The Chemopreventive Agent Resveratrol Stimulates Cyclic AMP–Dependent Chloride SecretionIn vitro

Abstract

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 À secretion and (b) to elucidate possible intracellular transduction pathways involved. Resveratrol caused a dose-and time-dependent increase in DIsc in T 84 cells. The specificity of resveratrol was confirmed by using piceatannol 100 Amol/L, the hydroxylated resveratrol analog, which did not alter DIsc. A significant elevation of [cAMP] i by resveratrol was assessed in T 84 cells. In mouse jejunum, resveratrol induced a time-and dose-dependent increase in DIsc as well. In bilateral Cl À -free medium, as well as after inhibition of protein kinase A, resveratrol-induced DIsc was reduced significantly. Preincubation of T 84 cells with butyrate 2 mmol/L (24 and 48 hours) significantly inhibited resveratrol as well as forskolin-induced Cl À 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.

Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and the antilipolytic action of insulin in isolated rat adipocytes

“…The rise in cAMP is crucial for the stimulation of lipolysis (reviewed by [36]). The resveratrol's ability to enhance cAMP was previously shown in breast [37] and colon cancer cells [38]. Interestingly, resveratrol failed to significantly augment lipolysis induced by dibutyryl-cAMP, a direct activator of PKA.…”

Effects of Resveratrol (trans-3,5,4′-Trihydroxystilbene) Treatment on Cardiac Remodeling following Myocardial Infarction

“…This is consistent with the notion that resveratrol treatment contributes to a preservation of cardiac contractile reserve, despite not attenuating remodeling and baseline hemodynamic function. Only a very limited number of studies have examined the interaction of resveratrol with ␤-adrenergic signaling, and although a few have described direct time-and dose-dependent activation of adenylyl-cyclase (El Mowafy and Alkhalaf, 2003;Blumenstein et al, 2005) the lack of positive inotropic effects in sham ϩ RES animals under dobutamine stress argues against this potential mechanism. Alternatively, resveratrol may cause upregulation of "spare" ␤ARs, that is, receptors not required for the production of the maximal inotropic response (Brown et al, 1992;Lee et al, 1999), particularly in light of the fact that resveratrol-induced increases in ␤AR density failed to enhance the dobutamine response in sham animals.…”

Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPC-A-1/CDDP cells

“…Furthermore, resveratrol has been shown to inhibit the local growth and dissemination of several transplantable tumours in laboratory animals (30). Due to its valuable biological properties and lack of significant side effects even after long-term administration, it seems that resveratrol is one of the most promising agents that could be applied in the future in cancer prevention strategies and cancer therapy in humans (31).…”