Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model.

Kiyoshi Terawaki,Yoshikazu Higami,Yuka Sudo,Yumi Sawada,Yoichi Ueta,Katsuya Ohbuchi,Hirofumi Hashimoto,Yohei Kashiwase,Seiji Shiraishi,Yasuhito Uezono,Masami Suzuki,Kanako Miyano,Mitsuhiro Yoshimura,Kazuyoshi Yanagihara,Yoshio Kase,Tomohisa Hattori,Zane B Andrews

doi:10.1371/journal.pone.0173113

Abstract

Cancer cachexia (CC) is a multifactorial disease characterized by decreased food intake and loss of body weight due to reduced musculature with or without loss of fat mass. Patients with gastric cancer have a high incidence of cachexia. We previously established a novel CC rat model induced by human gastric cancer-derived 85As2 cells in order to examine the pathophysiology of CC and identify potential therapeutics. In patients with CC, anorexia is often observed, despite elevation of ghrelin, suggesting that ghrelin resistance may develop in these patients. In this study, we aimed to clarify the occurrence of ghrelin resistance in CC rats accompanied by anorexia and we investigated whether rikkunshito (RKT), a traditional Japanese Kampo medicine that potentiates ghrelin signaling, ameliorated CC-related anorexia through alleviation of ghrelin resistance. 85As2-tumor-bearing rats developed severe CC symptoms, including anorexia and loss of body weight/musculature, with the latter symptoms being greater in cachectic rats than in non-tumor-bearing or pair-fed rats. CC rats showed poor responses to intraperitoneal injection of ghrelin. In CC rats, plasma ghrelin levels were elevated and hypothalamic anorexigenic peptide mRNA levels were decreased, whereas hypothalamic growth hormone secretagogue receptor (GHS-R) mRNA was not affected. In vitro, RKT directly enhanced ghrelin-induced GHS-R activation. RKT administrated orally for 7 days partly alleviated the poor response to ghrelin and ameliorated anorexia without affecting the elevation of plasma ghrelin levels in CC rats. The expression of hypothalamic orexigenic neuropeptide Y mRNA but not hypothalamic GHS-R mRNA was increased by RKT. Thus, the 85As2 cell-induced CC rat model developed ghrelin resistance, possibly contributing to anorexia and body weight loss. The mechanism through which RKT ameliorated anorexia in the CC rat model may involve alleviation of ghrelin resistance by enhancement of ghrelin signaling. These findings suggest that RKT may be a promising agent for the treatment of CC.

Highlights

Cancer anorexia-cachexia syndrome, which occurs in 80% of patients with advanced cancer, is a multifactorial disease characterized by decreased food intake and loss of body weight and accounts for at least 20% of cancer-related deaths [1,2,3]
The body weights of rats in the 85As2 group on day 10 were significantly lower than those in the control group, and thereafter, the differences gradually increased
We found that our cancer anorexia-cachexia rat model, induced by human gastric cancer-derived 85As2 cells, developed ghrelin resistance

Summary

Introduction

Cancer anorexia-cachexia syndrome, which occurs in 80% of patients with advanced cancer, is a multifactorial disease characterized by decreased food intake and loss of body weight and accounts for at least 20% of cancer-related deaths [1,2,3]. The mechanisms underlying this syndrome are not fully understood, and appropriate therapies for the treatment of cancer cachexia (CC) have not been established. In both the diagnosis of and therapy for cancer anorexia-cachexia, management of appetite is important because it reinforces physical strength and improves quality of life (QOL) and maintenance of body weight. Amelioration of cachexia-related anorexia in patients with cancer is the key to improving both QOL and prognosis

Objectives

Methods

Results

Conclusion