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Anti-proliferative effect of rhein, an anthraquinone isolated from Cassia species, on Caco-2 human adenocarcinoma cells
Objective: In recent years the use of anthraquinone laxatives, in particular senna, has been associated with damage to the intestinal epithelial layer and an increased risk of developing colorectal cancer. In the present study we evaluated the cytotoxicity of rhein, the active metabolite of senna, on human colon adenocarcinoma cells (Caco-2) and its effect on cell proliferation. Methods: Cytotoxicity studies were performed using MTT, NR and TEER assays whereas 3H-thymidine incorporation and western blot analysis were used to evaluate the effect of rhein on cell proliferation. Moreover, for genoprotection studies Comet assay and oxidative biomarkers measurement (malondialdehyde and reactive oxygen species) were used. Results: Rhein (0.1-10ÎĽg/ml) had no significant cytotoxic effect on proliferating and differentiated Caco-2 cells. Rhein (0.1 and 1 ÎĽg/ml) significantly reduced cell proliferation as well as MAP kinase activation; by contrast, at the high concentration (10ÎĽg/ml) rhein significantly increased cell proliferation and ERK phosphorylation. Moreover, rhein (0.1-10ÎĽg/ml) (i) did not adversely affect the integrity of tight junctions and hence epithelial barrier function, (ii) did not induce DNA damage rather it was able to reduce H2O2-induced DNA damage and (iii) significantly inhibited the increase in malondialdehyde and ROS levels induced by H2O2/Fe2+. Conclusions: Rhein, was devoid of cytotoxic and genotoxic effects in colon adenocarcinoma cells. Moreover, at concentrations present in the colon after a human therapeutic dosage of senna, rhein inhibited cell proliferation via a mechanism which seems to involve directly the MAP kinase pathway. Finally, rhein prevents the DNA damage probably via an anti-oxidant mechanism
Effect of anthraquinone derivatives on canine and rat intestinal motility.
The effects on gastrointestinal motility of 3 senna preparations containing 18% oxidized Ca-sennosides, 60% Ca-sennosides, or pure sennosides A + B were tested in dogs and rats as measured by electromyography. Oral administration of the oxidized products in the fasted animal increased the activity of the small intestine within 2 h and reduced both caecal and colonic contractions for 24 h. Severe diarrhoea was present 4-6 h after administration and lasted for at least 1 day. Ca-sennosides had a similar, but weaker effect while pure sennosides affected motility only 6-10 h after oral administration. The intracolonic administration of the oxidized products resulted in an immediate reduction of colon motility for 7-8 h and diarrhoea was present within 40 min. Intracolonic Ca-sennosides and sennosides A + B induced only small changes in the intestinal motility, but diarrhoea also appeared. The results confirm that pure sennosides act predominantly on large intestine motility after their degradation by colonic microorganisms. Oxidized products are already effective in the upper gastrointestinal tract. The early action of Ca-sennosides requires further investigation. Side effects after oral senna treatment such as griping or nausea may be caused by motility changes induced by the presence of small amounts of oxidized products in the drug
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