The AP-1/NF-kappaB double inhibitor SP100030 can revert muscle wasting during experimental cancer cachexia.
Daily treatment of rats bearing the cachectic Yoshida AH-130 ascites hepatoma with the double inhibitor of NF-kappaB and AP-1 SP100030 at a dose of 1 mg/kg of body weight resulted in a clear amelioration of the cachectic effect, especially at the level of skeletal muscle. Thus, tumour-bearing rats treated with SP100030 showed a significant recovery in the weights of gastrocnemius, EDL, tibialis and cardiac muscles. In addition, treatment with the inhibitor affected both liver and kidney weights. The amelioration in muscle weight was accompanied by an increase in MyoD gene expression, the main transcription factor of muscle tissue involved in muscle differentiation, in gastrocnemius muscle. At the dose used in this study, SP100030 was an effective inhibitor of AP-1; however, the NF-kappaB transcription factor was not affected. The effects of the inhibitor seem to be at the level of proteolysis since lower total proteolytic rates were found when incubating isolated rat muscles in the presence of SP100030. The inhibitor influenced the gene expression of the ubiquitin-conjugating enzyme E214K in skeletal muscle of tumour-bearing rats; this enzyme seems to be the main regulator of the activity of the main proteolytic system involved during cancer cachexia, the ubiquitin-proteasome system. In conclusion, treatment of cachectic tumour-bearing rats with SP100030 results in an amelioration of the muscle wasting effect, suggesting that the AP-1 signaling cascade plays an important role in the signaling of muscle wasting associated with disease.
Moore-Carrasco
Rodrigo
R
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
Busquets
Sílvia
S
Almendro
Vanessa
V
Palanki
Moorthy
M
López-Soriano
Francisco J
FJ
Argilés
Josep M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002100:Cachexia / Q000188:drug therapy*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009132:Muscles / Q000473:pathology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000096:biosynthesis* / Q000737:chemistry; D009374:Neoplasms, Experimental / Q000150:complications / Q000188:drug therapy*; D009930:Organic Chemicals / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D000813:Anilides; D001549:Benzamides; D011743:Pyrimidines
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D009930:Organic Chemicals; D018808:Transcription Factor AP-1; C102914:N-(3,5-bis(trifluoromethyl)phenyl)-2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxamide; D000813:Anilides; D001549:Benzamides; D011743:Pyrimidines