Curcumin and Genistein: the Combined Effects on Disease-associated CFTR Mutants and their Clinical Implications

Abstract

Genistein and curcumin are major components of Asian foods, soybean and curry turmeric respectively. These compounds have been intensively investigated for their chemical and biological features conferring their anti-cancer activity. Genistein and curcumin have also been investigated for their potentiation effects on disease-associated CFTR mutants such as ΔF508 and G551D. Recently, we investigated the combined effect of genistein and curcumin on G551D-CFTR, which exhibits gating defects without abnormalities in protein synthesis or trafficking using the patch-clamp technique. We found that genistein and curcumin showed additive effects on their potentiation of G551D-CFTR in high concentration range and also, more importantly, showed a significant synergistic effect in their minimum concentration ranges. These results are consistent with the idea that multiple mechanisms are involved in the action of these CFTR potentiators. In this review, we revisit the pharmacology of genistein and curcumin on CFTR and also propose new pharmaceutical implications of combined use of these compounds in the development of drugs for CF pharmacotherapy.

Nobiletin Stimulates Chloride Secretion in Human Bronchial Epithelia via a cAMP/PKA-Dependent Pathway

“…A similar stimulatory effect on CFTR channel activity was also observed by another citrus-derived flavonoid, tangeretin [7]. Because of its therapeutic potential in treating CF [41], the best-known and studied flavonoid, which can stimulate CFTR-dependent Cl - secretion, is genistein [42]. Genistein is a potent activator of CFTR and ∆F508 CFTR in human airway epithelial cell lines [43].…”

Transient Receptor Potential Channels as Targets for Phytochemicals

“…Curcumin has been shown to be effective in the disease caused by ΔF508 mutation, which results in the production of misfolded CFTR protein. 36−38 Curcumin activates TRPA1, which is expressed in the bronchial mucosa and relieves symptoms of cystic fibrosis.…”

Resveratrol and ivacaftor are additive G551D CFTR‐channel potentiators: therapeutic implications for cystic fibrosis sinus disease

“…Unfortunately, resveratrol exhibits poor bioavailability with attainable maximum plasma levels of approximately 2 μM – well below the optimum concentration. 16 However, multiple therapies for CF involve topical application of drugs to the sinuses and lungs, including hypertonic saline, dornase alpha, and antibiotic therapies. 33–35 The sinuses in particular are an excellent target area for topical CFTR potentiators delivered in saline rinse or aerosol.…”

“…14,15 However, several agents clearly exhibit an additive effect (e.g. UCCF-029 and UCCF-853, 15 genistein and curcumin 16 ). Whether resveratrol mediates CFTR channel potentiation according to an identical mechanism of action as ivacaftor is currently unknown.…”