ArticleScientific reports2021
Folate transporter dynamics and therapy with classic and tumor-targeted antifolates.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- A Systematic Review of Folate and the Human Enteric Microbiome: Biological Mechanisms and Clinical Implications.International journal of molecular sciences · 2026Pooled it
- Review
- Bridging mechanism and design: modern medicinal chemistry approaches to thymidylate synthase inhibitors.RSC advances · 2026Review
- Pharmacodynamic determinants of mitochondrial one-carbon flux and serine hydroxymethyltransferase inhibition in human tumors.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Pan-Cancer Characterization Identifies SLC19A1 as an Unfavorable Prognostic Marker and Associates It with Tumor Infiltration Features.Biomedicines · 2025Article
- Prodrug Approach as a Strategy to Enhance Drug Permeability.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Peripheral Blood Glucocorticoid Receptor α/β (GRα/GRβ) Ratio Predicts Response to Pemetrexed-Based Chemotherapy in Non-Squamous NSCLC: A Prospective Cohort Study.Cancer management and research · 2025Article
- Bioengineered miR-7-5p modulates non-small cell lung cancer cell metabolism to improve therapy.Molecular pharmacology · 2025Article
- Combating Methotrexate Resistance in Cancer Treatment: A Review on Navigating Pathways and Enhancing Its Efficacy With Fat-Soluble Vitamins.Scientifica · 2025Review
- Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer.Molecular cancer therapeutics · 2024Article
- Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review.Biomolecules · 2024Review
- Purine Nucleotide Alterations in Tumoral Cell Lines Maintained with Physiological Levels of Folic Acid.International journal of molecular sciences · 2023Article
- How Cryo-EM Has Expanded Our Understanding of Membrane Transporters.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival.JCI insight · 2023Article
- Concentrations of vitamin B12 and folate in maternal serum and fetal fluids, metabolite interrelationships, and hepatic transcript abundance of key folate and methionine cycle genes: the impacts of maternal nutrition during the first 50 d of gestation.Journal of animal science · 2023Article
- Methotrexate-Induced Liver Injury Is Associated with Oxidative Stress, Impaired Mitochondrial Respiration, and Endoplasmic Reticulum Stress In Vitro.International journal of molecular sciences · 2022Article
- Development of Folate-Group Impedimetric Biosensor Based on Polypyrrole Nanotubes Decorated with Gold Nanoparticles.Biosensors · 2022Article
- Biology and therapeutic applications of the proton-coupled folate transporter.Expert opinion on drug metabolism & toxicology · 2022Article
- Article
- The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
There are three major folate uptake systems in human tissues and tumors, including the reduced folate carrier (RFC), folate receptors (FRs) and proton-coupled folate transporter (PCFT). We studied the functional interrelationships among these systems for the novel tumor-targeted antifolates AGF94 (transported by PCFT and FRs but not RFC) and AGF102 (selective for FRs) versus the classic antifolates pemetrexed, methotrexate and PT523 (variously transported by FRs, PCFT and RFC). We engineered HeLa cell models to express FRα or RFC under control of a tetracycline-inducible promoter with or without constitutive PCFT. We showed that cellular accumulations of extracellular folates were determined by the type and levels of the major folate transporters, with PCFT and RFC prevailing over FRα, depending on expression levels and pH. Based on patterns of cell proliferation in the presence of the inhibitors, we established transport redundancy for RFC and PCFT in pemetrexed uptake, and for PCFT and FRα in AGF94 uptake; uptake by PCFT predominated for pemetrexed and FRα for AGF94. For methotrexate and PT523, uptake by RFC predominated even in the presence of PCFT or FRα. For both classic (methotrexate, PT523) and FRα-targeted (AGF102) antifolates, anti-proliferative activities were antagonized by PCFT, likely due to its robust activity in mediating folate accumulation. Collectively, our findings describe a previously unrecognized interplay among the major folate transport systems that depends on transporter levels and extracellular pH, and that determines their contributions to the uptake and anti-tumor efficacies of targeted and untargeted antifolates.
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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.