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.