Z-505 hydrochloride ameliorates chemotherapy-induced anorexia in rodents via activation of the ghrelin receptor, GHSR1a

Despite its therapeutic advantages, chemotherapy with anti-cancer drugs can cause adverse effects, including anorexia and weight loss. Although most patients with cancer suffer from anorexia during chemotherapy, resulting in the need to suspend or cease treatment and thereby worsening prognosis, treatment options for anorexia remain limited. Ghrelin is an orexigenic hormone that has been proposed to prevent anorexia. To investigate the potential of ghrelin receptor agonists, synthetic small-molecule compounds, as preventive therapies for chemotherapy-induced anorexia, we studied the effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, in cisplatin- and 5-fluorouracil (5-FU)-induced anorexia animal models. The agonistic activity of Z-505 was examined using calcium flux assays in Chinese hamster ovary (CHO-K1) cells stably expressing rat or mouse GHSR1a. Z-505 showed agonistic activity for rat GHSR1a and mouse GHSR1a, with a half maximal effective concentration (EC50) of 2.08 nM and 5.46 nM, respectively. In a cisplatin-induced anorexia rat model, administration of Z-505 (30, 100 or 300 mg/kg, p.o., once daily) significantly improved the cisplatin-induced reduction in food intake and body weight. In addition, treatment with Z-505 (100 or 300 mg/kg, p.o., once daily) prevented the 5-FU-induced decrease in food intake and body weight in the 5-FU-induced mouse model. Our results demonstrate that Z-505 ameliorates cisplatin- and 5-FU-induced anorexia through the activation of the ghrelin receptor, GHSR1a, suggesting its usefulness in the preventive treatment of anorexia during chemotherapy.