Guillotin, D, Austin, P, Begum, R et al. (6 more authors) (2017) Drug-repositioning screens identify Triamterene as a selective drug for the treatment of DNA Mismatch Repair deficient cells. Clinical Cancer Research, 23 (11). pp. 2869-2879. ISSN 1078-0432
Abstract
Purpose: The DNA Mismatch repair (MMR) pathway is required for the maintenance of genome stability. Unsurprisingly, mutations in MMR genes occur in a wide range of different cancers. Studies thus far have largely focused on specific tumor types or MMR mutations, however it is becoming increasingly clear that a therapy targeting MMR-deficiency in general would be clinically very beneficial. Experimental Design: Based on a drug-repositioning approach, we screened a large panel of cell lines with various MMR deficiencies from a range of different tumor types with a compound drug library of previously approved drugs. We have identified the potassium-sparing diuretic drug Triamterene, as a novel sensitizing agent in MMR-deficient tumor cells, in vitro and in vivo. Results: The selective tumor cell cytotoxicity of Triamterene occurs through its antifolate activity, and depends on the activity of the folate synthesis enzyme, thymidylate synthase. Triamterene leads to a thymidylate synthase-dependent differential increase in reactive oxygen species in MMR-deficient cells, ultimately resulting in an increase in DNA double strand breaks. Conclusion: Conclusively, our data reveal a new drug repurposing and novel therapeutic strategy that has potential for the treatment of MMR-deficiency in a range of different tumor types and could significantly improve patient survival.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016, American Association for Cancer Research. This is an author produced version of a paper published in Clinical Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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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 Cancer and Pathology (LICAP) > Pathology & Tumour Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Dec 2016 16:10 |
Last Modified: | 02 Dec 2017 01:38 |
Published Version: | https://doi.org/10.1158/1078-0432.CCR-16-1216 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Identification Number: | 10.1158/1078-0432.CCR-16-1216 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:109636 |