Back to Journals » Drug Design, Development and Therapy » Volume 13

Identification Of Natural Compound Derivative For Inhibition Of XLF And Overcoming Chemoresistance In Colorectal Cancer Cells

Authors Liu Z, Yu M, Fei B, Sun J, Wang D

Received 16 May 2019

Accepted for publication 27 September 2019

Published 6 November 2019 Volume 2019:13 Pages 3823—3834

DOI https://doi.org/10.2147/DDDT.S215967

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristian Vilos

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Cristiana Tanase


Zhuo Liu,1 Miao Yu,1 Bingyuan Fei,1 Jing Sun,2 Dongxin Wang3

1Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA; 3Department of Anesthesiology, Jilin Cancer Hospital, Jilin, People’s Republic of China

Correspondence: Dongxin Wang
Department of Anesthesiology, Jilin Cancer Hospital, 1018 Huguang Road, Changchun, Jilin 130031, People’s Republic of China
Tel +86 139 4487 2227
Email dongxingwang759@163.com

Purpose: A previous study has identified that XRCC4-like factor (XLF) is a potential target to overcome resistance to 5-fluorouracil (5-Fu) and oxaliplatin (OXA) in colorectal cancer (CRC). The purpose of this study is to develop potent XLF inhibitors to chemoresistance in CRC.
Methods: Virtual screening was adopted to identify novel XLF-binding compounds by initially testing 6800 molecules in Chemical Entities of Biological Interest library. Hit compounds were further validated by Western blot assay. Cell sensitivity to 5-Fu and OXA was measured using sulforhodamine B assay. The effect of XLF inhibitor on DNA repair efficiency was evaluated by comet assay, fluorescent-based nonhomologous end joining (NHEJ) and homologous recombination (HR) reporter assays. DNA-binding activity of NHEJ key factors was examined by chromatin fractionation assay.
Results: We identified G3, a novel and potent XLF inhibitor (IC50 0.47±0.02 μM). G3 induced XLF protein degradation in CRC cells. Significantly, G3 improved cell sensitivity to 5-Fu and OXA in chemoresistant CRC cell lines. Mechanistically, G3 depleted XLF expression, severely compromised NHEJ efficiency by up to 65% and inhibited NHEJ key factor assembly on DNA. G3 also inhibited HR efficiency in a time-dependent manner.
Conclusion: These results suggest that G3 overcomes 5-Fu and OXA resistance in CRC cells by inhibiting XLF expression. Thus, XLF is a promising target and its inhibitor G3 is a potential candidate for treatment of chemoresistant CRC patients.

Keywords: virtual screening, XLF inhibitor, chemoresistance, colorectal cancer
 

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]