Potential anti-cancer activity of 7-O-pentyl quercetin: Efficient, membrane-targeted kinase inhibition and pro-oxidant effect. (October 2017)

• Record Type: Journal Article
• Authors: Sassi, Nicola; Mattarei, Andrea; Espina, Virginia; Liotta, Lance; Zoratti, Mario; Paradisi, Cristina; Biasutto, Lucia
• Is Part Of: Pharmacological research. Volume 124(2017:Oct.)
• Page Start: 9
• Page End: 19
• Publication Date: 2017-10
• Subjects: Akt protein kinase B (PKB) -- CK2 casein kinase 2 -- CsA Cyclosporin A -- DMEM Dulbecco's Modified Eagle Medium -- DTT 1, 4-Dithiothreitol -- FBS fetal bovine serum -- GSK-3 glycogen synthase kinase 3 -- HBSS Hank's Balanced Salt Solution -- IKKα/β IκB kinase -- MARKS MAP/microtubule affinity-regulating kinase -- MEF Mouse Embryo Fibroblasts -- MEK1 Dual specificity mitogen-activated protein kinase kinase 1 -- MS mass spectrometry -- Nrf2 nuclear factor erythroid 2-related factor 2 -- PDK 3-phosphoinositide dependent protein kinase -- PH domain pleckstrin homology domain -- PI Propidium Iodide -- PI3K phosphatidylinositol-4, 5-bisphosphate 3-kinase -- PIP2 phosphatidylinositol (4, 5)-bisphosphate -- PIP3 phosphatidylinositol (3, 4, 5)-trisphosphate -- PVDF polyvinyldifluoride -- Q quercetin -- Q-7P 7-O-(n-pentyl)-quercetin -- RPPA reverse phase protein arrays -- s.d. standard deviation -- SDS sodium dodecyl sulfate -- SEM standard error of the mean; Quercetin -- Biomembranes -- Kinase inhibitor -- Reactive oxygen species (ROS) -- Apoptosis -- Cancer; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2017.07.016
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Quercetin is a redox-active plant-derived flavonoid with potential anticancer effects, stemming largely from its interaction with a number of proteins, and in particular from inhibition of pro-life kinases. To improve efficacy, we reasoned that a local increase in concentration of the compound at the level of cell membranes would result in a more efficient interaction with membrane-associated signaling kinases. We report here the synthesis of all five isomeric quercetin derivatives in which an n -pentyl group was linked via an ether bond to each hydroxyl of the flavonoid kernel. This strategy proved effective in directing quercetin to cellular membranes, and revealed a remarkable dependence of the derivatives' bioactivity on the specific site of functionalization. The isomer bearing the pentyl group in position 7, Q-7P, turned out to be the most effective and promising derivative, selectively inducing apoptosis in tumoral and fast-growing cells, while sparing slow-growing, non-tumoral ones. Cytotoxicity for tumoral cells was strongly enhanced compared to quercetin itself. Q-7P induced massive ROS production, which however accounted only partially for cell death. Alterations in the levels of various signaling phospho-proteins were observed in a proteomics screen. An important contribution seems to come from inhibition of the PI3K/Akt pathway. This work opens new perspectives in developing membrane-associating, polyphenol-based anticancer agents.