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Review

Biology and therapeutic applications of the proton-coupled folate transporter

, , &
Pages 695-706 | Received 26 Jul 2022, Accepted 11 Oct 2022, Published online: 20 Oct 2022

References

  • Stover PJ. Folate biochemical pathways and their regulation folate in health and disease Boca Raton. FL CRC Press; 2010. p. 49–74.
  • Hou Z, Gangjee A, Matherly LH. The evolving biology of the proton-coupled folate transporter: new insights into regulation, structure, and mechanism. FASEB J. 2022 Feb;36(2):e22164.
  • Matherly LH, Hou Z, Deng Y. Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev. 2007 Mar;26(1):111–128.
  • Zhao R, Goldman ID. The molecular identity and characterization of a Proton-coupled Folate Transporter–PCFT; biological ramifications and impact on the activity of pemetrexed. Cancer Metastasis Rev. 2007 Mar;26(1):129–139.
  • Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev. 2004 Apr 29;56(8):1067–1084.
  • Zhao R, Diop-Bove N, Visentin M, et al. Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr. 2011 Aug 21;31:177–201.
  • Zhao R, Russell RG, Wang Y, et al. Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs. J Biol Chem. 2001 Mar 30;276(13):10224–10228.
  • Matherly LH, Wilson MR, Hou Z. The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab Dispos. 2014 Apr;42(4):632–649.
  • Visentin M, Zhao R, Goldman ID. The antifolates. Hematol Oncol Clin North Am. 2012 Jun;26(3):629–648.
  • Qiu A, Jansen M, Sakaris A, et al., Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006. 127(5): 917–928.
  • Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005 Sep 9;122(5):789–801.
  • Desmoulin SK, Hou Z, Gangjee A, et al. The human proton-coupled folate transporter: biology and therapeutic applications to cancer. Cancer Biol Ther. 2012 Dec;13(14):1355–1373.
  • Qiu A, Min SH, Jansen M, et al. Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1669–78.
  • Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med. 2009;11:e4.
  • Giovannetti E, Zucali PA, Assaraf YG, et al. Role of proton-coupled folate transporter in pemetrexed-resistance of mesothelioma: clinical evidence and new pharmacological tools. Ann Oncol. 2017 Sep 01;28:2725–2732.
  • Hou Z, Gattoc L, O’Connor C, et al. Dual targeting of epithelial ovarian cancer via folate receptor alpha and the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine antifolates. Mol Cancer Ther. 2017 Jan 30;6(5):819–830.
  • Kugel Desmoulin S, Wang L, Hales E, et al. Therapeutic targeting of a novel 6-substituted pyrrolo [2,3-d]pyrimidine thienoyl antifolate to human solid tumors based on selective uptake by the proton-coupled folate transporter. Mol Pharmacol. 2011 Dec;80(6):1096–1107.
  • Wilson MR, Hou Z, Yang S, et al. Targeting nonsquamous nonsmall cell lung cancer via the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. Mol Pharmacol. 2016 Apr;89(4):425–434.
  • Matherly LH, Hou Z, Gangjee A. The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer. Cancer Chemother Pharmacol. 2018 Jan;81(1):1–15.
  • Parker JL, Deme JC, Kuteyi G, et al. Structural basis of antifolate recognition and transport by PCFT. Nature. 2021 Jul;595(7865):130–134.
  • Visentin M, Diop-Bove N, Zhao R, et al. The intestinal absorption of folates. Annu Rev Physiol. 2014;76:251–274.
  • Wang Y, Zhao R, Russell RG, et al. Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biochim Biophys Acta. 2001 Jul 2;1513(1):49–54.
  • Zhao R, Aluri S, Goldman ID. The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: hereditary folate malabsorption. Mol Aspects Med. 2017 Feb;53:57–72.
  • Aluri S, Zhao R, Lubout C, et al. Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter SLC46A1. Blood Adv. 2018;2(1):61–68.
  • Hou Z, O’Connor C, Fruhauf J, et al. Regulation of differential proton-coupled folate transporter gene expression in human tumors: transactivation by KLF15 with NRF-1 and the role of Sp1. Biochem J. 2019 Apr 26;476(8):1247–1266.
  • Stark M, Gonen N, Assaraf YG. Functional elements in the minimal promoter of the human proton-coupled folate transporter. Biochem Biophys Res Commun. 2009 Oct 9;388(1):79–85.
  • Furumiya M, Inoue K, Ohta K, et al. Transcriptional regulation of PCFT by KLF4, HNF4alpha, CDX2 and C/EBPalpha: implication in its site-specific expression in the small intestine. Biochem Biophys Res Commun. 2013 Feb 8;431(2):158–163.
  • Diop-Bove NK, Wu J, Zhao R, et al. Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line. Mol Cancer Ther. 2009 Aug;8(8):2424–2431.
  • Eloranta JJ, Zair ZM, Hiller C, et al. Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol. 2009 Nov;76(5):1062–1071.
  • Gonen N, Assaraf YG. The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1. J Biol Chem. 2010 Oct 29;285(44):33602–33613.
  • Gonen N, Bram EE, Assaraf YG. PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells. Biochem Biophys Res Commun. 2008 Nov 28;376(4):787–792.
  • Reddy VS, Saier MH Jr. BioV Suite–a collection of programs for the study of transport protein evolution. FEBS J. 2012 Jun;279(11):2036–2046.
  • Saier MH Jr. Eukaryotic transmembrane solute transport systems. Int Rev Cytol. 1999;190:61–136.
  • Hou Z, Kugel Desmoulin S, Etnyre E, et al. Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter. J Biol Chem. 2012 Feb 10;287(7):4982–4995.
  • Hou Z, Matherly LH. Oligomeric structure of the human reduced folate carrier: identification of homo-oligomers and dominant-negative effects on carrier expression and function. J Biol Chem. 2009 Jan 30;284(5):3285–3293.
  • Menter A, Thrash B, Cherian C, et al. Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther. 2012 Sep;342(3):696–708.
  • Deng Y, Zhou X, Kugel Desmoulin S, et al. Synthesis and biological activity of a novel series of 6-substituted thieno[2,3-d]pyrimidine antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors over the reduced folate carrier and proton-coupled folate transporter for cellular entry. J Med Chem. 2009 May 14;52(9):2940–2951.
  • O’Connor C, Wallace-Povirk A, Ning C, et al. Folate transporter dynamics and therapy with classic and tumor-targeted antifolates. Sci Rep. 2021 Mar 18;11(1):6389.
  • Nakai Y, Inoue K, Abe N, et al. Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469–476.
  • Halsted CH, Gandhi G, Tamura T. Sulfasalazine inhibits the absorption of folates in ulcerative colitis. N Engl J Med. 1981 Dec 17;305(25):1513–1517.
  • Zhao R, Najmi M, Aluri S, et al. Concentrative transport of antifolates mediated by the proton-coupled folate transporter (SLC46A1); Augmentation by a HEPES buffer. Mol Pharmacol. 2018 Mar;93(3):208–215.
  • Zhao R, Visentin M, Suadicani SO, et al. Inhibition of the proton-coupled folate transporter (PCFT-SLC46A1) by bicarbonate and other anions. Mol Pharmacol. 2013 Jul;84(1):95–103.
  • Unal ES, Zhao R, Chang MH, et al. The functional roles of the His247 and His281 residues in folate and proton translocation mediated by the human proton-coupled folate transporter SLC46A1 [research support, N.I.H., extramural]. J Biol Chem. 2009 Jun 26;284(26):17846–17857.
  • Tan J, Li X, Guo Y, et al. Hereditary folate malabsorption with a novel mutation on SLC46A1: a case report. Medicine (Baltimore). 2017 Dec;96(50):e8712.
  • Diop-Bove N, Jain M, Scaglia F, et al. A novel deletion mutation in the proton-coupled folate transporter (PCFT; SLC46A1) in a Nicaraguan child with hereditary folate malabsorption. Gene. 2013 Sep 25;527(2):673–674.
  • Mahadeo KM, Diop-Bove N, Ramirez SI, et al. Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico. J Pediatr. 2011 Oct;159(4):623–7 e1.
  • Mahadeo K, Diop-Bove N, Shin D, et al. Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. Am J Physiol Cell Physiol. 2010 Nov;299(5):C1153–61.
  • Atabay B, Turker M, Ozer EA, et al. Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. Pediatr Hematol Oncol. 2010 Nov;27(8):614–619.
  • Borzutzky A, Crompton B, Bergmann AK, et al. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clin Immunol. 2009 Dec;133(3):287–294
  • Lasry I, Berman B, Straussberg R, et al. A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood. 2008 Sep 1;112(5):2055–2061.
  • Zhao R, Min SH, Qiu A, et al. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood. 2007 Aug 15;110(4):1147–1152.
  • Zhao R, Shin DS, Diop-Bove N, et al. Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function [research support, N.I.H., extramural]. J Biol Chem. 2011 Jul 8;286(27):24150–24158.
  • Kishimoto K, Kobayashi R, Sano H, et al. Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption. Clin Immunol. 2014 Jul;153(1):17–22.
  • Erlacher M, Grünert SC, Cseh A, et al. Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption. Pediatr Blood Cancer. 2015 June 01;62(6):1091–1094.
  • Wang Q, Li X, Ding Y, et al. The first Chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1. Brain Dev. 2015 Jan;37(1):163–167.
  • Manea E, Gissen P, Pope S, et al. Role of intramuscular levofolinate administration in the treatment of hereditary folate malabsorption: report of three cases. JIMD Rep. 2018;39:7–12.
  • Min SH, Oh SY, Karp GI, et al. The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. J Pediatr. 2008 Sep;153(3):435–437.
  • Meyer E, Kurian MA, Pasha S, et al. A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption. Mol Genet Metab. 2010;99(3):325–328.
  • Tozawa Y, Abdrabou S, Nogawa-Chida N, et al. A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four unrelated Japanese patients with hereditary folate malabsorption (HFM). Clin Immunol. 2019 Nov;208:108256.
  • Aluri S, Zhao R, Fiser A, et al. Residues in the eighth transmembrane domain of the proton-coupled folate transporter (SLC46A1) play an important role in defining the aqueous translocation pathway and in folate substrate binding. Biochim Biophys Acta. 2017 Nov;1859(11):2193–2202.
  • Shin DS, Min SH, Russell L, et al. Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption. Blood. 2010 Dec 9;116(24):5162–5169.
  • Unal ES, Zhao R, Goldman ID. Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1 [Research Support, N.I.H., Extramural]. Am J Physiol Cell Physiol. 2009 Jul;297(1):C66–74.
  • Visentin M, Unal ES, Najmi M, et al. Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1). Am J Physiol Cell Physiol. 2015 Apr 15;308(8):C631–41.
  • Zhao R, Shin DS, Fiser A, et al. Identification of a functionally critical GXXG motif and its relationship to the folate binding site of the proton-coupled folate transporter (PCFT-SLC46A1). Am J Physiol Cell Physiol. 2012 Sep;303(6):C673–81.
  • Wilson MR, Hou Z, Matherly LH. Substituted cysteine accessibility reveals a novel transmembrane 2-3 reentrant loop and functional role for transmembrane domain 2 in the human proton-coupled folate transporter. J Biol Chem. 2014 Sep 5;289(36):25287–25295.
  • Shin DS, Zhao R, Fiser A, et al. Role of the fourth transmembrane domain in proton-coupled folate transporter function as assessed by the substituted cysteine accessibility method. Am J Physiol Cell Physiol. 2013 Jun 15;304(12):C1159–67.
  • Aluri S, Zhao R, Fiser A, et al. Substituted-cysteine accessibility and cross-linking identify an exofacial cleft in the 7th and 8th helices of the proton-coupled folate transporter (SLC46A1). Am J Physiol Cell Physiol. 2018 Mar 1;314(3):C289–c296.
  • Lasry I, Berman B, Glaser F, et al. Hereditary folate malabsorption: a positively charged amino acid at position 113 of the proton-coupled folate transporter (PCFT/SLC46A1) is required for folic acid binding. Biochem Biophys Res Commun. 2009 Aug 28;386(3):426–431.
  • Zhao R, Najmi M, Aluri S, et al. Impact of posttranslational modifications of engineered cysteines on the substituted cysteine accessibility method: evidence for glutathionylation. Am J Physiol Cell Physiol. 2017 Apr 01;312(4):C517–C526.
  • Aluri S, Zhao R, Lin K, et al. Substitutions that lock and unlock the proton-coupled folate transporter (PCFT-SLC46A1) in an inward-open conformation. J Biol Chem. 2019;294(18):7245–7258.
  • Zhan HQ, Najmi M, Lin K, et al. A proton-coupled folate transporter mutation causing hereditary folate malabsorption locks the protein in an inward-open conformation. J Biol Chem. 2020 Nov 13;295(46):15650–15661.
  • Wilson MR, Hou Z, Wilson LJ, et al. Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6-7 linker. Biochem J. 2016 Oct 15;473(20):3545–3562.
  • Najmi M, Zhao R, Fiser A, et al. Role of the tryptophan residues in proton-coupled folate transporter (PCFT-SLC46A1) function. Am J Physiol Cell Physiol. 2016 Jul 1;311(1):C150–7.
  • Zhao R, Unal ES, Shin DS, et al. Membrane topological analysis of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method. Biochemistry. 2010 Apr 6;49(13):2925–2931.
  • Shi Y. Common folds and transport mechanisms of secondary active transporters. Annu Rev Biophys. 2013;42:51–72.
  • Yan N. Structural advances for the major facilitator superfamily (MFS) transporters. Trends Biochem Sci. 2013 Mar;38(3):151–159.
  • Chattopadhyay S, Moran RG, Goldman ID. Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther. 2007 Feb;6(2):404–417.
  • Cohen MH, Cortazar P, Justice R, et al. Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC). Oncologist. 2010;15(12):1352–1358.
  • Cohen MH, Justice R, Pazdur R. Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer. Oncologist. 2009 Sep;14(9):930–935.
  • Hazarika M, White RM, Johnson JR, et al. FDA drug approval summaries: pemetrexed (Alimta). Oncologist. 2004;9(5):482–488.
  • Thompson CA. FDA approves pralatrexate for treatment of rare lymphoma [News]. Am J Health-system Pharm. 2009 Nov 1;66(21):1890.
  • Chu E, Callender MA, Farrell MP, et al. Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol. 2003 Jul;52(Suppl 1):S80–9.
  • Surmont VF, van Meerbeeck JP. Raltitrexed in mesothelioma [Review]. Expert Rev Anticancer Ther. 2011 Oct;11(10):1481–1490.
  • Goldman ID, Matherly LH. The cellular pharmacology of methotrexate. Pharmacol Ther. 1985;28(1):77–102.
  • Gorlick R, Goker E, Trippett T, et al. Defective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression. Blood. 1997 Feb 1;89(3):1013–1018.
  • Matherly LH, Taub JW, Ravindranath Y, et al. Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia. Blood. 1995 Jan 15;85(2):500–509.
  • Sowers R, Wenzel BD, Richardson C, et al. Impairment of methotrexate transport is common in osteosarcoma tumor samples. Sarcoma. 2011;2011:834170.
  • Golani LK, Wallace-Povirk A, Deis SM, et al. Tumor targeting with novel 6-substituted pyrrolo [2,3-d]pyrimidine antifolates with heteroatom bridge substitutions via cellular uptake by folate receptor alpha and the proton-coupled folate transporter and inhibition of de novo purine nucleotide biosynthesis. J Med Chem. 2016 Sep 08;59(17):7856–7876.
  • Kugel Desmoulin S, Wang Y, Wu J, et al. Targeting the proton-coupled folate transporter for selective delivery of 6-substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of de novo purine biosynthesis in the chemotherapy of solid tumors. Mol Pharmacol. 2010 Oct;78(4):577–587.
  • Ravindra M, Wallace-Povirk A, Karim MA, et al. Tumor targeting with novel pyridyl 6-substituted pyrrolo[2,3- d]pyrimidine antifolates via cellular uptake by folate receptor alpha and the proton-coupled folate transporter and inhibition of de novo purine nucleotide biosynthesis. J Med Chem. 2018 Mar 8;61(5):2027–2040.
  • Ravindra M, Wilson MR, Tong N, et al. Fluorine-substituted pyrrolo[2,3- d]pyrimidine analogues with tumor targeting via cellular uptake by folate receptor alpha and the proton-coupled folate transporter and inhibition of de novo purine nucleotide biosynthesis. J Med Chem. 2018 May 10;61(9):4228–4248.
  • Wang L, Cherian C, Desmoulin SK, et al. Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry. J Med Chem. 2010 Feb 11;53(3):1306–1318.
  • Wang L, Cherian C, Kugel Desmoulin S, et al. Synthesis and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier. J Med Chem. 2012 Jan 13;55(4):1758–1770.
  • Wang L, Desmoulin SK, Cherian C, et al. Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits beta-glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150–7164.
  • Wang L, Wallace A, Raghavan S, et al. 6-Substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as targeted antifolates for folate receptor alpha and the proton-coupled folate transporter in human tumors. J Med Chem. 2015 Aug 28;58(17):6938–6959.
  • Kugel Desmoulin S, Wang L, Polin L, et al. Functional loss of the reduced folate carrier enhances the antitumor activities of novel antifolates with selective uptake by the proton-coupled folate transporter. Mol Pharmacol. 2012 Jun 26;82(4):591–600.
  • Cherian C, Kugel Desmoulin S, Wang L, et al. Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporter. Cancer Chemother Pharmacol. 2013 Apr;71(4):999–1011.
  • Gangjee A, Zeng Y, McGuire JJ, et al. Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J Med Chem. 2005 Aug 11;48(16):5329–5336.
  • Gangjee A, Zeng Y, McGuire JJ, et al. Synthesis of classical, three-carbon-bridged 5-substituted Furo[2,3- d]pyrimidine and 6-substituted Pyrrolo[2,3- d]pyrimidine analogues as antifolates. J Med Chem. 2004 Dec 30;47(27):6893–6901.
  • Wang Y, Cherian C, Orr S, et al. Tumor-targeting with novel non-benzoyl 6-substituted straight chain pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor alpha and inhibition of de novo purine nucleotide biosynthesis. J Med Chem. 2013 Nov 14;56(21):8684–8695.
  • Golani LK, George C, Zhao S, et al. Structure-activity profiles of novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with modified amino acids for cellular uptake by folate receptors alpha and beta and the proton-coupled folate transporter. J Med Chem. 2014 Oct 9;57(19):8152–8166.
  • Deis SM, Doshi A, Hou Z, et al. Structural and enzymatic analysis of tumor-targeted antifolates that inhibit glycinamide ribonucleotide formyltransferase. Biochemistry. 2016 Aug 16;55(32):4574–4582.
  • Wallace-Povirk A, Rubinsak L, Malysa L, et al. Targeted therapy of pyrrolo[2,3-d]pyrimidine antifolates in a syngeneic mouse model of high grade serous ovarian cancer and the impact on the tumor microenvironment. Sci Rep. 2022;12(1):11346.
  • Toffoli G, Cernigoi C, Russo A, et al. Overexpression of folate binding protein in ovarian cancers. Int J Cancer. 1997 Apr 22;74(2):193–198.
  • Nunez MI, Behrens C, Woods DM, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation. J Thorac Oncol. 2012 May;7(5):833–840
  • Gates SB, Worzalla JF, Shih C, et al. Dietary folate and folylpolyglutamate synthetase activity in normal and neoplastic murine tissues and human tumor xenografts. Biochem Pharmacol. 1996 Nov 8;52(9):1477–1479.
  • Ifergan I, Jansen G, Assaraf YG. Cytoplasmic confinement of breast cancer resistance protein (BCRP/ABCG2) as a novel mechanism of adaptation to short-term folate deprivation. Mol Pharmacol. 2005 Apr;67(4):1349–1359.
  • Bronder JL, Moran RG. A defect in the p53 response pathway induced by de novo purine synthesis inhibition. J Biol Chem. 2003 Dec 5;278(49):48861–48871.
  • Howell SB, Mansfield SJ, Taetle R. Thymidine and hypoxanthine requirements of normal and malignant human cells for protection against methotrexate cytotoxicity. Cancer Res. 1981 Mar;41(3):945–950.
  • Jackson RC, Harkrader RJ. The contributions of de-novo and salvage pathways of nucleotide biosynthesis in normal and malignant cells. In: Tattersall MHN, Fox RM, editors. Nucleosides and cancer treatment. Sydney: Academic Press; 1981. p. 18–31.
  • Wright NJ, Fedor JG, Zhang H, et al. Methotrexate recognition by the human reduced folate carrier SLC19A1. Nature. 2022 Sep 7;609(7929):1056–1062.
  • Burton JB, Carruthers NJ, Hou Z, et al. Pattern analysis of organellar maps for interpretation of proteomic data. Proteomes. 2022 May 23;10(2):18.
  • Webb BA, Chimenti M, Jacobson MP, et al. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer. 2011 Sep;11(9):671–677.
  • Fischer K, Hoffmann P, Voelkl S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007 May 01;109(9):3812–3819.
  • Gottfried E, Kunz-Schughart LA, Ebner S, et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006 Mar 01;107(5):2013–2021.
  • Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway–a report of the Tumour Angiogenesis Research Group. J Clin Oncol. 2006 Sep 10;24(26):4301–4308.
  • Chang Q, Jurisica I, Do T, et al. Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res. 2011 Apr 15;71(8):3110–3120.
  • Pennacchietti S, Michieli P, Galluzzo M, et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003 Apr;3(4):347–361.
  • Yotnda P, Wu D, Swanson AM. Hypoxic tumors and their effect on immune cells and cancer therapy. Methods Mol Biol. 2010;651:1–29.
  • Raz S, Sheban D, Gonen N, et al. Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death Dis. 2014;5(2):e1067.
  • Galluzzi L, Zitvogel L, Kroemer G. Immunological mechanisms underneath the efficacy of cancer therapy. Cancer Immunol Res. 2016 Nov;4(11):895–902.
  • Samaniego R, Palacios BS, Domiguez-Soto A, et al. Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A. J Leukoc Biol. 2014 May;95(5):797–808.
  • Keshet R, Lee JS, Adler L, et al. Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors. Nat Cancer. 2020 Sep;1(9):894–908.
  • Vijayan D, Young A, Teng MWL, et al. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017 Dec;17(12):709–724.
  • Young A, Mittal D, Stagg J, et al. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 2014 Aug;4(8):879–888.
  • Dekhne AS, Hou Z, Gangjee A, et al. Therapeutic targeting of mitochondrial one-carbon metabolism in cancer. Mol Cancer Ther. 2020 Nov;19(11):2245–2255.

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