Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice

Abstract

BackgroundCachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide α-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure.Methodology/Principal FindingsSNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation) of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass.Conclusions/SignificanceIn contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients.

Melanocortin system in cancer-related cachexia

“…The results reported from this study are well in accordance with previous studies describing robust orexigenic effects and showing that endogenous peptidic or small molecule MC4R antagonists enhance food intake in healthy animals [44,50]. Besides the experiments using SNT2007707 and SNT207858 in C26 adenocarcinoma mice performed by Weyermann [45], a number of other compounds with MC4R antagonist effects were investigated elsewhere -Chen et al [52] reported on a new compound from piperazine family, the name of which is yet to be attributed, Vos et al [53] investigated effects of ML00253764 in C26 adenocarcinoma mice, Nicholson et al [44] investigated ML00253764 in Lewis Lung carcinoma mice. Cheung et al [54] investigated effects of a MC4R antagonist called NBI-12i in rodent models of cachexia with 5/6 nephrectomy where 3 mg/kg of NBI-12i or saline was given to subtotally nephrectomized or sham-operated mice intraperitoneally, twice per day, for a period of 14 days.…”

“…The other molecule, SNT207858 is a 22 nM MC4R antagonist with a 170-fold selectivity vs. MC3R and a 40-fold selectivity versus MC5R [49,50]. In mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass thus confirming significant anti-cachexia effects of both compounds [45], whereas a single subcutaneous injection of 20 mg/kg of either SNT207707 or SNT207858 distinctly increased food intake of the mice (p < 0.001) and the amount of food taken during the four hours observation period was roughly 3-fold the amount taken by the vehicle treated controls. The results reported from this study are well in accordance with previous studies describing robust orexigenic effects and showing that endogenous peptidic or small molecule MC4R antagonists enhance food intake in healthy animals [44,50].…”

“…As the anorexigenic pathway of α-MSH is believed to play the pivotal role in physiology and pathophysiology of food intake regulation, it was suggested that the blockade of MC4R as its main physiological target could result in anti-cachexia effects [45]. This idea was further suppported by the observation that AgRP, the endogenous inverse agonists of MC4R, expressed significant effects on both major aspects of cachexia, as it was promoting food intake and reducing energy expenditure in animal experiments [45].…”

“…This idea was further suppported by the observation that AgRP, the endogenous inverse agonists of MC4R, expressed significant effects on both major aspects of cachexia, as it was promoting food intake and reducing energy expenditure in animal experiments [45]. Cancer patients express multiple metabolic maladaptive responses resulting in inappropriate high energy expenditure despite low caloric intake and therefore the cancer-related cachexia cannot be treated simply as a lack of appetite.…”

“…The desired features of the possible therapeutic molecules with MC4R antagonist properties are high affinity and selectivity for the MC4R antagonism of MC4-mediated responses in functional assays, good central nervous system penetration and desirable pharmacokinetic properties for systemic oral administration [48]. The extended search to find selective, potent and orally active antagonists of MC4R resulted in discovery of two molecules: SNT207707 and SNT207858 [45]. The first molecule, SNT207707 binds to the MC4R with affinity of 8 nM and expresses more than 200-fold selectivity vs. MC3R and MC5R.…”