Citrus Flavonoids Luteolin, Apigenin, and Quercetin Inhibit Glycogen Synthase Kinase-3β Enzymatic Activity by Lowering the Interaction Energy Within the Binding Cavity

Jodee Johnson

Sanjeewa Rupasinghe

Felicia Stefani

Mary Schuler

Elvira de Mejia

^{Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA}

^{Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA}

^{Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA}

^{Corresponding author.}

Address correspondence to: Elvira Gonzalez de Mejia, 228 Edward R. Madigan Laboratory, MC-051, 1201 W. Gregory Drive, Urbana, IL 61801 USA, E-mail:Email: ude.sionilli@aijemede

Received 2010 Nov 14; Accepted 2011 Jan 7.

Abstract

Pancreatic cancer studies have shown that inhibition of glycogen synthase kinase-3β (GSK-3β) leads to decreased cancer cell proliferation and survival by abrogating nuclear factor κB (NFκB) activity. In this investigation, various citrus compounds, including flavonoids, phenolic acids, and limonoids, were individually investigated for their inhibitory effects on GSK-3β by using a luminescence assay. Of the 22 citrus compounds tested, the flavonoids luteolin, apigenin, and quercetin had the highest inhibitory effects on GSK-3β, with 50% inhibitory values of 1.5, 1.9, and 2.0 μM, respectively. Molecular dockings were then performed to determine the potential interactions of each citrus flavonoid with GSK-3β. Luteolin, apigenin, and quercetin were predicted to fit within the binding pocket of GSK-3β with low interaction energies (−76.4, −76.1, and −84.6 kcal·mol^{, respectively) and low complex energies (−718.1, −688.1, and −719.7 kcal·mol}^{, respectively). Our results indicate that several citrus flavonoids inhibit GSK-3β activity and suggest that these have potential to suppress the growth of pancreatic tumors.}

Key Words: Glycogen synthase kinase-3β, GSK-3β, citrus compounds, flavonoids, luminescence assay, molecular docking

Abstract

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