ArticleBlood advances2021
DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes.
Article in Blood advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06923488 (Phase I/II Study of Leflunomide in Combination With Decitabine for Treatment of Relapsed or Refractory), which is not on this map. Cited by 21 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Phase I/II Study of Leflunomide in Combination With Decitabine for Treatment of Relapsed or Refractory (R/R) Myelodysplastic Syndromes (MDS)
Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- The mitochondria-targeting compound PTC299 enhances megakaryocyte and platelet production.Stem cells translational medicine · 2026Article
- DHODH links mitochondrial bioenergetics, one-carbon metabolism, and DNA repair to sustain aggressive prostate adenocarcinoma.Cell communication and signaling : CCS · 2026Article
- In vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.Nature communications · 2026Article
- Article
- Uridine 5'-monophosphate (UMP) synthesis connects nucleotide metabolism to programmed cell death in C. elegans.Cell death and differentiation · 2026Article
- Combining drugs that bypass p53 to treat TP53-mutated leukemias.Blood advances · 2025Article
- Chromatin accessibility in stem cells unveils progressive transcriptional alterations in myelodysplastic syndrome.Nature communications · 2025Article
- Advances and challenges in the treatment of myelodysplastic syndromes.Experimental hematology & oncology · 2025Review
- Chemical catalyst manipulating cancer epigenome and transcription.Nature communications · 2025Article
- Off-Target Inhibition of Human Dihydroorotate Dehydrogenase (ACS pharmacology & translational science · 2024Article
- Mechanisms of S-phase arrest and mitochondrial dysfunction in complex III by DHODH inhibitors in tumorigenic TNBC cells.Histochemistry and cell biology · 2024Article
- A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation.Scientific reports · 2024Article
- Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization.Nature communications · 2024Article
- In Vivo Chemical Screening in Zebrafish Embryos Identified FDA-Approved Drugs That Induce Differentiation of Acute Myeloid Leukemia Cells.International journal of molecular sciences · 2024Article
- Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma.Scientific reports · 2024Article
- Cloning and Characterization of YakAnimals : an open access journal from MDPI · 2023Article
- A Sox17 downstream gene Rasip1 is involved in the hematopoietic activity of intra-aortic hematopoietic clusters in the midgestation mouse embryo.Inflammation and regeneration · 2023Article
- Nucleotide metabolism: a pan-cancer metabolic dependency.Nature reviews. Cancer · 2023Review
- GPX4-independent ferroptosis-a new strategy in disease's therapy.Cell death discovery · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
24 authors at 8 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.