Abstract
The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.
Highlights
The cancer anorexia-cachexia syndrome (CACS) is characterized by reduced dietary intake, tissue wasting, severe body weight loss, and weakness [1]
In tumor-bearing mice, HM01 increased food intake, body weight (BW), fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, macrophage-inhibitory cytokine-1 (MIC-1), muscle RING-finger-protein-1 (MuRF-1) or muscle atrophy F-box (MAFbx), which were not affected by HM01
HM01 counteracts CACS in a tumor model that is characterized by pronounced cachexia in the absence of severe anorexia
Summary
The cancer anorexia-cachexia syndrome (CACS) is characterized by reduced dietary intake, tissue wasting, severe body weight loss, and weakness [1]. Inflammatory signaling molecules (e.g., cytokines) released by the tumor itself or the host immune system in response to the malignancy are important mediators of CACS [2]. CACS affects up to 80% of patients with advanced cancer. Regardless of the type of malignancy, cancer patients suffering from CACS show poor responsiveness to anti-cancer treatments, reduced quality of life and increased mortality [3,4,5]. Despite the high prevalence of CACS in cancer patients, to date no effective treatment exists to counteract this condition. Therapeutic approaches against CACS should stimulate energy intake and anabolism to defeat catabolic processes and increase lean mass and body weight [5]. While a few drugs have been developed to improve appetite and increase body weight, none of these drugs effectively increased lean body mass [6]
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