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

Yokogawa, Tatsushi; Yano, Wakako; Tsukioka, Sayaka; Osada, Akiko; Wakasa, Takeshi; Ueno, Hiroyuki; Hoshino, Takuya; Yamamura, Keisuke; Fujioka, Akio; Fukuoka, Masayoshi; Ohkubo, Shinji; Matsuo, Keitaro

doi:10.1111/cas.14718

Cited by 21 publications

(11 citation statements)

References 46 publications

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“…5-FU, a typical inhibitor of TS, plays a key role in thymidine synthesis, leading to DNA duplication and cell growth [28]. HCT116/R cells showed the overexpression of TS at both the mRNA and protein levels (Figure 2E-G), which was significantly attenuated by co-treatment with 5-FU and CRE (Figure 3C-G).…”

Section: Discussionmentioning

confidence: 99%

Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Kang

Lee

et al. 2021

Molecules

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Colorectal cancer (CRC) is a malignancy of the colon or rectum. It is ranked as the third most common cancer in both men and women worldwide. Early resection permitted by early detection is the best treatment, and chemotherapy is another main treatment, particularly for patients with advanced CRC. A well-known thymidylate synthase (TS) inhibitor, 5-fluorouracil (5-FU), is frequently prescribed to CRC patients; however, drug resistance is a critical limitation of its clinical application. Based on the hypothesis that Coptidis Rhizoma extract (CRE) can abolish this 5-FU resistance, we explored the efficacy and underlying mechanisms of CRE in 5-FU-resistant (HCT116/R) and parental HCT116 (HCT116/WT) cells. Compared to treatment with 5-FU alone, combination treatment with CRE and 5-FU drastically reduced the viability of HCT116/R cells. The cell cycle distribution assay showed significant induction of the G0/G1 phase arrest by co-treatment with CRE and 5-FU. In addition, the combination of CRE and 5-FU notably suppressed the activity of TS, which was overexpressed in HCT116/R cells, as compared to HCT116/WT cells. Our findings support the potential of CRE as an adjuvant agent against 5-FU-resistant colorectal cancers and indicate that the underlying mechanisms might involve inhibition of TS expression.

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Section: Discussionmentioning

confidence: 99%

Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Kang

Lee

et al. 2021

Molecules

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“…Previous studies have shown that dUTPase can be targeted by several molecules that can inhibit dUTPase activity efficiency by competing with substrates at enzyme catalytic sites [28,29]. In the course of cancer treatment, dUTPase normally prevents incorporation of dUTP and 5FU-nucleotide FdUTP into DNA and reduces the effectiveness of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Epitope of ASFV-Encoded dUTPase by Monoclonal Antibodies

Zhang

Wang

Zhu

et al. 2021

Viruses

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Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) of African swine fever virus (ASFV) is an essential enzyme required for efficient virus replication. Previous crystallography data have indicated that dUTPase (E165R) may serve as a therapeutic target for inhibiting ASFV replication; however, the specificity of the targeting site(s) in ASFV dUTPase remains unclear. In this study, 19 mouse monoclonal antibodies (mAbs) were produced, in which four mAbs showed inhibitory reactivity against E165R recombinant protein. Epitope mapping studies indicated that E165R has three major antigenic regions: 100–120 aa, 120–140 aa, and 140–165 aa. Three mAbs inhibited the dUTPase activity of E165R by binding to the highly conserved 149–RGEGRFGSTG–158 amino acid sequence. Interestingly, 8F6 mAb specifically recognized ASFV dUTPase but not Sus scrofa dUTPase, which may be due to structural differences in the amino acids of F151, R153, and F154 in the motif V region. In summary, we developed anti-E165R-specific mAbs, and identified an important antibody-binding antigenic epitope in the motif V of ASFV dUTPase. Our study provides a comprehensive analysis of mAbs that target the antigenic epitope of ASFV dUTPase, which may contribute to the development of novel antibody-based ASFV therapeutics.

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“…Perturbation of dUTP/dTTP pools is also a direct effect of numerous anti-cancer drugs widely used in the clinic (e.g., fluoropyrimidines against thymidylate synthase) [ 26 ]. Combined use of thymidylate synthase and dUTPase inhibitors is associated with a synergetic effect in killing cancer cells [ 28 ]. A similar increased effect has been observed upon parallel inhibition of UNG and thymidylate synthase [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to basic academic interest, detailed characterization of these proteins may help to develop new cancer therapies and antibacterial treatments [ 23 ]. For example, thymidylate synthase inhibitors, such as 5-fluorouracil (5-FU) or 5-fluorodeoxyuridine (5-FdUrd), are widely used in cancer therapies [ 24 , 25 , 26 ] and the first dUTPase inhibitors are undergoing detailed investigations [ 23 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Inhibition of uracil DNA glycosylase also sensitizes cancer cells to 5-FdUrd similar to like dUTPase inhibition [ 35 ].…”

Section: Ung Inhibitors and Their Potential Biotechnological Applicationsmentioning

confidence: 99%

Viruses with U-DNA: New Avenues for Biotechnology

Nagy

Skurnik

Vértessy

2021

Viruses

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Deoxyuridine in DNA has recently been in the focus of research due to its intriguing roles in several physiological and pathophysiological situations. Although not an orthodox DNA base, uracil may appear in DNA via either cytosine deamination or thymine-replacing incorporations. Since these alterations may induce mutation or may perturb DNA–protein interactions, free living organisms from bacteria to human contain several pathways to counteract uracilation. These efficient and highly specific repair routes uracil-directed excision repair initiated by representative of uracil-DNA glycosylase families. Interestingly, some bacteriophages exist with thymine-lacking uracil-DNA genome. A detailed understanding of the strategy by which such phages can replicate in bacteria where an efficient repair pathway functions for uracil-excision from DNA is expected to reveal novel inhibitors that can also be used for biotechnological applications. Here, we also review the several potential biotechnological applications already implemented based on inhibitors of uracil-excision repair, such as Crispr-base-editing and detection of nascent uracil distribution pattern in complex genomes.

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

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 21 publications

References 46 publications

Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Identification and Characterization of a Novel Epitope of ASFV-Encoded dUTPase by Monoclonal Antibodies

Viruses with U-DNA: New Avenues for Biotechnology

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