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Cited by 58Cancer-related Molecular PathwaysBiochemical and Molecular ResearchDNA Repair Mechanisms

Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

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Hubackova, Sona, Davidova, Eliska, Boukalova, Stepana, Kovarova, Jaromira, Bajzikova, Martina, Coelho, Ana, Terp, Mikkel G., Ditzel, Henrik J. +2 more·2020·Cell Death & Disease
DOI 10.1038/s41419-020-2224-7PMC PMC7007433
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Abstract

p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53- and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53-dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.

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  • Combination therapy using leflunomide with checkpoint kinase 1 (CHK1) inhibitors has shown enhanced efficacy in reducing growth of P53-deficient breast tumors and inducing cell apoptosis compared to leflunomide alone.

    “Combination therapy using leflunomide with checkpoint kinase 1 (CHK1) inhibitors has shown enhanced efficacy in reducing the growth of P53-deficient breast tumors and inducing cell apoptosis compared to treatment with leflunomide alone.108”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [108]

    The Results section on simultaneous Chk1 and DHODH inhibition reports less growth of p53-deficient breast tumors with the combination than with leflunomide alone. The Results section on cell death also reports increased death in leflunomide-treated cells after Chk1 inhibition, but describes it as cell death rather than establishing that it was specifically apoptosis. Page numbers are unavailable in our copy. (LLM, conf=0.84)

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Cited by

Sorted by citations

  • Drug repurposing for cancer therapy

    Xia, Y., Sun, M., Huang, H., & Jin, W.-L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01808-1 · Cited by 443 · see citing works

    “108 Furthermore, in a phase I clinical trial aimed at refractory multiple myeloma, le fl unomide displayed manageable side effects, with disease stabilization occurring in 9 of the 11 patients (NCT: NCT02509052).”
    Background

Authors
Hubackova, S., Davidova, E., Boukalova, S., Kovarova, J., Bajzikova, M., Coelho, A., Terp, M. G., Ditzel, H. J., Rohlena, J., & Neuzil, J.
Affiliations
  • Czech Academy of Sciences (CZ)
  • University of Southern Denmark (DK)
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2020-02-07
Volume
11
Issue
2
Pages
110-110
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-020-2224-7
PMC
PMC7007433
OpenAlex
W3004950633
Cited by
58
References
2
Citations by year
2026: 10 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 9 · 2020: 3 · 2019: 1
FWCI
2.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Griffith Research Online (submittedVersion, cc-by)
Funders
  • Univerzita Karlova v Praze (CZ.02.1.01/0.0/0.0/16_013/0001775, 86652036)
  • Grantová Agentura, Univerzita Karlova (CZ.02.1.01/0.0/0.0/16_013/0001775, GA UK 1560218, LM2015062)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (CZ.02.1.01/ 0.0/0.0/16 013/0001775, CZ.02., RVO:86652036, CZ.02.1.01, LM2015062, CZ.1.05, CZ.02.1.01/0.0, 86652036)
  • Grantová Agentura České Republiky (CZ.02.1.01/0.0, RVO 86652036, GA18-02550S, GC17-01192J, CZ.1.05/1.1.00/02.0109, GA19-20553S, 86652036, CZ.02.1.01, CZ.02.1.01/0.0/0.0/16_013/0001775, GA17-20904S, GA17-07635S, GA20-18513S)
  • Fundação para a Ciência e a Tecnologia (SFRH/BD/103399/2014)
  • European Regional Development Fund (CZ.1.05/1.100, 02.1.01/0.0/0.0, CZ.02, CZ.1.05/1.100/02.0109, CZ.02.1.01, CZ.02.1.01/0.0, /16_013/0001775, LM2015062, CZ.02.1.01/0.0/0.0, CZ.02.1.01/0.0/0.0/16_013/0001775, 86652036)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
dihydroorotate dehydrogenase inhibition, pyrimidine synthesis, replication stress, ribosomal stress, ribosome biogenesis, Chk1, cell cycle arrest, metastasis, chemoresistance, combination therapy
MeSH terms
Checkpoint Kinase 1, Leflunomide, Dihydroorotate Dehydrogenase, Animals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Female, Humans, Mice, Inbred BALB C, Mice, Transgenic, Phenylurea Compounds, Pyrazines, Pyrimidines, Ribosomes, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Mice, SCID, Mice, Inbred NOD, Genes, erbB-2, Oxidoreductases Acting on CH-CH Group Donors, HCT116 Cells, Protein Kinase Inhibitors, Cell Proliferation, Cell Cycle Checkpoints, MCF-7 Cells

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