Webster, PJ, Littlejohns, AT, Gaunt, HJ et al. (3 more authors) (2017) AZD1775 Induces Toxicity Through Double-Stranded DNA Breaks Independently of Chemotherapeutic Agents in p53-Mutated Colorectal Cancer Cells. Cell Cycle, 16 (22). pp. 2176-2182. ISSN 1538-4101
Abstract
AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 μM to 3.5 μM. Flow cytometry showed a significant increase in the mitotic marker pHH3 (3.4% vs. 56.2%) and DS-DNA break marker γH2AX (5.1% vs. 50.7%) for combination therapy compared to 5-FU alone. Combination therapy also increased the amount of caspase-3 dependent apoptosis compared to 5-FU alone (4% vs. 13%). The addition of exogenous nucleosides to combination therapy significantly rescued the increased DS-DNA breaks and caspase-3 dependent apoptosis almost to the levels of 5-FU monotherapy. In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells. This finding is important for designers of future clinical trials when considering the optimal timing and duration of AZD1775 treatment.
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Copyright, Publisher and Additional Information: | © 2017 Peter John Webster, Anna Tiffany Littlejohns, Hannah Jane Gaunt, K. Raj Prasad, David John Beech, and Dermot Anthony Burke. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. | ||||||||||
Keywords: | DNA damage; cell cycle; checkpoint kinase; colorectal cancer; mitosis | ||||||||||
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Institution: | The University of Leeds | ||||||||||
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Academic Unit of Cardiovascular Medicine (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Trans Anaesthetics & Surgical Sciences (Leeds) |
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Depositing User: | Symplectic Publications | ||||||||||
Date Deposited: | 03 Apr 2017 13:06 | ||||||||||
Last Modified: | 29 Jan 2018 06:07 | ||||||||||
Published Version: | https://doi.org/10.1080/15384101.2017.1301329 | ||||||||||
Status: | Published | ||||||||||
Publisher: | Taylor & Francis | ||||||||||
Identification Number: | https://doi.org/10.1080/15384101.2017.1301329 |