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The Chemopreventive Agent Resveratrol Stimulates Cyclic AMP–Dependent Chloride Secretion In vitro

Authors' Affiliation: Division of Gastroenterology and Clinical Nutrition, 1^st Department of Medicine, ZAFES, J.W. Goethe-Universität, Theodor-Stern-Kai 7, Frankfort on the Main, Germany

Requests for reprints: Irina Blumenstein, Division of Gastroenterology and Clinical Nutrition, 1st Department of Medicine, ZAFES, J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfort on the Main, Germany. Phone: 49-69-6301-5917; Fax: 49-69-6301-83112; E-mail: J.Stein{at}em.uni-frankfurt.de.

Resveratrol and its analogs are promising cancer chemoprevention agents, currently under investigation in clinical trials. However, patients administered other plant polyphenols experienced severe diarrhea, likely due to an increase in intracellular cyclic AMP (cAMP). Resveratrol itself raises intracellular cAMP levels in breast cancer cells in vitro. Its future use as a cancer chemopreventive agent could therefore be compromised by its severe side effects. The aim of the study was (a) to define the influence of resveratrol on intestinal Cl^– secretion and (b) to elucidate possible intracellular transduction pathways involved. Resveratrol caused a dose- and time-dependent increase in Isc in T₈₄ cells. The specificity of resveratrol was confirmed by using piceatannol 100 µmol/L, the hydroxylated resveratrol analog, which did not alter Isc. A significant elevation of [cAMP]_i by resveratrol was assessed in T₈₄ cells. In mouse jejunum, resveratrol induced a time- and dose-dependent increase in Isc as well. In bilateral Cl^–-free medium, as well as after inhibition of protein kinase A, resveratrol-induced Isc was reduced significantly. Preincubation of T₈₄ cells with butyrate 2 mmol/L (24 and 48 hours) significantly inhibited resveratrol as well as forskolin-induced Cl^– secretion. In summary, the main mechanism of action of resveratrol in intestinal epithelia is cAMP-induced chloride secretion which can be suppressed by butyrate. It can therefore be suggested that in cancer chemoprevention, both agents should be combined to reduce an undesired side effect such as diarrhea and to benefit from the known agonistic effect of both agents on differentiation of colon cancer cells.

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