Yuchen Zhang, Joanne Wang. Targeting uptake transporters for cancer imaging and treatment[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 79-90

Targeting uptake transporters for cancer imaging and treatment
Yuchen Zhang, Joanne Wang
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
Cancer cells reprogram their gene expression to promote growth, survival, proliferation, and invasiveness. The unique expression of certain uptake transporters in cancers and their innate function to concentrate small molecular substrates in cells make them ideal targets for selective delivering imaging and therapeutic agents into cancer cells. In this review, we focus on several solute carrier (SLC) transporters known to be involved in transporting clinically used radiopharmaceutical agents into cancer cells, including the sodium/iodine symporter (NIS), norepinephrine transporter (NET), glucose transporter 1 (GLUT1), and monocarboxylate transporters (MCTs). The molecular and functional characteristics of these transporters are reviewed with special emphasis on their specific expressions in cancers and interaction with imaging or theranostic agents [e.g., I-123, I-131, 123I-iobenguane (mIBG), 18F-fluorodeoxyglucose (18F-FDG) and 13C pyruvate]. Current clinical applications and research areas of these transporters in cancer diagnosis and treatment are discussed. Finally, we offer our views on emerging opportunities and challenges in targeting transporters for cancer imaging and treatment. By analyzing the few clinically successful examples, we hope much interest can be garnered in cancer research towards uptake transporters and their potential applications in cancer diagnosis and treatment.
Key words:    Uptake transporter    Warburg effect    Cancer imaging    Neuroblastoma    Thyroid cancer    mIBG   
Received: 2019-06-28     Revised: 2019-09-27
DOI: 10.1016/j.apsb.2019.12.005
Funds: This study was supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences (Grant R01 GM066233, USA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Corresponding author: Joanne Wang
Author description:
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Yuchen Zhang
Joanne Wang

1. Schiffman JD, Fisher PG, Gibbs P. Early detection of cancer: past, present, and future. Am Soc Clin Oncol Educ Book 2015;35:57-65.
2. Frangioni JV. New technologies for human cancer imaging. J Clin Oncol 2008;26:4012-21.
3. Fass L. Imaging and cancer: a review. Mol Oncol 2008;2:115-52.
4. Gambhir SS. Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2002;2:683-93.
5. Del Monte U. Does the cell number 109 still really fit one gram of tumor tissue?. Cell Cycle 2009;8:505-6.
6. Weissleder R. Molecular imaging in cancer. Science 2006;312: 1168-71.
7. Lin L, Yee SW, Kim RB, Giacomini KM. SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov 2015;14:543-60.
8. International Transporter Consortium, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer K, et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9:215-36.
9. FDA. In vitro metabolism and transporter-mediated drugedrug interaction studies: guidance for industry. 2017. Available from:
10. Mao Q, Lai Y, Wang J. Drug transporters in xenobiotic disposition and pharmacokinetic prediction. Drug Metab Dispos 2018;46: 561-6.
11. Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics. Pharmacol Ther 2012;135:355-70.
12. Verburg FA, Brans B, Mottaghy FM. Molecular nuclear therapies for thyroid carcinoma. Methods 2011;55:230-7.
13. Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 1996;379:458-60.
14. Smanik A, Ryu KY, Theil KS, Mazzaferri EL, Jhiang SM. Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology 1997;138:3555-8.
15. Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, et al. The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 2003;24:48-77.
16. Dohan O, Portulano C, Basquin C, Reyna-Neyra A, Amzel LM, Carrasco N. The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc Natl Acad Sci U S A 2007;104:20250-5.
17. Kogai T, Endo T, Saito T, Miyazaki A, Kawaguchi A, Onaya T. Regulation by thyroid-stimulating hormone of sodium/iodide symporter gene expression and protein levels in FRTL-5 cells. Endocrinology 1997;138:2227-32.
18. Jhiang SM, Cho JY, Ryu KY, DeYoung BR, Smanik A, McGaughy VR, et al. An immunohistochemical study of Na+/Ie symporter in human thyroid tissues and salivary gland tissues. Endocrinology 1998;139:4416-9.
19. Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, et al. The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med 2000;6:871-8.
20. Ravera S, Reyna-Neyra A, Ferrandino G, Amzel LM, Carrasco N. The sodium/iodide symporter (NIS): molecular physiology and preclinical and clinical applications. Annu Rev Physiol 2017;79:261-89.
21. Kogai T. Sodium iodide symporter in the fight against thyroid cancer. Future Oncol 2013;9:1679-82.
22. Ahn BC. Sodium iodide symporter for nuclear molecular imaging and gene therapy: from bedside to bench and back. Theranostics 2012;2:392-402.
23. Gaitan-Hernandez R. Characterization and fruit-body production of neolentinus suffrutescens strains obtained by crossing in vitro in a pilot plant. Rev Iberoam Micol 2000;17:20-4.
24. Wong KK, Zarzhevsky N, Cahill JM, Frey KA, Avram AM. Hybrid SPECT-CT and PET-CT imaging of differentiated thyroid carcinoma. Br J Radiol 2009;82:860-76.
25. Singh N, Lewington V. Molecular radiotheragnostics in thyroid disease. Clin Med (Lond) 2017;17:453-7.
26. Lee WW, Moon DH, Park SY, Jin J, Kim SJ, Lee H. Imaging of adenovirus-mediated expression of human sodium iodide symporter gene by 99mTcO4 scintigraphy in mice. Nucl Med Biol 2004;31:31-40.
27. Chen L, Altman A, Mier W, Lu H, Zhu R, Haberkorn U. 99mTc-pertechnetate uptake in hepatoma cells due to tissue-specific human sodium iodide symporter gene expression. Nucl Med Biol 2006;33: 575-80.
28. Schipper ML, Riese CG, Seitz S, Weber A, Behe M, Schurrat T, et al. Efficacy of 99mTc pertechnetate and 131I radioisotope therapy in sodium/iodide symporter (NIS)-expressing neuroendocrine tumors in vivo. Eur J Nucl Med Mol Imaging 2007;34:638-50.
29. Zuckier LS, Dohan O, Li Y, Chang CJ, Carrasco N, Dadachova E. Kinetics of perrhenate uptake and comparative biodistribution of perrhenate, pertechnetate, and iodide by NaI symporter-expressing tissues in vivo. J Nucl Med 2004;45:500-7.
30. Van Sande J, Massart C, Beauwens R, Schoutens A, Costagliola S, Dumont JE, et al. Anion selectivity by the sodium iodide symporter. Endocrinology 2003;144:247-52.
31. Jauregui-Osoro M, Sunassee K, Weeks AJ, Berry DJ, Paul RL, Cleij M, et al. Synthesis and biological evaluation of [18F]tetrafluoroborate: a PET imaging agent for thyroid disease and reporter gene imaging of the sodium/iodide symporter. Eur J Nucl Med Mol Imaging 2010;37:2108-16.
32. Min JJ, Chung JK, Lee YJ, Jeong JM, Lee DS, Jang JJ, et al. Relationship between expression of the sodium/iodide symporter and 131 I uptake in recurrent lesions of differentiated thyroid carcinoma. Eur J Nucl Med 2001;28:639-45.
33. Chung JK, Youn HW, Kang JH, Lee HY, Kang KW. Sodium iodide symporter and the radioiodine treatment of thyroid carcinoma. Nucl Med Mol Imaging 2010;44:4-14.
34. Ward LS, Santarosa L, Granja F, da Assumpcao LV, Savoldi M, Goldman GH. Low expression of sodium iodide symporter identifies aggressive thyroid tumors. Cancer Lett 2003;200:85-91.
35. Kogai T, Curcio F, Hyman S, Cornford EM, Brent GA, Hershman JM. Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. J Endocrinol 2000;167:125-35.
36. Riedel C, Levy O, Carrasco N. Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin. J Biol Chem 2001;276: 21458-63.
37. Ladenson W, Braverman LE, Mazzaferri EL, Brucker-Davis F, Cooper DS, Garber JR, et al. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 1997;337:888-96.
38. Kogai T, Schultz JJ, Johnson LS, Huang M, Brent GA. Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line. Proc Natl Acad Sci U S A 2000;97:8519-24.
39. Schmutzler C, Winzer R, Meissner-Weigl J, Kohrle J. Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells. Biochem Biophys Res Commun 1997;240:832-8.
40. Hingorani M, Spitzweg C, Vassaux G, Newbold K, Melcher A, Pandha H, et al. The biology of the sodium iodide symporter and its potential for targeted gene delivery. Curr Cancer Drug Targets 2010;10:242-67.
41. Dwyer RM, Bergert ER, O’Connor MK, Gendler SJ, Morris JC. Adenovirus-mediated and targeted expression of the sodium-iodide symporter permits in vivo radioiodide imaging and therapy of pancreatic tumors. Hum Gene Ther 2006;17:661-8.
42. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203-16.
43. Brodeur GM, Iyer R, Croucher JL, Zhuang T, Higashi M, Kolla V. Therapeutic targets for neuroblastomas. Expert Opin Ther Targets 2014;18:277-92.
44. Park JR, Bagatell R, London WB, Maris JM, Cohn SL, Mattay KK, et al. Children’s oncology group’s 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer 2013;60:985-93.
45. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin N Am 2010;24:65-86.
46. Carlin S, Mairs RJ, McCluskey AG, Tweddle DA, Sprigg A, Estlin C, et al. Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[131I]iodobenzylguanidine by neuroblastoma tumors. Clin Cancer Res 2003;9:3338-44.
47. Dubois SG, Geier E, Batra V, Yee SW, Neuhaus J, Segal M, et al. Evaluation of norepinephrine transporter expression and metaiodobenzylguanidine avidity in neuroblastoma: a report from the children’s oncology group. Int J Mol Imaging 2012;2012:250834.
48. Streby KA, Shah N, Ranalli MA, Kunkler A, Cripe T. Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy. Pediatr Blood Cancer 2015;62:5-11.
49. Wieland DM, Wu J, Brown LE, Mangner TJ, Swanson D, Beierwaltes WH. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J Nucl Med 1980;21:349-53.
50. Parisi MT, Eslamy H, Park JR, Shulkin BJ, Yanik GA. 131I-Metaiodobenzylguanidine theranostics in neuroblastoma: historical perspectives; practical applications. Semin Nucl Med 2016;46: 184-202.
51. Mandela P, Ordway GA. The norepinephrine transporter and its regulation. J Neurochem 2006;97:310-33.
52. Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, et al. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. Dis Model Mech 2013;6:1001-11.
53. van Berkel A, Rao JU, Lenders JW, Pellegata NS, Kusters B, Piscaer I, et al. Semiquantitative 123I-metaiodobenzylguanidine scintigraphy to distinguish pheochromocytoma and paraganglioma from physiologic adrenal uptake and its correlation with genotypedependent expression of catecholamine transporters. J Nucl Med 2015;56:839-46.
54. Saveanu A, Muresan M, de Micco C, Taieb D, Germanetti AL, Sebag F, et al. Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas. Endocr Relat Cancer 2011;18:287-300.
55. Sharp SE, Trout AT, Weiss BD, Gelfand MJ. MIBG in neuroblastoma diagnostic imaging and therapy. RadioGraphics 2016;36:258-78.
56. Treuner J, Feine U, Niethammer D, Muller-Schaumburg W, Meinke J, Eibach E, et al. Scintigraphic imaging of neuroblastoma with [131-I]iodobenzylguanidine. Lancet 1984;1:333-4.
57. Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MN. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer 2014;50:801-15.
58. Irwin MS, Park JR. Neuroblastoma: paradigm for precision medicine. Pediatr Clin N Am 2015;62:225-56.
59. Pandit-Taskar N, Modak S. Norepinephrine transporter as a target for imaging and therapy. J Nucl Med 2017;58:39S-53S.
60. Vaidyanathan G, Affleck DJ, Zalutsky MR. No-carrier-added (4-fluoro-3-[131I]iodobenzyl)guanidine and (3-[211At]astato-4-fluorobenzyl)guanidine. Bioconjug Chem 1996;7:102-7.
61. Suh M, Park HJ, Choi HS, So Y, Lee BC, Lee WW. Case report of PET/CT imaging of a patient with neuroblastoma using 18F-FPBG. Pediatrics 2014;134:e1731-4.
62. Pandit-Taskar N, Zanzonico P, Staton KD, Carrasquillo JA, ReidyLagunes D, Lyashchenko S, et al. Biodistribution and dosimetry of 18 F-meta-fluorobenzylguanidine: a first-in-human PET/CT imaging study of patients with neuroendocrine malignancies. J Nucl Med 2018;59:147-53.
63. Bonfiglioli R, Nanni C, Martignani C, Zanoni L, La Donna R, Diemberger I, et al. 11C-mHED for PET/CT: principles of synthesis, methodology and first clinical applications. Curr Radiopharm 2014; 7:79-83.
64. Ding YS, Fowler JS, Gatley SJ, Dewey SL, Wolf A, Schlyer DJ. Synthesis of high specific activity 6-[18F]fluorodopamine for positron emission tomography studies of sympathetic nervous tissue. J Med Chem 1991;34:861-3.
65. Minn H, Kemppainen J, Kauhanen S, Forsback S, Seppanen M. 18Ffluorodihydroxyphenylalanine in the diagnosis of neuroendocrine tumors. PET Clin 2014;9:27-36.
66. Mastrangelo R, Tornesello A, Lasorella A, Iavarone A, Mastrangelo S, Riccardi R, et al. Optimal use of the 131I-metaiodobenzylguanidine and cisplatin combination in advanced neuroblastoma. J Neuro Oncol 1997;31:153-8.
67. Rutgers M, Buitenhuis CK, Hoefnagel CA, Voute A, Smets LA. Targeting of meta-iodobenzylguanidine to SK-N-SH human neuroblastoma xenografts: tissue distribution, metabolism and therapeutic efficacy. Int J Cancer 2000;87:412-22.
68. Apparsundaram S, Galli A, DeFelice LJ, Hartzell HC, Blakely RD. Acute regulation of norepinephrine transport: I. protein kinase Clinked muscarinic receptors influence transport capacity and transporter density in SK-N-SH cells. J Pharmacol Exp Ther 1998;287: 733-43.
69. Mueller S, Yang X, Sottero TL, Gragg A, Prasad G, Polley MY, et al. Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: efficacy and underlying mechanisms. Cancer Lett 2011;306:223-9.
70. Duan H, Wang J. Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther 2010;335:743-53.
71. Wagner DJ, Hu T, Wang J. Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res 2016;111:237-46.
72. Yin J, Wang J. Renal drug transporters and their significance in drugedrug interactions. Acta Pharm Sin B 2016;6:363-73.
73. Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, Wang J. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem 2014;289: 7055-64.
74. Liberti MV, Locasale JW. The Warburg Effect: how does it benefit cancer cells?. Trends Biochem Sci 2016;41:211-8.
75. Weber WA, Schwaiger M, Avril N. Quantitative assessment of tumor metabolism using FDG-PET imaging. Nucl Med Biol 2000;27:683-7.
76. Fletcher JW, Djulbegovic B, Soares H, Siegel BA, Lowe VJ, Lyman GH, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008;49:480-508.
77. Ancey B, Contat C, Meylan E. Glucose transporters in cancerdfrom tumor cells to the tumor microenvironment. FEBS J 2018;285: 2926-43.
78. Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, et al. Sequence and structure of a human glucose transporter. Science 1985;229:941-5.
79. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Asp Med 2013;34:121-38.
80. Dahlin A, Royall J, Hohmann JG, Wang J. Expression profiling of the solute carrier gene family in the mouse brain. J Pharmacol Exp Ther 2009;329:558-70.
81. Yamamoto T, Seino Y, Fukumoto H, Koh G, Yano H, Inagaki N, et al. Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun 1990;170:223-30.
82. Carvalho KC, Cunha IW, Rocha RW, Ayala FR, Cajaiba MM, Begnami MD, et al. GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker. Clinics (Sao Paulo) 2011;66: 965-72.
83. Wang J, Ye C, Chen C, Xiong H, Xie B, Zhou J, et al. Glucose transporter GLUT1 expression and clinical outcome in solid tumors: a systematic review and meta-analysis. Oncotarget 2017;8: 16875-86.
84. FDA. New fludeoxyglucose F18 injection PET drug approved in less than 6 months. 2014. Available from:
85. Agrawal A, Rangarajan V. Appropriateness criteria of FDG PET/CT in oncology. Indian J Radiol Imaging 2015;25:88-101.
86. Chung JH, Cho KJ, Lee SS, Baek HJ, Park JH, Cheon GJ, et al. Overexpression of Glut1 in lymphoid follicles correlates with falsepositive 18F-FDG PET results in lung cancer staging. J Nucl Med 2004;45:999-1003.
87. Bar-Shalom R, Yefremov N, Guralnik L, Gaitini D, Frenkel A, Kuten A, et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med 2003;44:1200-9.
88. Horiuchi C, Tsukuda M, Taguchi T, Ishiguro Y, Okudera K, Inoue T. Correlation between FDG-PET findings and GLUT1 expression in salivary gland pleomorphic adenomas. Ann Nucl Med 2008;22: 693-8.
89. Mano Y, Aishima S, Kubo Y, Tanaka Y, Motomura T, Toshima T, et al. Correlation between biological marker expression and fluorine-18 fluorodeoxyglucose uptake in hepatocellular carcinoma. Am J Clin Pathol 2014;142:391-7.
90. Kitamura K, Hatano E, Higashi T, Narita M, Seo S, Nakamoto Y, et al. Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis. J Hepatol 2011;55:846-57.
91. Higashi T, Saga T, Nakamoto Y, Ishimori T, Mamede MH, Wada M, et al. Relationship between retention index in dual-phase 18F-FDG PET, and hexokinase-II and glucose transporter-1 expression in pancreatic cancer. J Nucl Med 2002;43:173-80.
92. Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T, et al. Biologic correlation of 2-[18F]-fluoro-2-deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors. J Clin Oncol 2010;28:3746-53.
93. Wang ZG, Yu MM, Han Y, Wu FY, Yang GJ, Li DC, et al. Correlation of Glut-1 and Glut-3 expression with F-18 FDG uptake in pulmonary inflammatory lesions. Medicine (Baltim) 2016;95:e5462.
94. Hong R, Lim SC. 18F-fluoro-2-deoxyglucose uptake on PET CT and glucose transporter 1 expression in colorectal adenocarcinoma. World J Gastroenterol 2012;18:168-74.
95. Groheux D, Giacchetti S, Moretti JL, Porcher R, Espie M, LehmannChe J, et al. Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer. Eur J Nucl Med Mol Imaging 2011;38:426-35.
96. Kitajima K, Miyoshi Y. Present and future role of FDG-PET/CT imaging in the management of breast cancer. Jpn J Radiol 2016; 34:167-80.
97. Godoy A, Ulloa V, Rodriguez F, Reinicke K, Yañez AJ, Garcia Mde L, et al. Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J Cell Physiol 2006;207:614-27.
98. Wuest M, Hamann I, Bouvet V, Glubrecht D, Marshall A, Trayner B, et al. Molecular imaging of GLUT1 and GLUT5 in breast cancer: a multitracer positron emission tomography imaging study in mice. Mol Pharmacol 2018;93:79-89.
99. Warburg O. On the origin of cancer cells. Science 1956;123:309-14.
100. Kong SC, Nohr-Nielsen A, Zeeberg K, Reshkin SJ, Hoffmann EK, Novak I, et al. Monocarboxylate transporters MCT1 and MCT4 regulate nigration and invasion of pancreatic ductal adenocarcinoma cells. Pancreas 2016;45:1036-47.
101. Pinheiro C, Longatto-Filho A, Azevedo-Silva J, Casal M, Schmitt FC, Baltazar F. Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr 2012;44:127-39.
102. Baltazar F, Pinheiro C, Morais-Santos F, Azevedo-Silva J, Queiros O, Preto A, et al. Monocarboxylate transporters as targets and mediators in cancer therapy response. Histol Histopathol 2014;29:1511-24.
103. Kurhanewicz J, Vigneron DB, Ardenkjaer-Larsen JH, Bankson JA, Brindle K, Cunningham CH, et al. Hyperpolarized 13C MRI: path to clinical translation in oncology. Neoplasia 2019;21:1-16.
104. Jackson VN, Halestrap AP. The kinetics, substrate, and inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator, 20,70-bis(-carboxyethyl)-5(6)-carboxyfluorescein. J Biol Chem 1996;271:861-8.
105. Halestrap AP. The SLC16 gene familydstructure, role and regulation in health and disease. Mol Asp Med 2013;34:337-49.
106. Morris ME, Felmlee MA. Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse gamma-hydroxybutyric acid. AAPS J 2008;10:311-21.
107. Halestrap AP. The monocarboxylate transporter familydstructure and functional characterization. IUBMB Life 2012;64:1-9.
108. Broer S, Schneider HP, Broer A, Rahman B, Hamprecht B, Deitmer JW. Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 1998;333(1):167-74.
109. Manning Fox JE, Meredith D, Halestrap AP. Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol 2000;529 Pt 2:285-93.
110. Halestrap AP, Meredith D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 2004;447:619-28.
111. Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA. Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic beta-cells leads to relative hyperinsulinism during exercise. Diabetes 2012;61:1719-25.
112. He L, Wang H, Zhang Y, Geng L, Yang M, Xu Z, et al. Evaluation of monocarboxylate transporter 4 in inflammatory bowel disease and its potential use as a diagnostic marker. Dis Markers 2018;2018: 2649491.
113. Halestrap AP, Wilson MC. The monocarboxylate transporter familydrole and regulation. IUBMB Life 2012;64:109-19.
114. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig 2008;118:3930-42.
115. Choi SY, Xue H, Wu R, Fazli L, Lin D, Collins CC, et al. The MCT4 gene: a novel, potential target for therapy of advanced prostate cancer. Clin Cancer Res 2016;22:2721-33.
116. Payen VL, Hsu MY, Radecke KS, Wyart E, Vazeille T, Bouzin C, et al. Monocarboxylate transporter MCT1 promotes tumor metastasis independently of its activity as a lactate transporter. Cancer Res 2017;77:5591-601.
117. Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell 2017;171:358-371 e9.
118. Latif A, Chadwick AL, Kitson SJ, Gregson HJ, Sivalingam VN, Bolton J, et al. Monocarboxylate transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer. BMC Clin Pathol 2017;17:27.
119. Keshari KR, Sriram R, Koelsch BL, van Criekinge M, Wilson DM, Kurhanewicz J, et al. Hyperpolarized 13C-pyruvate magnetic resonance reveals rapid lactate export in metastatic renal cell carcinomas. Cancer Res 2013;73:529-38.
120. Sriram R, Gordon J, Baligand C, Ahamed F, Delos Santos J, Qin H, et al. Non-invasive assessment of lactate production and compartmentalization in renal cell carcinomas using hyperpolarized 13C pyruvate MRI. Cancers (Basel) 2018;10:313.
121. Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PE, Harzstark AL, Ferrone M, et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate. Sci Transl Med 2013;5:198ra08.
122. Scroggins BT, Matsuo M, White AO, Saito K, Munasinghe JP, Sourbier C, et al. Hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts efficacy of targeting the warburg effect. Clin Cancer Res 2018;24:3137-48.
123. Glaudemans AW, Enting RH, Heesters MA, Dierckx RA, van Rheenen RW, Walenkamp AM, et al. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur J Nucl Med Mol Imaging 2013;40:615-35.
124. Watabe T, Ikeda H, Nagamori S, Wiriyasermkul P, Tanaka Y, Naka S, et al. 18F-FBPA as a tumor-specific probe of L-type amino acid transporter 1 (LAT1): a comparison study with 18F-FDG and 11 C-methionine PET. Eur J Nucl Med Mol Imaging 2017;44: 321-31.