Evidence against resveratrol as a viable therapy for the rescue of defective ΔF508 CFTR

Abstract

BACKGROUND Resveratrol, a natural phenolic compound, has been reported to rescue mutant ΔF508 CFTR in expression systems and primary epithelial cells. Although this implies a therapeutic benefit to patients with CF, investigations were performed using resveratrol concentrations greatly in excess of those achievable in plasma. We evaluated the efficacy of resveratrol as a CFTR corrector in relevant primary airway cells, using physiologically achievable resveratrol concentrations. METHODS Cells expressing wt or ΔF508 CFTR were exposed to chronic or acute resveratrol. CFTR mRNA and protein expression were monitored. The effects of resveratrol on primary ΔF508 human airway cells were evaluated by equivalent current analysis using modified Ussing chambers. RESULTS Consistent with previously published data in heterologous expression systems, high doses of resveratrol increased CFTR expression; however physiologically relevant concentrations were without effect. In contrast to heterologous expression systems, resveratrol was unable to increase mutant CFTR channel activity in primary airway cells. Elevated amiloride-sensitive currents, indicative of sodium transport and characteristically elevated in CF airway cells, were also unaffected by resveratrol CONCLUSIONS High concentrations of resveratrol can increase CFTR mRNA and protein in some cell types. In addition, acute resveratrol exposure can stimulate CFTR mediated chloride secretion, probably by increasing cellular cAMP levels. Resveratrol at physiologically achievable levels yielded no benefit in primary ΔF508 airway cells, either in terms of amiloride-sensitive currents of CFTR currents.

Natural Compounds as Therapeutic Agents in the Treatment Cystic Fibrosis

“…Interestingly, resveratrol by itself could stimulate chloride secretion across a human colonic monolayer, a stimulation that was markedly enhanced by the addition of a small amount of forskolin. Such observations are at least consistent with the hypothesis that resveratrol can enhance CFTR activity by acting as a phosphodiesterase inhibitor [ 50 , 51 ]. It is possible that resveratrol works directly on CFTR by acting as a potentiator, indeed, resveratrol has been reported to increase the open probability (Po) of murine CFTR, although it should be noted that murine CFTR has different electrophysiological properties than human CFTR [ 47 , 52 ].…”

“…One interesting observation was that resveratrol appeared to increase the activity of ENaC, enhancing absorptive sodium transport, potentially further exacerbating the enhanced sodium hyper-absorption seen in CF airways [ 47 , 49 ]. In the hands of other researchers, resveratrol was able to increase wt CFTR expression, but was unable to increase ΔF508 CFTR expression in expression systems [ 50 ]. Using primary human airway epithelial cells from patients homozygous for the ΔF508 CFTR mutation, our studies were unable to demonstrate any benefit from resveratrol exposure, even though known “correctors” were effective [ 50 ].…”

“…In the hands of other researchers, resveratrol was able to increase wt CFTR expression, but was unable to increase ΔF508 CFTR expression in expression systems [ 50 ]. Using primary human airway epithelial cells from patients homozygous for the ΔF508 CFTR mutation, our studies were unable to demonstrate any benefit from resveratrol exposure, even though known “correctors” were effective [ 50 ]. Moreover we were also unable to see any effects on amiloride sensitive sodium currents, suggesting that ENaC was not a target for resveratrol.…”

“…The majority of studies seeing efficaciousness of resveratrol do so at concentrations >50 μM. Indeed the studies of Jai et al also see an effect of resveratrol on wt CFTR at concentrations above 50 μM [ 50 ]. However, as with curcumin, the issue of effective in vitro concentration versus achievable plasma concentration is an issue that has to be addressed.…”

Calcium-induced chloride secretion is decreased by Resveratrol in ileal porcine tissue

“…described for sinonasal epithelial cells [12, 13], a pancreatic cell line [14] and rat colonocytes [15]. Other studies failed to demonstrate effects which is discussed with regards to the models and the concentration of RSV [16, 17]. …”