Anticachectic effects of formoterol: A drug for potential treatment of muscle wasting

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 18; pp. 6725 - 6731
• Main Authors: BUSQUETS, Silvia, FIGUERAS, Maria T, FUSTER, Gemma, ALMENDRO, Vanessa, MOORE-CARRASCO, Rodrigo, AMETLLER, Elisabet, ARGILES, Josep M, LOPEZ-SORIANO, Francisco J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2004
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Cachexia - drug therapy; Cachexia - metabolism; Cachexia - pathology; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Disease Models, Animal; Eating - drug effects; Ethanolamines - pharmacology; Formoterol Fumarate; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Muscle Proteins - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Sarcoma, Yoshida - metabolism; Sarcoma, Yoshida - pathology; Tumors; Drug; Agonist; Treatment; β2-Adrenergic receptor; β-Adrenergic receptor agonist; Formoterol; Muscle; Wasting disease
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0425

In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the beta2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the beta2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.