dUTPase inhibition augments replication defects of 5-Fluorouracil

The antimetabolite 5-Fluorouracil (5-FU) is used in the treatment of various forms of cancer and has a complex mode of action. Despite 6 decades in clinical application the contribution of 5-FdUTP and dUTP [(5-F)dUTP] and 5-FUTP misincorporation into DNA and RNA respectively, for 5-FU-induced toxici...

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Bibliographic Details
Published in:Oncotarget 2017-04, Vol.8 (14), p.23713-23726
Main Authors: Hagenkort, Anna, Paulin, Cynthia B J, Desroses, Matthieu, Sarno, Antonio, Wiita, Elisée, Mortusewicz, Oliver, Koolmeister, Tobias, Loseva, Olga, Jemth, Ann-Sofie, Almlöf, Ingrid, Homan, Evert, Lundbäck, Thomas, Gustavsson, Anna-Lena, Scobie, Martin, Helleday, Thomas
Format: Article
Language:English
Subjects:
Antimetabolites, Antineoplastic - administration & dosage
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Cell Line, Tumor
DNA Replication - drug effects
Drug Synergism
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - pharmacology
Fluorouracil - administration & dosage
Fluorouracil - pharmacology
HeLa Cells
Humans
Medicin och hälsovetenskap
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - genetics
Pyrophosphatases - antagonists & inhibitors
Research Paper
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Summary:The antimetabolite 5-Fluorouracil (5-FU) is used in the treatment of various forms of cancer and has a complex mode of action. Despite 6 decades in clinical application the contribution of 5-FdUTP and dUTP [(5-F)dUTP] and 5-FUTP misincorporation into DNA and RNA respectively, for 5-FU-induced toxicity is still under debate.This study investigates DNA replication defects induced by 5-FU treatment and how (5-F)dUTP accumulation contributes to this effect. We reveal that 5-FU treatment leads to extensive problems in DNA replication fork progression, causing accumulation of cells in S-phase, DNA damage and ultimately cell death. Interestingly, these effects can be reinforced by either depletion or inhibition of the deoxyuridine triphosphatase (dUTPase, also known as DUT), highlighting the importance of (5-F)dUTP accumulation for cytotoxicity.With this study, we not only extend the current understanding of the mechanism of action of 5-FU, but also contribute to the characterization of dUTPase inhibitors. We demonstrate that pharmacological inhibition of dUTPase is a promising approach that may improve the efficacy of 5-FU treatment in the clinic.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.15785