dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.


Journal

Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776

Informations de publication

Date de publication:
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

422-432

Subventions

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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Auteurs

Tatsushi Yokogawa (T)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Wakako Yano (W)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Sayaka Tsukioka (S)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Akiko Osada (A)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Takeshi Wakasa (T)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Hiroyuki Ueno (H)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Takuya Hoshino (T)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Keisuke Yamamura (K)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Akio Fujioka (A)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Masayoshi Fukuoka (M)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Shuichi Ohkubo (S)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

Kenichi Matsuo (K)

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

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Classifications MeSH