dUTPase inhibition augments replication defects of 5-Fluorouracil.

Abstract

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.

• Authors: Anna Hagenkort, Cynthia B J Paulin, Matthieu Desroses, Antonio Sarno, Elisée Wiita, Oliver Mortusewicz, Tobias Koolmeister, Olga Loseva, Ann-Sofie Jemth, Ingrid Almlöf, Evert Homan, Thomas Lundbäck, Anna-Lena Gustavsson, Martin Scobie, Thomas Helleday
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 14 Pg. 23713-23726 (Apr 04 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28423595 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Enzyme Inhibitors
• Pyrophosphatases
• dUTP pyrophosphatase
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• DNA Replication (drug effects)
• Drug Synergism
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Fluorouracil (administration & dosage, pharmacology)
• HeLa Cells
• Humans
• Neoplasms (drug therapy, enzymology, genetics)
• Pyrophosphatases (antagonists & inhibitors)