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European Journal of Pharmacology Sep 2017Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent...
Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC) value of 0.45nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a.
Topics: Adipose Tissue; Administration, Oral; Animals; BALB 3T3 Cells; Body Weight; CHO Cells; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Cricetulus; Disease Models, Animal; Disease Progression; Eating; Ghrelin; Hormones; Humans; Male; Mice; Quinolines; Rats; Receptors, Ghrelin
PubMed: 28529141
DOI: 10.1016/j.ejphar.2017.05.036 -
Journal of Nutrigenetics and... 2013Plant phenolics can inhibit, retard or reverse carcinogenesis, and may thus help prevent or treat cancer. Oil palm phenolics (OPP) previously showed anti-tumour...
BACKGROUND/AIM
Plant phenolics can inhibit, retard or reverse carcinogenesis, and may thus help prevent or treat cancer. Oil palm phenolics (OPP) previously showed anti-tumour activities in vivo via a cytostatic mechanism at 1,500 ppm gallic acid equivalent. Here, we report other possible molecular mechanisms by which this extract attenuates cancer, especially those concerning the immune response.
METHODS
We subcutaneously injected J558 myeloma cells in BALB/c mice and supplemented OPP orally at 1,500 ppm gallic acid equivalent. We observed the physiology parameters of these animals and harvested their spleens and livers after 18 h, 1 week and 4 weeks for microarray gene expression analysis using Illumina MouseRef-8 BeadChips.
RESULTS
Time course microarray analysis on spleens after injecting J558 myeloma cells in mice revealed that the immune response of tumour-bearing mice supplemented with OPP was lower compared to controls, thus suggesting delayed inflammation in response to OPP. In livers, cholesterol biosynthesis genes were upregulated while inflammatory genes were downregulated through time, further suggesting attenuation of systemic inflammation and cachexia. These effects correlated with the delayed in vivo development of syngeneic tumours in mice given OPP.
CONCLUSIONS
This study suggests the possible utilisation of OPP as an anti-tumour and anti-cachexia agent.
Topics: Animals; Cachexia; Dietary Supplements; Gallic Acid; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Inflammation; Liver; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Palm Oil; Phenol; Plant Oils; Spleen; Tissue Distribution
PubMed: 24642698
DOI: 10.1159/000357948 -
Cancer Research Jun 1983In view of the postulated role of cathepsin D in cachexia, investigations have been pursued on the host tissue response of cathepsin D activity in DBA/2 mice inoculated...
In view of the postulated role of cathepsin D in cachexia, investigations have been pursued on the host tissue response of cathepsin D activity in DBA/2 mice inoculated with 5 X 10(5) L1210 tumor cells. The results confirmed previous investigators' findings of the increase in cathepsin D activity (specific activity) in liver and muscle of tumor bearers. In addition, it was found that this increase was a general response of the host since heart, kidney, lung, and spleen cathepsin D specific activity were also enhanced in tumor bearers. These increases ranged from an average of 10% for spleen to 100% for gastrocnemius muscle. This effect was age related in heart and kidney. As a working hypothesis, we propose the concept that tumor bearers release protease-enhancing factor(s) which trigger increase or enhancement of cathepsin D activity in host tissues by yet unknown mechanisms. Pepstatin (60 mg/kg), a known inhibitor of cathepsin D in vitro, was shown to provide long-lasting inhibition (3 to 6 days) of cathepsin D in vivo in non-tumor bearers particularly in spleen, liver, kidney, lung, and heart. Evidence is provided from assays of cell fractions that this inhibition takes place at or in the lysosome. The duration of the effectiveness of pepstatin was altered in tumor bearers in that cathepsin D activity of heart, lung, and spleen had returned to near normal values in 48 hr following pepstatin injection. However, in muscle, liver, and kidney, significant inhibition (90%) still persisted in tumor bearers as it did in non-tumor bearers. Pepstatin or related antiproteases may prove useful as "anticachexia" agents by decreasing proteolysis in muscle and other tissues.
Topics: Age Factors; Animals; Cathepsin D; Cathepsins; Leukemia L1210; Mice; Mice, Inbred DBA; Oligopeptides; Pepstatins; Tissue Distribution
PubMed: 6850578
DOI: No ID Found