Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival

Transl Psychiatry. 2011 Jul 26;1(7):e23. doi: 10.1038/tp.2011.25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / drug therapy
  • Anorexia / etiology*
  • Anorexia / mortality
  • Cachexia / drug therapy
  • Cachexia / etiology*
  • Cachexia / mortality
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / mortality
  • Corticotropin-Releasing Hormone / pharmacology
  • Corticotropin-Releasing Hormone / physiology
  • Disease Models, Animal
  • Drug Synergism
  • Drugs, Chinese Herbal / administration & dosage
  • Drugs, Chinese Herbal / pharmacology*
  • Ghrelin / antagonists & inhibitors*
  • Ghrelin / deficiency
  • Ghrelin / physiology*
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Hypothalamus / physiology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / mortality
  • Male
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2C / physiology
  • Receptors, Ghrelin / antagonists & inhibitors
  • Receptors, Ghrelin / physiology
  • Retrospective Studies
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Survival Analysis

Substances

  • Drugs, Chinese Herbal
  • Ghrelin
  • Ghsr1a protein, rat
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Ghrelin
  • Corticotropin-Releasing Hormone