:therapeutic use; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology*; D045744:Cell Line, Tumor; D007249:Inflammation / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008175:Lung Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D010084:Oxidation-Reduction; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use; D014443:Tyrosine / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001897:Boronic Acids; D002070:Butadienes; D009124:Muscle Proteins; D016328:NF-kappa B; D009570:Nitriles; D011719:Pyrazines; C113580:U 0126; D012460:Sulfasalazine; D014443:Tyrosine; D000069286:Bortezomib