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The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer

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Abstract

This review considers the “promise” of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT-targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting.

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References

  1. Matherly LH, Hou Z, Deng Y (2007) Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev 26(1):111–128. doi:10.1007/s10555-007-9046-2

    Article  CAS  PubMed  Google Scholar 

  2. Matherly LH, Wilson MR, Hou Z (2014) The major facilitative folate transporters SLC19A1 and SLC46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab Dispos 42(4):632–649. doi:10.1124/dmd.113.055723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Visentin M, Zhao R, Goldman ID (2012) The antifolates. Hematol Oncol Clin North Am 26(3):629–648. doi:10.1016/j.hoc.2012.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  4. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127(5):917–928. doi:10.1016/j.cell.2006.09.041

    Article  CAS  PubMed  Google Scholar 

  5. Zhao R, Aluri S, Goldman ID (2017) The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption. Mol Aspects Med 53:57–72. doi:10.1016/j.mam.2016.09.002

    Article  CAS  PubMed  Google Scholar 

  6. Shin DS, Zhao R, Yap EH, Fiser A, Goldman ID (2012) A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding. Am J Physiol Cell Physiol 302(9):C1405-C1412. doi:10.1152/ajpcell.00435.2011

    Article  PubMed Central  CAS  Google Scholar 

  7. Zhao R, Shin DS, Fiser A, Goldman ID (2012) 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 303(6):C673-681. doi:10.1152/ajpcell.00123.2012

    Article  CAS  Google Scholar 

  8. Shin DS, Zhao R, Fiser A, Goldman ID (2013) The role of the fourth transmembrane domain in proton-coupled folate transporter (PCFT) function as assessed by the substituted cysteine accessibility method. Am J Physiol Cell Physiol 304:C1159-1167. doi:10.1152/ajpcell.00353.2012

    Article  CAS  Google Scholar 

  9. Wilson MR, Hou Z, Matherly LH (2014) 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 289(36):25287–25295. doi:10.1074/jbc.M114.578252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Visentin M, Unal ES, Najmi M, Fiser A, Zhao R, Goldman ID (2015) 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 308(8):C631-641. doi:10.1152/ajpcell.00238.2014

    Article  CAS  Google Scholar 

  11. Wilson MR, Hou Z, Wilson LJ, Ye J, Matherly LH (2016) Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6–7 linker. Biochem J 473(20):3545–3562. doi:10.1042/BCJ20160399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao R, Najmi M, Fiser A, Goldman ID (2016) Identification of an extracellular gate for the proton-coupled folate transporter (PCFT-SLC46A1) by cysteine cross-linking. J Biol Chem 291(15):8162–8172. doi:10.1074/jbc.M115.693929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao R, Najmi M, Aluri S, Goldman ID (2017) Impact of posttranslational modifications of engineered cysteines on the substituted cysteine accessibility method: evidence for glutathionylation. Am J Physiol Cell Physiol 312(4):C517-C526. doi:10.1152/ajpcell.00350.2016

    Article  PubMed  Google Scholar 

  14. Zhao R, Min SH, Qiu A, Sakaris A, Goldberg GL, Sandoval C, Malatack JJ, Rosenblatt DS, Goldman ID (2007) The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110(4):1147–1152. doi:10.1182/blood-2007-02-077099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhao R, Qiu A, Tsai E, Jansen M, Akabas MH, Goldman ID (2008) The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol 74(3):854–862. doi:10.1124/mol.108.045443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gonen N, Bram EE, Assaraf YG (2008) PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells. Biochem Biophys Res Commun 376(4):787–792. doi:10.1016/j.bbrc.2008.09.074

    Article  CAS  PubMed  Google Scholar 

  17. Lasry I, Berman B, Straussberg R, Sofer Y, Bessler H, Sharkia M, Glaser F, Jansen G, Drori S, Assaraf YG (2008) 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 112(5):2055–2061. doi:10.1182/blood-2008-04-150276

    Article  CAS  PubMed  Google Scholar 

  18. Stark M, Gonen N, Assaraf YG (2009) Functional elements in the minimal promoter of the human proton-coupled folate transporter. Biochem Biophys Res Commun 388(1):79–85. doi:10.1016/j.bbrc.2009.07.116

    Article  CAS  PubMed  Google Scholar 

  19. Diop-Bove NK, Wu J, Zhao R, Locker J, Goldman ID (2009) Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line. Mol Cancer Ther 8(8):2424–2431. doi:10.1158/1535-7163.MCT-08-0938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Unal ES, Zhao R, Chang MH, Fiser A, Romero MF, Goldman ID (2009) The functional roles of the His247 and His281 residues in folate and proton translocation mediated by the human proton-coupled folate transporter SLC46A1. J Biol Chem 284(26):17846–17857. doi:10.1074/jbc.M109.008060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Unal ES, Zhao R, Goldman ID (2009) Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1. Am J Physiol Cell Physiol 297(1):C66-74. doi:10.1152/ajpcell.00096.2009

    Article  PubMed  CAS  Google Scholar 

  22. Mahadeo K, Diop-Bove N, Shin D, Unal ES, Teo J, Zhao R, Chang MH, Fulterer A, Romero MF, Goldman ID (2010) 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 299(5):C1153-1161. doi:10.1152/ajpcell.00113.2010

    Article  CAS  Google Scholar 

  23. Shin DS, Min SH, Russell L, Zhao R, Fiser A, Goldman ID (2010) Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption. Blood 116(24):5162–5169. doi:10.1182/blood-2010-06-291237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao R, Unal ES, Shin DS, Goldman ID (2010) Membrane topological analysis of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method. BioChemistry 49(13):2925–2931. doi:10.1021/bi9021439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shin DS, Mahadeo K, Min SH, Diop-Bove N, Clayton P, Zhao R, Goldman ID (2011) Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Mol Genet Metab 103(1):33–37. doi:10.1016/j.ymgme.2011.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhao R, Shin DS, Diop-Bove N, Ovits CG, Goldman ID (2011) Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function. J Biol Chem 286(27):24150–24158. doi:10.1074/jbc.M111.236539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao R, Visentin M, Suadicani SO, Goldman ID (2013) Inhibition of the proton-coupled folate transporter (PCFT-SLC46A1) by bicarbonate and other anions. Mol Pharmacol 84:95–103. doi:10.1124/mol.113.085605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Najmi M, Zhao R, Fiser A, Goldman ID (2016) Role of the tryptophan residues in proton-coupled folate transporter (PCFT-SLC46A1) function. Am J Physiol Cell Physiol 311(1):C150-157. doi:10.1152/ajpcell.00084.2016

    Article  Google Scholar 

  29. Aluri S, Zhao R, Fiser A, Goldman ID (2017) 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 1859(11):2193–2202. doi:10.1016/j.bbamem.2017.08.006

    Article  CAS  PubMed  Google Scholar 

  30. Desmoulin SK, Hou Z, Gangjee A, Matherly LH (2012) The human proton-coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol Ther 13(14):1355–1373. doi:10.4161/cbt.22020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kugel Desmoulin S, Wang Y, Wu J, Stout M, Hou Z, Fulterer A, Chang MH, Romero MF, Cherian C, Gangjee A, Matherly LH (2010) 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 78(4):577–587. doi:10.1124/mol.110.065896

    Article  CAS  Google Scholar 

  32. Wang L, Cherian C, Desmoulin SK, Polin L, Deng Y, Wu J, Hou Z, White K, Kushner J, Matherly LH, Gangjee A (2010) 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 53(3):1306–1318. doi:10.1021/jm9015729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kugel Desmoulin S, Wang L, Hales E, Polin L, White K, Kushner J, Stout M, Hou Z, Cherian C, Gangjee A, Matherly LH (2011) 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 80(6):1096–1107. doi:10.1124/mol.111.073833

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Wang L, Kugel Desmoulin S, Cherian C, Polin L, White K, Kushner J, Fulterer A, Chang MH, Mitchell-Ryan S, Stout M, Romero MF, Hou Z, Matherly LH, Gangjee A (2011) 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 54(20):7150–7164. doi:10.1021/jm200739e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang L, Cherian C, Kugel Desmoulin S, Mitchell-Ryan S, Hou Z, Matherly LH, Gangjee A (2012) 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 55(4):1758–1770. doi:10.1021/jm201688n

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cherian C, Kugel Desmoulin S, Wang L, Polin L, White K, Kushner J, Stout M, Hou Z, Gangjee A, Matherly LH (2013) 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 71(4):999–1011. doi:10.1007/s00280-013-2094-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Golani LK, George C, Zhao S, Raghavan S, Orr S, Wallace A, Wilson MR, Hou Z, Matherly LH, Gangjee A (2014) 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 57:8152–8166. doi:10.1021/jm501113m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang L, Wallace A, Raghavan S, Deis SM, Wilson MR, Yang S, Polin L, White K, Kushner J, Orr S, George C, O’Connor C, Hou Z, Mitchell-Ryan S, Dann CE, 3rd, Matherly LH, Gangjee A (2015) 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 58 (17):6938–6959. doi:10.1021/acs.jmedchem.5b00801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Golani LK, Wallace-Povirk A, Deis SM, Wong J, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin L, de Waal PW, White K, Kushner J, O’Connor C, Hou Z, Xu HE, Melcher K, Dann CE, 3rd, Matherly LH, Gangjee A (2016) 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 59 (17):7856–7876. doi:10.1021/acs.jmedchem.6b00594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wilson MR, Hou Z, Yang S, Polin L, Kushner J, White K, Huang J, Ratnam M, Gangjee A, Matherly LH (2016) Targeting nonsquamous nonsmall cell lung cancer via the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. Mol Pharmacol 89(4):425–434. doi:10.1124/mol.115.102798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hou Z, Gattoc L, O’Connor C, Yang S, Wallace-Povirk A, George C, Orr S, Polin L, White K, Kushner J, Morris RT, Gangjee A, Matherly LH (2017) 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 16:819–830. doi:10.1158/1535-7163.MCT-16-0444

    Article  CAS  PubMed  Google Scholar 

  42. Avallone A, Di Gennaro E, Silvestro L, Iaffaioli VR, Budillon A (2014) Targeting thymidylate synthase in colorectal cancer: critical re-evaluation and emerging therapeutic role of raltitrexed. Expert Opin Drug Saf 13(1):113–129. doi:10.1517/14740338.2014.845167

    Article  CAS  PubMed  Google Scholar 

  43. Hazarika M, White RM, Johnson JR, Pazdur R (2004) FDA drug approval summaries: pemetrexed (Alimta). Oncologist 9(5):482–488. doi:10.1634/theoncologist.9-5-482

    Article  CAS  PubMed  Google Scholar 

  44. Cohen MH, Justice R, Pazdur R (2009) Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer. Oncologist 14(9):930–935. doi:10.1634/theoncologist.2009-0092

    Article  CAS  PubMed  Google Scholar 

  45. Thompson CA (2009) FDA approves pralatrexate for treatment of rare lymphoma. Am J Health Syst Pharm 66(21):1890. doi:10.2146/news090080

    PubMed  Google Scholar 

  46. Zain J, O’Connor O (2010) Pralatrexate: basic understanding and clinical development. Expert Opin Pharmacother 11(10):1705–1714. doi:10.1517/14656566.2010.489552

    Article  CAS  PubMed  Google Scholar 

  47. Chattopadhyay S, Moran RG, Goldman ID (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther 6(2):404–417. doi:10.1158/1535-7163.MCT-06-0343

    Article  CAS  PubMed  Google Scholar 

  48. Shih C, Thornton DE (1999) Preclinical pharmacology studies and the clinical development of a novel multitargeted antifolate, MTA (LY231514). In: Jackman AL (ed) Anticancer drug development guide: antifolate drugs in cancer therapy. Humana, Totowa, pp 183–201

    Chapter  Google Scholar 

  49. Racanelli AC, Rothbart SB, Heyer CL, Moran RG (2009) Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res 69(13):5467–5474. doi:10.1158/0008-5472.CAN-08-4979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rothbart SB, Racanelli AC, Moran RG (2010) Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res 70(24):10299–10309. doi:10.1158/0008-5472.CAN-10-1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Agarwal S, Bell CM, Rothbart SB, Moran RG (2015) AMP-activated Protein Kinase (AMPK) Control of mTORC1 Is p53- and TSC2-independent in Pemetrexed-treated Carcinoma Cells. J Biol Chem 290(46):27473–27486. doi:10.1074/jbc.M115.665133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Beardsley GP, Moroson BA, Taylor EC, Moran RG (1989) A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis. J Biol Chem 264(1):328–333

    CAS  PubMed  Google Scholar 

  53. Mendelsohn LG, Worzalla JF, Walling JM (1999) Preclinical and clinical evaluation of the glycinamide ribonucleotide formyltransferase inhibitors lometrexol and LY309887. In: Jackman AL (ed) Anticancer drug development guide: antifolate drugs in cancer therapy. Humana, Totowa, pp 261–280

    Chapter  Google Scholar 

  54. Moran RG, Baldwin SW, Taylor EC, Shih C (1989) The 6S- and 6R-diastereomers of 5, 10-dideaza-5, 6, 7, 8-tetrahydrofolate are equiactive inhibitors of de novo purine synthesis. J Biol Chem 264(35):21047–21051

    CAS  PubMed  Google Scholar 

  55. Ray MS, Muggia FM, Leichman CG, Grunberg SM, Nelson RL, Dyke RW, Moran RG (1993) Phase I study of (6R)-5,10-dideazatetrahydrofolate: a folate antimetabolite inhibitory to de novo purine synthesis. J Natl Cancer Inst 85(14):1154–1159

    Article  CAS  PubMed  Google Scholar 

  56. Boritzki TJ, Barlett CA, Zhang C, Howland EF (1996) AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase. Invest New Drugs 14(3):295–303

    Article  CAS  PubMed  Google Scholar 

  57. Bissett D, McLeod HL, Sheedy B, Collier M, Pithavala Y, Paradiso L, Pitsiladis M, Cassidy J (2001) Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034. Br J Cancer 84(3):308–312. doi:10.1054/bjoc.2000.1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Budman DR, Johnson R, Barile B, Bowsher RR, Vinciguerra V, Allen SL, Kolitz J, Ernest CS, 2nd, Kreis W, Zervos P, Walling J (2001) Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis. Cancer Chemother Pharmacol 47 (6):525–531

    Article  CAS  PubMed  Google Scholar 

  59. Bronder JL, Moran RG (2002) Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function. Cancer Res 62(18):5236–5241

    CAS  PubMed  Google Scholar 

  60. Bronder JL, Moran RG (2003) A defect in the p53 response pathway induced by de novo purine synthesis inhibition. J Biol Chem 278(49):48861–48871. doi:10.1074/jbc.M304844200

    Article  CAS  PubMed  Google Scholar 

  61. Hori H, Tran P, Carrera CJ, Hori Y, Rosenbach MD, Carson DA, Nobori T (1996) Methylthioadenosine phosphorylase cDNA transfection alters sensitivity to depletion of purine and methionine in A549 lung cancer cells. Cancer Res 56(24):5653–5658

    CAS  PubMed  Google Scholar 

  62. Lubin M, Lubin A (2009) Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy. PLoS One 4(5):e5735. doi:10.1371/journal.pone.0005735

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Zhao R, Goldman ID (2003) Resistance to antifolates. Oncogene 22(47):7431–7457. doi:10.1038/sj.onc.1206946

    Article  CAS  PubMed  Google Scholar 

  64. Gonen N, Assaraf YG (2012) Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat 15(4):183–210. doi:10.1016/j.drup.2012.07.002

    Article  CAS  PubMed  Google Scholar 

  65. Matherly LH, Angeles SM, McGuire JJ (1993) Determinants of the disparate antitumor activities of (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate and methotrexate toward human lymphoblastic leukemia cells, characterized by severely impaired antifolate membrane transport. Biochem Pharmacol 46(12):2185–2195

    Article  CAS  PubMed  Google Scholar 

  66. Qiu A, Min SH, Jansen M, Malhotra U, Tsai E, Cabelof DC, Matherly LH, Zhao R, Akabas MH, Goldman ID (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. Am J Physiol Cell Physiol 293(5):C1669-1678. doi:10.1152/ajpcell.00202.2007

    Article  CAS  Google Scholar 

  67. Inoue K, Nakai Y, Ueda S, Kamigaso S, Ohta KY, Hatakeyama M, Hayashi Y, Otagiri M, Yuasa H (2008) Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model. Am J Physiol Gastrointest Liver Physiol 294(3):G660-668. doi:10.1152/ajpgi.00309.2007

    Article  CAS  Google Scholar 

  68. Wollack JB, Makori B, Ahlawat S, Koneru R, Picinich SC, Smith A, Goldman ID, Qiu A, Cole PD, Glod J, Kamen B (2008) Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model. J Neurochem 104(6):1494–1503. doi:10.1111/j.1471-4159.2007.05095.x

    Article  CAS  PubMed  Google Scholar 

  69. Unal ES, Zhao R, Qiu A, Goldman ID (2008) N-linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT). Biochim Biophys Acta 1778(6):1407–1414. doi:10.1016/j.bbamem.2008.03.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Giovannetti E, Zucali PA, Assaraf YG, Funel N, Gemelli M, Stark M, Thunnissen E, Hou Z, Muller IB, Struijs EA, Perrino M, Jansen G, Matherly LH, Peters GJ (2017) Role of proton-coupled folate transporter in pemetrexed-resistance of mesothelioma: clinical evidence and new pharmacological tools. Ann Oncol. doi:10.1093/annonc/mdx499

    PubMed  Google Scholar 

  71. Elnakat H, Ratnam M (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev 56(8):1067–1084. doi:10.1016/j.addr.2004.01.001

    Article  CAS  PubMed  Google Scholar 

  72. Zhao R, Goldman ID (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol Aspects Med 34(2–3):373–385. doi:10.1016/j.mam.2012.07.006

    Article  PubMed  CAS  Google Scholar 

  73. Assaraf YG, Leamon CP, Reddy JA (2014) The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist Updat 17(4–6):89–95. doi:10.1016/j.drup.2014.10.002

    Article  PubMed  Google Scholar 

  74. Gibbs DD, Theti DS, Wood N, Green M, Raynaud F, Valenti M, Forster MD, Mitchell F, Bavetsias V, Henderson E, Jackman AL (2005) BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. Cancer Res 65(24):11721–11728. doi:10.1158/0008-5472.CAN-05-2034

    Article  CAS  PubMed  Google Scholar 

  75. Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ, McKie AT (2005) Identification of an intestinal heme transporter. Cell 122(5):789–801. doi:10.1016/j.cell.2005.06.025

    Article  CAS  PubMed  Google Scholar 

  76. Hou Z, Matherly LH (2014) Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr 73:175–204. doi:10.1016/B978-0-12-800223-0.00004-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hou Z, Kugel Desmoulin S, Etnyre E, Olive M, Hsiung B, Cherian C, Wloszczynski PA, Moin K, Matherly LH (2012) Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter. J Biol Chem 287(7):4982–4995. doi:10.1074/jbc.M111.306860

    Article  CAS  PubMed  Google Scholar 

  78. Wilson MR, Kugel S, Huang J, Wilson LJ, Wloszczynski PA, Ye J, Matherly LH, Hou Z (2015) Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6. Biochem J 469(1):33–44. doi:10.1042/BJ20150169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chattopadhyay S, Tamari R, Min SH, Zhao R, Tsai E, Goldman ID (2007) Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability. Oncologist 12(7):808–815. doi:10.1634/theoncologist.12-7-808

    Article  CAS  PubMed  Google Scholar 

  80. Deng Y, Zhou X, Kugel Desmoulin S, Wu J, Cherian C, Hou Z, Matherly LH, Gangjee A (2009) 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 52(9):2940–2951. doi:10.1021/jm8011323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gallagher FA, Kettunen MI, Day SE, Hu DE, Ardenkjaer-Larsen JH, Zandt R, Jensen PR, Karlsson M, Golman K, Lerche MH, Brindle KM (2008) Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453(7197):940–943. doi:10.1038/nature07017

    Article  CAS  PubMed  Google Scholar 

  82. Webb BA, Chimenti M, Jacobson MP, Barber DL (2011) Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11(9):671–677. doi:10.1038/nrc3110

    Article  CAS  PubMed  Google Scholar 

  83. Mitchell-Ryan S, Wang Y, Raghavan S, Ravindra MP, Hales E, Orr S, Cherian C, Hou Z, Matherly LH, Gangjee A (2013) Discovery of 5-substituted pyrrolo[2,3-d]pyrimidine antifolates as dual-acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: implications of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase to ampk activation and antitumor activity. J Med Chem 56(24):10016–10032. doi:10.1021/jm401328u

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL (2005) 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 48(16):5329–5336. doi:10.1021/jm058213s

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gangjee A, Zeng Y, McGuire JJ, Mehraein F, Kisliuk RL (2004) 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 47(27):6893–6901. doi:10.1021/jm040123k

    Article  CAS  PubMed  Google Scholar 

  86. Deng Y, Wang Y, Cherian C, Hou Z, Buck SA, Matherly LH, Gangjee A (2008) Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity. J Med Chem 51(16):5052–5063. doi:10.1021/jm8003366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kugel Desmoulin S, Wang L, Polin L, White K, Kushner J, Stout M, Hou Z, Cherian C, Gangjee A, Matherly LH (2012) 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 82(4):591–600. doi:10.1124/mol.112.079004

    Article  CAS  Google Scholar 

  88. Deis SM, Doshi A, Hou Z, Matherly LH, Gangjee A, Dann CE, 3rd (2016) Structural and enzymatic analysis of tumor-targeted antifolates that inhibit glycinamide ribonucleotide formyltransferase. BioChemistry 55 (32):4574–4582. doi:10.1021/acs.biochem.6b00412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gates SB, Worzalla JF, Shih C, Grindey GB, Mendelsohn LG (1996) Dietary folate and folylpolyglutamate synthetase activity in normal and neoplastic murine tissues and human tumor xenografts. Biochem Pharmacol 52(9):1477–1479

    Article  CAS  PubMed  Google Scholar 

  90. Ifergan I, Jansen G, Assaraf YG (2005) Cytoplasmic confinement of breast cancer resistance protein (BCRP/ABCG2) as a novel mechanism of adaptation to short-term folate deprivation. Mol Pharmacol 67(4):1349–1359. doi:10.1124/mol.104.008250

    Article  CAS  PubMed  Google Scholar 

  91. Howell SB, Mansfield SJ, Taetle R (1981) Thymidine and hypoxanthine requirements of normal and malignant human cells for protection against methotrexate cytotoxicity. Cancer Res 41(3):945–950

    CAS  PubMed  Google Scholar 

  92. Jackson RC, Harkrader RJ (1981) The contributions of de-novo and salvage pathways of nucleotide biosynthesis in normal and malignant cells. In: Tattersall MHN, Fox RM (eds) Nucleosides and cancer treatment. Academic, Sydney, pp 18–31

    Google Scholar 

  93. Issaeva N, Thomas HD, Djureinovic T, Jaspers JE, Stoimenov I, Kyle S, Pedley N, Gottipati P, Zur R, Sleeth K, Chatzakos V, Mulligan EA, Lundin C, Gubanova E, Kersbergen A, Harris AL, Sharma RA, Rottenberg S, Curtin NJ, Helleday T (2010) 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res 70(15):6268–6276. doi:10.1158/0008-5472.CAN-09-3416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899. doi:10.1038/nrc1478

    Article  CAS  PubMed  Google Scholar 

  95. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  96. Gillies RJ, Robey I, Gatenby RA (2008) Causes and consequences of increased glucose metabolism of cancers. J Nucl Med 49 Suppl 2:24S-42S. doi:10.2967/jnumed.107.047258

  97. Gatenby RA, Gillies RJ (2008) A microenvironmental model of carcinogenesis. Nat Rev Cancer 8(1):56–61. doi:10.1038/nrc2255

    Article  CAS  PubMed  Google Scholar 

  98. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. doi:10.1126/science.1160809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69(1):358–368. doi:10.1158/0008-5472.CAN-08-2470

    Article  CAS  PubMed  Google Scholar 

  100. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109(9):3812–3819. doi:10.1182/blood-2006-07-035972

    Article  CAS  PubMed  Google Scholar 

  101. Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M (2006) Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107(5):2013–2021. doi:10.1182/blood-2005-05-1795

    Article  CAS  PubMed  Google Scholar 

  102. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL, Tumour Angiogenesis Research G (2006) 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 24(26):4301–4308. doi:10.1200/JCO.2006.05.9501

    Article  CAS  PubMed  Google Scholar 

  103. Chang Q, Jurisica I, Do T, Hedley DW (2011) Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res 71(8):3110–3120. doi:10.1158/0008-5472.CAN-10-4049

    Article  CAS  PubMed  Google Scholar 

  104. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3(4):347–361

    Article  PubMed  Google Scholar 

  105. Yotnda P, Wu D, Swanson AM (2010) Hypoxic tumors and their effect on immune cells and cancer therapy. Methods Mol Biol 651:1–29. doi:10.1007/978-1-60761-786-0_1

    Article  CAS  PubMed  Google Scholar 

  106. Durand RE (1994) The influence of microenvironmental factors during cancer therapy. In Vivo 8(5):691–702

    CAS  PubMed  Google Scholar 

  107. Tannock IF (1998) Conventional cancer therapy: promise broken or promise delayed? The Lancet 351(Suppl 2):SII9-16

    Google Scholar 

  108. Tannock IF (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22(2):258–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379(6560):88–91. doi:10.1038/379088a0

    Article  CAS  PubMed  Google Scholar 

  110. Yuan J, Glazer PM (1998) Mutagenesis induced by the tumor microenvironment. Mutat Res 400(1–2):439–446

    Article  CAS  PubMed  Google Scholar 

  111. Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1(6):401–408. doi:10.1016/j.cmet.2005.05.001

    Article  CAS  PubMed  Google Scholar 

  112. Vaupel P, Hockel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9(8):1221–1235. doi:10.1089/ars.2007.1628

    Article  CAS  PubMed  Google Scholar 

  113. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47. doi:10.1038/nrc704

    Article  CAS  PubMed  Google Scholar 

  114. Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol 76(5):589–605

    Article  CAS  PubMed  Google Scholar 

  115. Blancher C, Harris AL (1998) The molecular basis of the hypoxia response pathway: tumour hypoxia as a therapy target. Cancer Metastasis Rev 17(2):187–194

    Article  CAS  PubMed  Google Scholar 

  116. Semenza GL (2000) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 35(2):71–103. doi:10.1080/10409230091169186

    Article  CAS  PubMed  Google Scholar 

  117. Wang Y, Ohh M (2010) Oxygen-mediated endocytosis in cancer. J Cell Mol Med 14(3):496–503. doi:10.1111/j.1582-4934.2010.01016.x

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8(3):180–192. doi:10.1038/nrc2344

    Article  CAS  PubMed  Google Scholar 

  119. Raz S, Sheban D, Gonen N, Stark M, Berman B, Assaraf YG (2014) Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell death disease 5:e1067. doi:10.1038/cddis.2014.39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. McKeown SR (2014) Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br J Radiol 87(1035):20130676. doi:10.1259/bjr.20130676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Brown JM (2007) Tumor hypoxia in cancer therapy. Methods Enzymol 435:297–321. doi:10.1016/S0076-6879(07)35015-5

    CAS  PubMed  Google Scholar 

  122. Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, Hong K, Dewhirst MW (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56(23):5522–5528

    CAS  PubMed  Google Scholar 

  123. Brurberg KG, Thuen M, Ruud EB, Rofstad EK (2006) Fluctuations in pO2 in irradiated human melanoma xenografts. Radiat Res 165(1):16–25

    Article  CAS  PubMed  Google Scholar 

  124. Lohse I, Rasowski J, Cao P, Pintilie M, Do T, Tsao MS, Hill RP, Hedley DW (2016) Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302. Oncotarget 7(23):33571–33580. doi:10.18632/oncotarget.9654

    Article  PubMed  PubMed Central  Google Scholar 

  125. Sun JD, Liu Q, Ahluwalia D, Li W, Meng F, Wang Y, Bhupathi D, Ruprell AS, Hart CP (2015) Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer. Cancer Biol Ther 16(3):438–449. doi:10.1080/15384047.2014.1003005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410. doi:10.1038/nrc3064

    Article  CAS  PubMed  Google Scholar 

  127. Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK (2012) Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336(6084):1040–1044. doi:10.1126/science.1218595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kim D, Fiske BP, Birsoy K, Freinkman E, Kami K, Possemato RL, Chudnovsky Y, Pacold ME, Chen WW, Cantor JR, Shelton LM, Gui DY, Kwon M, Ramkissoon SH, Ligon KL, Kang SW, Snuderl M, Vander Heiden MG, Sabatini DM (2015) SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 520(7547):363–367. doi:10.1038/nature14363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lee GY, Haverty PM, Li L, Kljavin NM, Bourgon R, Lee J, Stern H, Modrusan Z, Seshagiri S, Zhang Z, Davis D, Stokoe D, Settleman J, de Sauvage FJ, Neve RM (2014) Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. Cancer Res 74(11):3114–3126. doi:10.1158/0008-5472.CAN-13-2683

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 421 East Canfield Street, Detroit, MI, 48201, USA

    Larry H. Matherly & Zhanjun Hou

  2. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Larry H. Matherly & Zhanjun Hou

  3. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Larry H. Matherly

  4. Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA, 15282, USA

    Aleem Gangjee

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  1. Larry H. Matherly
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Correspondence to Larry H. Matherly.

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Funding

This study was supported by grants from the National Cancer Institute, National Institutes of Health [R01 CA53535 (LHM, ZH), R01 CA152316 (LHM, AG), R01 CA166711 (AG, LHM)], the Eunice and Milton Ring Endowed Chair for Cancer Research (LHM), and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (AG).

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Larry H. Matherly declares that he has no conflict of interest. Zhanjun Hou declares that he has no conflict of interest. Aleem Gangjee declares that he has no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Matherly, L.H., Hou, Z. & Gangjee, A. The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer. Cancer Chemother Pharmacol 81, 1–15 (2018). https://doi.org/10.1007/s00280-017-3473-8

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