Next Article in Journal
Potential Prebiotic Properties of Nuts and Edible Seeds and Their Relationship to Obesity
Next Article in Special Issue
Health Benefits of Bioactive Compounds from the Genus Ilex, a Source of Traditional Caffeinated Beverages
Previous Article in Journal
Human Breast Milk Bacteriome in Health and Disease
Previous Article in Special Issue
Habitual Tea Consumption and Risk of Fracture in 0.5 Million Chinese Adults: A Prospective Cohort Study
Article Menu

Export Article

Open AccessArticle
Nutrients 2018, 10(11), 1644; https://doi.org/10.3390/nu10111644

Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells

1
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
2
Department of Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA
3
Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
4
Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA
5
Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA
6
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
7
Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada
8
Departments of Oncology, Pharmacology, and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
These authors contributed equally.
Current Address: Cancer Prevention and Control Program, Fox Chase Cancer Center, Lewis Katz School of Medicine, Philadelphia, PA 19111, USA.
§
Current Address: School of Pharmacy, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
*
Author to whom correspondence should be addressed.
Received: 8 October 2018 / Revised: 24 October 2018 / Accepted: 29 October 2018 / Published: 3 November 2018
(This article belongs to the Special Issue Tea in Health and Disease)
Full-Text   |   PDF [3403 KB, uploaded 3 November 2018]   |  

Abstract

The 5′-3′ structure-specific endonuclease ERCC1/XPF (Excision Repair Cross-Complementation Group 1/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum-based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors. View Full-Text
Keywords: ERCC1/XPF; cisplatin; DNA repair; chemoresistance; green tea polyphenols ERCC1/XPF; cisplatin; DNA repair; chemoresistance; green tea polyphenols
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Heyza, J.R.; Arora, S.; Zhang, H.; Conner, K.L.; Lei, W.; Floyd, A.M.; Deshmukh, R.R.; Sarver, J.; Trabbic, C.J.; Erhardt, P.; Chan, T.-H.; Dou, Q.P.; Patrick, S.M. Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells. Nutrients 2018, 10, 1644.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Nutrients EISSN 2072-6643 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top