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

PLoS One. 2017 Mar 1;12(3):e0173113. doi: 10.1371/journal.pone.0173113. eCollection 2017.

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.

MeSH terms

  • Animals
  • Cachexia / drug therapy*
  • Cachexia / metabolism
  • Cell Line, Tumor
  • Drug Resistance
  • Drugs, Chinese Herbal / administration & dosage
  • Drugs, Chinese Herbal / therapeutic use*
  • Ghrelin / blood*
  • Ghrelin / therapeutic use
  • Humans
  • Male
  • Medicine, Kampo / methods*
  • Palliative Care
  • Rats
  • Rats, Inbred F344
  • Stomach Neoplasms / complications*

Substances

  • Drugs, Chinese Herbal
  • Ghrelin
  • liu-jun-zi-tang

Grants and funding

Grant support was provided to KT by: 1. Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan [http://www.jsps.go.jp/j-grantsinaid/index.html] Grant no. 22590510. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2. The Foundation for Promotion of Cancer Research in Japan [http://www.ncc.go.jp/jp/]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Grant support was provided to Y. Uezono by: 1. The Third-term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare, Japan; [http://www.mhlw.go.jp/] Grant no. H22-General-035. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2. Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; [http://www.jsps.go.jp/j-grantsinaid/index.html] Grant no. 24590740. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 3. Grants from the Research Project for Improving Quality in Healthcare and Collecting Scientific Evidence on Integrative Medicine [http://www.amed.go.jp/] Grant no. 15lk0310003h0001, 16lk0310020h0001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 4. The Practical Research for Innovative Cancer Controlfrom Japan Agency for Medical Research and Development, AMED; [http://www.amed.go.jp/] Grant no. 15ck0106059h0002, 16nk0101311h0002. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 5. The National Cancer Center Research and Development Fund [http://www.ncc.go.jp/jp/] Grant nos. 23-A-2, 23-A-29, and 23-A-38. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 6. A grant from Tsumura & Co. (Ibaraki, Japan) [https://www.tsumura.co.jp/]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.