Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice

• Published in: PloS one Vol. 4; no. 3; p. e4774
• Main Authors: Weyermann, Philipp, Dallmann, Robert, Magyar, Josef, Anklin, Corinne, Hufschmid, Martina, Dubach-Powell, Judith, Courdier-Fruh, Isabelle, Henneböhle, Marco, Nordhoff, Sonja, Mondadori, Cesare
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.03.2009; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adipocytes; Agouti-related protein; Animal behavior; Animals; Anorexia; Appetite; Blood-brain barrier; Body fat; Body mass; Body Weight; Body weight loss; Brain; Brain Chemistry; Cachexia; Cachexia - drug therapy; Cancer; Cell Line, Tumor; Chronic illnesses; Cytokines; Eating - drug effects; Energy expenditure; Female; Food; Food intake; Functional morphology; Homeostasis; Humans; Implantation; Kaplan-Meier Estimate; Laboratories; Lean body mass; Male; Melanocortin; Melanocyte stimulating hormone; Metabolic syndrome; Metabolism; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Nervous system; Neuroscience/Neurobiology of Disease and Regeneration; Non-Clinical Medicine; Nutrition/Malnutrition; Oncology; Oral administration; Peptides; Pharmaceuticals; Pharmacology; Physiological aspects; Proteins; Random Allocation; Receptor, Melanocortin, Type 4 - antagonists & inhibitors; Regulation; Rodents; Switzerland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004774

Cachexia 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 alpha-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. SNT207707 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. In 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.