Trifluridine induces p53-dependent sustained G2 phase arrest with its massive misincorporation into DNA and few DNA strand breaks

Kazuaki Matsuoka, Makoto Iimori, Shinichiro Niimi, Hiroshi Tsukihara, Sugiko Watanabe, Shinichi Kiyonari, Mamoru Kiniwa, Koji Ando, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hiroyuki Kitao

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2′-deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTDinduced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102.

Original languageEnglish
Pages (from-to)1004-1013
Number of pages10
JournalMolecular Cancer Therapeutics
Volume14
Issue number4
DOIs
Publication statusPublished - Jan 1 2015

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Trifluridine
DNA Breaks
G2 Phase
Cyclin B1
Deoxyuridine
DNA
Proteins
Thymidine Phosphorylase
HCT116 Cells
Thymidylate Synthase
Proteasome Endopeptidase Complex
Fluorouracil
Antineoplastic Agents
Colorectal Neoplasms
Phosphorylation
Clinical Trials
Gene Expression
Cell Line
TAS 102
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Trifluridine induces p53-dependent sustained G2 phase arrest with its massive misincorporation into DNA and few DNA strand breaks. / Matsuoka, Kazuaki; Iimori, Makoto; Niimi, Shinichiro; Tsukihara, Hiroshi; Watanabe, Sugiko; Kiyonari, Shinichi; Kiniwa, Mamoru; Ando, Koji; Tokunaga, Eriko; Saeki, Hiroshi; Oki, Eiji; Maehara, Yoshihiko; Kitao, Hiroyuki.

In: Molecular Cancer Therapeutics, Vol. 14, No. 4, 01.01.2015, p. 1004-1013.

Research output: Contribution to journalArticle

Matsuoka, Kazuaki ; Iimori, Makoto ; Niimi, Shinichiro ; Tsukihara, Hiroshi ; Watanabe, Sugiko ; Kiyonari, Shinichi ; Kiniwa, Mamoru ; Ando, Koji ; Tokunaga, Eriko ; Saeki, Hiroshi ; Oki, Eiji ; Maehara, Yoshihiko ; Kitao, Hiroyuki. / Trifluridine induces p53-dependent sustained G2 phase arrest with its massive misincorporation into DNA and few DNA strand breaks. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 4. pp. 1004-1013.
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AU - Kiyonari, Shinichi

AU - Kiniwa, Mamoru

AU - Ando, Koji

AU - Tokunaga, Eriko

AU - Saeki, Hiroshi

AU - Oki, Eiji

AU - Maehara, Yoshihiko

AU - Kitao, Hiroyuki

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