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

BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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

The effects of p.o. administration of (A) SNT207707 and (B) SNT207858 on light phase food intake in healthy mice.

<p>Animals were held in groups of three. Food intake per cage (n = 6 cages/dose) was recorded over a period of 4 hrs starting after administration of compound. Each bar represents mean±SEM. Statistical difference vs. Vehicle ** p<0.01.</p

The effects of C26 tumor on development of cachexia (defined as loss of more than 5% of body weight (BW) after inoculation of tumor cells) in mice.

<p>(A) Left panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207707 30 mg/kg (grey line) group (n = 9 each). (B) Right panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207858 30 mg/kg (grey line) group (n = 9 each). Note: Statistical comparison between Vehicle+Tumor and treatment groups was significant.</p

Peak plasma and brain levels and 0-6-hr plasma and brain AUC of MC4-R antagonists SNT207707 and SNT207858 in CD-1 mice after oral application (n = 3 per group).

<p>Note: Brain/plasma ratio is calculated from area under the curve (AUC).</p

The effects of (A) SNT207707 and (B) SNT207858 in C26 tumor bearing mice.

<p>Left panels: Mean body weight development of Vehicle control (open squares), Vehicle+Tumor control (closed squares), and 30 mg/kg (A) SNT207707 and (B) SNT207858 (grey triangles) group (n = 9 each). Middle and right panels: Difference in lean body mass and fat mass between day of tumor inoculation (day 0) and end of experiment (day 15). Each value represents mean±SEM. Statistical difference vs. Vehicle+Tumor * p<0.05, *** p<0.001.</p