Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/80372
Title: 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
Authors: Heyza, JR
Arora, S
Zhang, H
Conner, KL
Lei, W
Floyd, AM
Deshmukh, RR
Sarver, J
Trabbic, CJ
Erhardt, P
Chan, TH 
Dou, QP
Patrick, SM
Keywords: Chemoresistance
Cisplatin
DNA repair
ERCC1/XPF
Green tea polyphenols
Issue Date: 2018
Publisher: Molecular Diversity Preservation International (MDPI)
Source: Nutrients, 2018, v. 10, no. 11, 1644 How to cite?
Journal: Nutrients 
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.
URI: http://hdl.handle.net/10397/80372
ISSN: 2072-6643
DOI: 10.3390/nu10111644
Rights: © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
The following publication: 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 is available at https://doi.org/10.3390/nu10111644
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