Z-505 hydrochloride, an orally active ghrelin agonist, attenuates the progression of cancer cachexia via anabolic hormones in Colon 26 tumor-bearing mice.

Abstract

Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC50) value of 0.45nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a.

• Authors: Makoto Yoshimura, Yoshihiro Shiomi, Yuta Ohira, Mineo Takei, Takao Tanaka
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 811 Pg. 30-37 (Sep 15 2017) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 28529141 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Ghrelin
• Hormones
• Quinolines
• Receptors, Ghrelin

Topics

• Adipose Tissue (drug effects, pathology)
• Administration, Oral
• Animals
• BALB 3T3 Cells
• Body Weight (drug effects)
• CHO Cells
• Cachexia (complications, drug therapy, metabolism, physiopathology)
• Cell Line, Tumor
• Colonic Neoplasms (complications)
• Cricetulus
• Disease Models, Animal
• Disease Progression
• Eating (drug effects)
• Ghrelin (agonists, metabolism)
• Hormones (metabolism)
• Humans
• Male
• Mice
• Quinolines (administration & dosage, metabolism, pharmacology, therapeutic use)
• Rats
• Receptors, Ghrelin (metabolism)