title: Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.
abstract: Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.
authors: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors: N
authors: N
authors: Fujitsuka
authors: A
authors: A
authors: Asakawa
authors: Y
authors: Y
authors: Uezono
authors: K
authors: K
authors: Minami
authors: T
authors: T
authors: Yamaguchi
authors: A
authors: A
authors: Niijima
authors: T
authors: T
authors: Yada
authors: Y
authors: Y
authors: Maejima
authors: U
authors: U
authors: Sedbazar
authors: T
authors: T
authors: Sakai
authors: T
authors: T
authors: Hattori
authors: Y
authors: Y
authors: Kase
authors: A
authors: A
authors: Inui
mesh_terms: D000818:Animals; D000855:Anorexia / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D054439:Ghrelin / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000502:physiology; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D016019:Survival Analysis
chemical_list: D004365:Drugs, Chinese Herbal; D054439:Ghrelin; C571124:Ghsr1a protein, rat; D044405:Receptor, Serotonin, 5-HT2C; D054440:Receptors, Ghrelin; D003346:Corticotropin-Releasing Hormone