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.
Highlights
Cachexia is characterized by weight loss, fat and muscle tissue wasting, psychological distress and a lower quality of life
Significant decreases in the hypothalamic expression of appetiteregulating peptides, neuropeptide Y (NPY), agouti-related peptide, proopiomelanocortin (POMC), urocortin-2,3 and Corticotropin-releasing factor (CRF), were observed in tumor-bearing rats compared to pair-fed controls (Figure 1d)
Weight loss is a potent stimulus of food intake in healthy humans and animals, and ghrelin secretion increases under conditions of negative energy balance such as starvation
Summary
Cachexia is characterized by weight loss, fat and muscle tissue wasting, psychological distress and a lower quality of life. Anorexia development is frequently associated with the presence of cachexia, resulting in the socalled cancer anorexia–cachexia syndrome.[1] This syndrome is observed in 80% of patients with advanced-stage cancer and is a frequent cause of death.[2] Recent reports have indicated that an imbalance between anorexigenic and orexigenic peptides leads to appetite suppression.[3,4,5] Anorexia–cachexia is caused predominantly by cytokines that are either produced by cancer cells or released by the host immune system in response to the cancer,[6] but the neurochemical mechanisms responsible for cancer anorexia–cachexia remain uncertain. A better understanding of the underlying mechanisms of this syndrome will help in the development of new therapies to improve quality of life and potentially to prolong survival in patients with cancer-induced anorexia–cachexia
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