Freya Wolter

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

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 ΔIsc in T84 cells. The specificity of resveratrol was confirmed by using piceatannol 100 μmol/L, the hydroxylated resveratrol analog, which did not alter ΔIsc. 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 ΔIsc as well. In bilateral Cl−-free medium, as well as after inhibition of protein kinase A, resveratrol-induced ΔIsc 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.