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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


Checked for plagiarism Yes

Review by Single-blind

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

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

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