Modulation of polyamine metabolism as a chemopreventive strategy of phytochemicals in a cell culture model of colorectal cancers
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Resveratrol a natural occuring polyphenol present in red wine, peanuts and grapes, has been reported to exhibit a wide range of biological and pharmacological properties. In addition to cardioprotective and antiinflammatory effects, potent chemopreventive activities of resveratrol and its analogs in various carcinogenesis models are described and there has been a great deal of experimental effort directed toward defining these effects. We and others could previously demonstrate that resveratrol inhibits cell growth in several malignant cell lines via modulation of polyamine metabolism. In detail, resveratrol was shown to simultaneously inhibit biosynthetic ornithine decarboxylase (ODC) and activate catabolic spermine/spermidine acetyltransferase (SSAT). One aim of this work was to specify the underlying molecular mechanisms of resveratrol actions in colorectal cancer cells and especially to identify possible roles of transcription factor peroxisome-proliferator activated receptor gamma (PPARgamma) and the sphingolipid metabolite ceramide. Previous studies could demonstrate that ursolic acid (UA), a pentacyclic triterpene found in berries and plants, has antiproliferative as well as proapoptotic activities on cancer cells. The objective of this second project was to elucidate the underlying molecular mechanisms of these chemopreventive effects. On the basis of our findings, p38 MAPK as well as transcription factor PPARgamma can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity respectively in a cell culture model of colon cancer. Moreover, the results provide evidence for the involvement of ceramide de novo biosynthesis in resveratrol mediated inhibition of ODC activity. The observed reduction of cell growth of colon cancer cell lines after treatment with ursolic acid presumably results from a large increase in the number of apoptotic cells. The induction of the catabolic enzyme SSAT via PPARgamma-dependent mechanisms therby seems to present the major molecular target in the induction of programmed cell death. Due to these results the phytochemicals resveratrol as well as ursolic acid could show great chemopreventive and therapeutic potential in the treatment of colorectal cancers.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Cancer Res, 66(14) (2006), S.7348-54; Biochem Pharmacol, 74(2) (2007), S. 281-9; J Nutr, 134(2) (2004), S.3219-22; Mol Nutr Food Res, 49(5) (2005), S.452-61