dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Chickens
DNA Damage
/ drug effects
DNA Repair
/ drug effects
Enzyme Inhibitors
/ pharmacology
Floxuridine
/ pharmacology
HeLa Cells
Humans
Pyrimidines
/ pharmacology
Pyrophosphatases
/ antagonists & inhibitors
Sulfonamides
/ pharmacology
Thymidylate Synthase
/ antagonists & inhibitors
5-fluorouracil/uracil misincorporation
DNA repair
base excision repair
dUTPase
homologous recombination
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
01
07
2020
revised:
28
10
2020
accepted:
30
10
2020
pubmed:
4
11
2020
medline:
2
3
2021
entrez:
3
11
2020
Statut:
ppublish
Résumé
Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5-Fluorouracil (5-FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS-114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5-FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5-FU incorporation into RNA. TAS-114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short-term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5-FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA-treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5-FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.
Identifiants
pubmed: 33140501
doi: 10.1111/cas.14718
pmc: PMC7780055
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Pyrimidines
0
Sulfonamides
0
TAS-114
0
Floxuridine
039LU44I5M
Thymidylate Synthase
EC 2.1.1.45
Pyrophosphatases
EC 3.6.1.-
dUTP pyrophosphatase
EC 3.6.1.23
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
422-432Subventions
Organisme : Taiho Pharmaceutical Co., Ltd.
Informations de copyright
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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