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Article

Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6

1
Microbiology Research Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
2
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
3
South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa
4
Laboratory of Computational Modeling of Drugs, South Ural State University, 76 Lenin Prospekt, 454080 Chelyabinsk, Russia
5
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
6
Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3526; https://doi.org/10.3390/ijms21103526
Received: 7 April 2020 / Revised: 24 April 2020 / Accepted: 24 April 2020 / Published: 15 May 2020
(This article belongs to the Special Issue Cytokines/Chemokines in Cancer Metastasis)
Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of K = 107 M−1 and subsequently inhibits its enzyme activity with an IC50 value of 3.053 µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies. View Full-Text
Keywords: cyclin-dependent kinase 6; natural products; ellagic acid; molecular dynamics simulation; kinase inhibitor; drug design and discovery; anticancer therapy cyclin-dependent kinase 6; natural products; ellagic acid; molecular dynamics simulation; kinase inhibitor; drug design and discovery; anticancer therapy
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MDPI and ACS Style

Yousuf, M.; Shamsi, A.; Khan, P.; Shahbaaz, M.; AlAjmi, M.F.; Hussain, A.; Hassan, G.M.; Islam, A.; Rizwanul Haque, Q.M.; Hassan, M.I. Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6. Int. J. Mol. Sci. 2020, 21, 3526. https://doi.org/10.3390/ijms21103526

AMA Style

Yousuf M, Shamsi A, Khan P, Shahbaaz M, AlAjmi MF, Hussain A, Hassan GM, Islam A, Rizwanul Haque QM, Hassan MI. Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6. International Journal of Molecular Sciences. 2020; 21(10):3526. https://doi.org/10.3390/ijms21103526

Chicago/Turabian Style

Yousuf, Mohd, Anas Shamsi, Parvez Khan, Mohd Shahbaaz, Mohamed F. AlAjmi, Afzal Hussain, Gulam Mustafa Hassan, Asimul Islam, Qazi Mohd Rizwanul Haque, and Md. Imtaiyaz Hassan. 2020. "Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6" International Journal of Molecular Sciences 21, no. 10: 3526. https://doi.org/10.3390/ijms21103526

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