title: 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.
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.
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ami-machi, Inashiki-gun, Ibaraki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Terawaki
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kashiwase
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshimura
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ami-machi, Inashiki-gun, Ibaraki, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ohbuchi
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sudo
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyano
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shiraishi
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Higami
authors.affiliation: Division of Biomarker Discovery, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ami-machi, Inashiki-gun, Ibaraki, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ami-machi, Inashiki-gun, Ibaraki, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kase
authors.affiliation: Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ueta
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Division of Supportive Cancer Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chuo-ku, Tokyo, Japan.|Innovation Center for Supportive, Palliative and Psychosocial Care, National Cancer Center, Chuo-ku, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
mesh_terms: D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004351:Drug Resistance; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000627:therapeutic use*; D054439:Ghrelin / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020835:Medicine, Kampo / Q000379:methods*; D010166:Palliative Care; D051381:Rats; D011916:Rats, Inbred F344; D013274:Stomach Neoplasms / Q000150:complications*
chemical_list: D004365:Drugs, Chinese Herbal; D054439:Ghrelin; C084136:liu-jun-zi-tang