Quercetin inhibits a large panel of kinases implicated in cancer cell biology

Abstract

Abstract. Flavonoids are polyphenolic secondary metabolites from plants that possess a common phenylbenzopyrone structure (C6-C3-C6). Depending upon variations in their heterocyclic C-ring, flavonoids are categorised into one of the following groups: flavones, flavonols, flavanones, flavanols, anthocyanidins, isoflavones or chalcones. Flavonols include, among others, the molecules quercetin, myricetin and kaempferol. The anticancer activity of flavonols was first attributed to their electron-donating ability, which comes from the presence of phenolic hydroxyl groups. However, an emerging view is that flavonoids, including quercetin, may also exert modulatory actions in cells by acting through the protein kinase and lipid kinase signalling pathways. Data from the current study showed that 2 μM quercetin, a low concentration that represents less than 10% of its IC 50 growthinhibitory concentration as calculated from the average of eight distinct cancer cell lines, decreased the activity of 16 kinases by more than 80%, including ABL1, Aurora-A, -B, -C, CLK1, FLT3, JAK3, MET, NEK4, NEK9, PAK3, PIM1, RET, FGF-R2, PDGF-R· and -Rß. Many of these kinases are involved in the control of mitotic processes. Quantitative video microscopy analyses revealed that quercetin displayed strong anti-mitotic activity, leading to cell death. In conclusion, quercetin partly exerts its anticancer activity through the inhibition of the activity of a large set of kinases. Quercetin could be an interesting chemical scaffold from which to generate novel derivatives possessing various types of antikinase activities.

Quercetin Therapy for Selected Patients with PIM1 Kinase-Positive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pilot Study

“…Our findings suggest that inhibition of PIM1 kinase may have a role in regulating lymphocyte proliferation in CLL/SLL. However, as quercetin is known to inhibit many kinases in vitro [4], it is possible that the inhibitory effects on lymphocytes demonstrated here may be attributable to kinases other than, or in addition to, the PIM1 kinase.…”

“…Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a flavonoid naturally occurring in fruits and vegetables [3] and is commercially available for human use as a dietary supplement. It is known to inhibit many kinases, including PIM1 (∼95% inhibition in cell culture) and is cytostatic rather than cytotoxic [4]. It was administered in a phase I clinical trial to 51 patients with cancer not amenable to standard therapies in 1996 [5].…”

Plant-Derived Anti-Inflammatory Compounds: Hopes and Disappointments regarding the Translation of Preclinical Knowledge into Clinical Progress

“…Moreover, phosphodiesterases (PDEs) were suggested to be affected by quercetin [94], as well as topoisomerases I and II [95] and Mcl-1 [86]. Most importantly, quercetin was identified as a broad-spectrum kinase inhibitor [96, 97]. Has all this knowledge been translated into therapy or prevention?…”

Quercetin intake with exercise modulates lipoprotein metabolism and reduces atherosclerosis plaque formation

“…Moreover, vitamin E supplementation was found to counteract the beneficial effects of exercise by preventing the induction of aortic catalase activity and endothelial NO synthase expression [23]. Flavonoids are a class of naturally occurring compounds widely present in fruits, vegetables and beverages derived from plants that have known antioxidant activity [24,25]. One such flavonoid, quercetin, has been shown to be an effective free-radical scavenger that inhibits lipoprotein oxidation [24].…”

“…Recent studies have also suggested that quercetin possesses anti-inflammatory properties as well as antioxidant activity. As an antioxidant and anti-inflammatory, quercetin appears to alleviate oxidative stress via diverse pathways, including NF-κB dependent mechanism [25], decrease activity of JAK3 [26], and/or by blocking the activation of pro-inflammatory/oxidative stress mediator signal transduction [27]. Quercetin has also been shown to prevent the accumulation of fat in the liver of mice fed a high fat diet [28] and to lower blood lipids in people with dyslipidemia [29].…”