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

Abstract

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.

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

“…The cell viability results are consistent with previous reports, which suggested that inhibition of CDK6 decreases the growth of cancer cells. 65 , 66 …”

“…CDK6 expressed in Codon + competent cells, which were purified by our previously reported protocol. 66 In brief, the recombinant cells were grown and induction was done at 18 °C by 0.5 mM IPTG (Sigma, Saint Louis, USA). The pellet obtained from this culture was dissolved in 50 mM Tris–HCl, 200 mM MgCl 2 buffer, pH 8.0.…”

“…The sample cell contained 15 μM CDK6, while 500 μM quercetin present in the syringe was titrated into the cell that was filled with CDK6 and analyzed for binding parameters. 66 To nullify the heat of dilution of solvent, the titration of the ligand was performed in buffer and substracted from the protein–ligand dilutions before final fitting of binding data. The MicroCal Origin 8.0 was used to analyze the stoichiometry of binding ( n ), enthalpy change (Δ H ), and an association constant ( K a ).…”

Chebulinic acid inhibits MDA‐MB‐231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy

“…Chebulagic acid has been shown to have significant anti angiogenic (Athira et al, 2017) and antitumor activity against colorectal carcinoma and retinoblastoma cell lines (Kumar, Gangappa, Gupta, & Karnati, 2014; Reddy et al, 2009). Similarly, it has been demonstrated that ellagic acid can induce apoptosis in breast, prostrate, colon, and lung cancer cells (Alhakamy et al, 2020, Duan et al, 2020; Mohammed Saleem and Selim, 2020; Yousuf et al, 2020). Gallic acid, another polyphenol present in Triphala preparation also demonstrates significant anticancer and apoptotic activity (Alfei, Marengo, Zuccari, Turrini, & Domenicotti, 2020; Jang, Ko, & Choi, 2020; Patra et al, 2020, Priyadarshi et al, 2020).…”

Current Perspectives of the Applications of Polyphenols and Flavonoids in Cancer Therapy

“…One of the last studies that examined the breast cancer treatment with ellagic acid was published by Yousuf et al [ 147 ]. This work evaluated the capacity of numerous phytochemicals in addition to ellagic acid (capsaicin, tocopherol, rosmarinic acid, ursolic acid, limonene, caffeic acid, and ferulic acid) to inhibit the activity of cyclin-dependent kinase 6 (CDK6), which is an important gene associated with cancer progression.…”