ArticleMolecular cancer therapeutics2024
Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer.
Article in Molecular cancer therapeutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- Serine Hydroxymethyltransferase (SHMT) in biology and disease: molecular mechanisms and therapeutic targeting.Journal of translational medicine · 2026Review
- Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.Current oncology (Toronto, Ont.) · 2026Review
- Cisplatin resistance in ovarian cancer: exploration and insights from metal ion homeostasis imbalance.Frontiers in cell and developmental biology · 2026Review
- Multifaceted role of serine hydroxymethyltransferase in health and disease.Molecules and cells · 2025Review
- One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.Cancer research communications · 2025Article
- Pharmacodynamic determinants of mitochondrial one-carbon flux and serine hydroxymethyltransferase inhibition in human tumors.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion.bioRxiv : the preprint server for biology · 2025Article
- Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma.Cell death & disease · 2025Article
- Mechanism and Therapeutic Progress of One-Carbon Metabolic Key Enzyme: Serine Hydroxymethyltransferase 2 in Cancer.Clinical Medicine Insights. Oncology · 2025Review
- Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates.Molecular pharmacology · 2024Article
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Authors and funding
16 authors at 6 institutions in 1 country.
Funding
Abstract
One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly elevated in primary epithelial ovarian cancer (EOC) specimens compared with normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin-sensitive (A2780, CaOV3, IGROV1) and cisplatin-resistant (A2780-E80, SKOV3) EOC cells. In SKOV3 and A2780-E80 cells, colony formation was inhibited. AGF347 induced apoptosis in SKOV3 cells. In IGROV1 cells, AGF347 was transported by folate receptor (FR) α. AGF347 was also transported into IGROV1 and SKOV3 cells by the proton-coupled folate transporter (SLC46A1) and the reduced folate carrier (SLC19A1). AGF347 accumulated to high levels in the cytosol and mitochondria of SKOV3 cells. By targeted metabolomics with [2,3,3-2H]L-serine, AGF347, AGF359, and AGF362 inhibited SHMT2 in the mitochondria. In the cytosol, SHMT1 and de novo purine biosynthesis (i.e., glycinamide ribonucleotide formyltransferase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) were targeted; AGF359 also inhibited thymidylate synthase. Antifolate treatments of SKOV3 cells depleted cellular glycine, mitochondrial NADH and glutathione, and showed synergistic in vitro inhibition toward SKOV3 and A2780-E80 cells when combined with cisplatin. In vivo studies with subcutaneous SKOV3 EOC xenografts in SCID mice confirmed significant antitumor efficacy of AGF347. Collectively, our studies demonstrate a unique metabolic vulnerability in EOC involving mitochondrial and cytosolic C1 metabolism, which offers a promising new platform for therapy.
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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.