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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Thompson CA (2009) FDA approves pralatrexate for treatment of rare lymphoma. Am J Health Syst Pharm 66(21):1890. doi:10.2146/news090080
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
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
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
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
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
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
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
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
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
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
Boritzki TJ, Barlett CA, Zhang C, Howland EF (1996) AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase. Invest New Drugs 14(3):295–303
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
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
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
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
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
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
Zhao R, Goldman ID (2003) Resistance to antifolates. Oncogene 22(47):7431–7457. doi:10.1038/sj.onc.1206946
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899. doi:10.1038/nrc1478
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013
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
Gatenby RA, Gillies RJ (2008) A microenvironmental model of carcinogenesis. Nat Rev Cancer 8(1):56–61. doi:10.1038/nrc2255
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
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
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
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
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
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
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
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
Durand RE (1994) The influence of microenvironmental factors during cancer therapy. In Vivo 8(5):691–702
Tannock IF (1998) Conventional cancer therapy: promise broken or promise delayed? The Lancet 351(Suppl 2):SII9-16
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
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
Yuan J, Glazer PM (1998) Mutagenesis induced by the tumor microenvironment. Mutat Res 400(1–2):439–446
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
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
Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47. doi:10.1038/nrc704
Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol 76(5):589–605
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
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
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
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
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
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
Brown JM (2007) Tumor hypoxia in cancer therapy. Methods Enzymol 435:297–321. doi:10.1016/S0076-6879(07)35015-5
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
Brurberg KG, Thuen M, Ruud EB, Rofstad EK (2006) Fluctuations in pO2 in irradiated human melanoma xenografts. Radiat Res 165(1):16–25
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
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
Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410. doi:10.1038/nrc3064
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
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
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
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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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DOI: https://doi.org/10.1007/s00280-017-3473-8