Anticachectic Effects of Formoterol

Abstract

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.

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

“…Formoterol treatment did not result in any changes of tumour cell content, as previously described 29. Bearing in mind the strong anti‐tumoural action of Sor, one would expect a consequent and consistent reduction of cachexia appearance.…”

“…The mode of action of this drug is based on its ability to prevent muscle wasting by inhibiting proteolysis and apoptosis in skeletal muscle. Thereby, F decreased the activation of the ubiquitin‐dependent proteolytic system, the main mechanism activated in muscle‐wasting conditions, and decreased muscle apoptosis in TB animals 29, 35. The anti‐wasting effects of the drug were also observed in terms of total physical activity and grip force, thus resulting in an improvement in physical performance in cachectic TB rats 36…”

“…With regard to finding a pharmacological strategy to counteract metabolic changes, our laboratory introduced the use of formoterol (F)—a highly potent β2‐adrenoceptor‐selective agonist—as a possible drug for the treatment of cachexia 29. The administration of beta‐adrenergic agonists had been related with hypertrophy of skeletal muscles 30, 31, 32, 33.…”

“…Formoterol combines the clinical advantages of the rapid onset with the duration of the action, and it is currently in use in humans for the treatment of bronchospasm associated with asthma 34. In animal models, data from our laboratory demonstrated that F had important anti‐cachectic effects 29. The mode of action of this drug is based on its ability to prevent muscle wasting by inhibiting proteolysis and apoptosis in skeletal muscle.…”

Cancer cachexia, mechanism and treatment

“…β2-agonists are also proposed to have a protective action against the apoptosis of skeletal muscle. Formoterol may be potential therapeutic tool in pathologic states [170] .…”