Manipulation of glycolysis in malignant tumors: Fantasy or therapy?

Current Medicinal Chemistry

Volumn 17, Issue 2, 2010, Pages 96-108

  Sattler, U G A ^a   Hirschhaeuser, F ^a   Mueller Klieser, W F ^a  

^a JOHANNES GUTENBERG UNIVERSITY   (Germany)

Author keywords

Glycolysis inhibition; Redox state; Targeted therapy; Therapy resistance; Tumor cell metabolism imaging; Tumor markers; Tumor metabolism

Indexed keywords

ALPHA CYANO 4 HYDROXY CINNAMATE; ANTINEOPLASTIC AGENT; BROMOPYRUVIC ACID; CARBONATE DEHYDRATASE IX; DEOXYGLUCOSE; DEXTRO PHENYLALANYLCYSTEINYLTYROSYL DEXTRO TRYPTOPHYLLYSYLCYSTEINYLTHREONINAMIDE 2,6 DISULFIDE; DICHLOROACETIC ACID; GLUCOSE TRANSPORTER 1; LACTATE DEHYDROGENASE; LACTIC ACID; LONIDAMINE; MONOCARBOXYLATE TRANSPORTER; MONOCARBOXYLATE TRANSPORTER 1; OXAMIC ACID; OXYTHIAMINE; PYRUVATE KINASE; SCAVENGER; TRANSKETOLASE; TUMOR MARKER; UNCLASSIFIED DRUG;

CANCER CELL; CANCER DIAGNOSIS; CARBOHYDRATE METABOLISM; CELL METABOLISM; COMPUTER ASSISTED TOMOGRAPHY; DRUG STRUCTURE; DRUG TARGETING; GLYCOLYSIS; HUMAN; IMAGING; MALIGNANT NEOPLASTIC DISEASE; MALIGNANT TRANSFORMATION; MITOCHONDRIAL RESPIRATION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; POSITRON EMISSION TOMOGRAPHY; REVIEW; SOLID TUMOR; TREATMENT RESPONSE;

FREE RADICAL SCAVENGERS; GLYCOLYSIS; HUMANS; NEOPLASMS;

EID: 77149174857     PISSN: 09298673     EISSN: None     Source Type: Journal    
DOI: 10.2174/092986710790112657     Document Type: Review

References (118)

1. Vaupel, P. The role of hypoxia-induced factors in tumor progression. Oncologist, 2004, 9 Suppl 5, 10-17.
2. Bartrons, R.; Caro, J. Hypoxia, glucose metabolism and the Warburg's effect. J. Bioenerg. Biomembr., 2007, 39, 223-229.
3. Denko, N.C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer, 2008, 8, 705-713.
4. Yeung, S.J.; Pan, J.; Lee, M.H. Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol. Life Sci., 2008, 65, 3981-3999.
5. Roudier, E.; Perrin, A. Considering the role of pyruvate in tumor cells during hypoxia. Biochim. Biophys. Acta, 2009, 1796, 55-62.
6. Gatenby, R.A.; Gillies, R.J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer, 2004, 4, 891-899.
7. Moreno-Sanchez, R.; Rodriguez-Enriquez, S.; Marin-Hernandez, A.; Saavedra, E. Energy metabolism in tumor cells. FEBS J., 2007, 274, 1393-1418.
8. DeBerardinis, R.J.; Sayed, N.; Ditsworth, D.; Thompson, C.B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev., 2008, 18, 54-61.
9. Gillies, R.J.; Robey, I.; Gatenby, R.A. Causes and consequences of increased glucose metabolism of cancers. J. Nucl. Med., 2008, 49 Suppl 2, 24S-42S.
10. Dang, C.V.; Semenza, G.L. Oncogenic alterations of metabolism. Trends Biochem. Sci., 1999, 24, 68-72.
11. Semenza, G.L. Regulation of cancer cell metabolism by hypoxiainducible factor 1. Semin. Cancer Biol., 2009, 19, 12-16.
12. Chun, Y.S.; Kim, M.S.; Park, J.W. Oxygen-dependent and - independent regulation of HIF-1alpha. J. Korean Med. Sci., 2002, 17, 581-588.
13. Lu, H.; Forbes, R.A.; Verma, A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem., 2002, 277, 23111-23115.
14. Swietach, P.; Vaughan-Jones, R.D.; Harris, A.L. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev., 2007, 26, 299-310.
15. Sonveaux, P.; Vegran, F.; Schroeder, T.; Wergin, M.C.; Verrax, J.; Rabbani, Z.N.; De Saedeleer, C.J.; Kennedy, K.M.; Diepart, C.; Jordan, B.F.; Kelley, M.J.; Gallez, B.; Wahl, M.L.; Feron, O.; Dewhirst, M.W. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest., 2008, 118, 3930-3942.
16. Brindle, K. New approaches for imaging tumour responses to treatment. Nat. Rev. Cancer, 2008, 8, 94-107.
17. Plathow, C.; Weber, W.A. Tumor cell metabolism imaging. J. Nucl. Med., 2008, 49 Suppl 2, 43S-63S.
18. Kelloff, G.J.; Hoffman, J.M.; Johnson, B.; Scher, H.I.; Siegel, B.A.; Cheng, E.Y.; Cheson, B.D.; O'Shaughnessy, J.; Guyton, K.Z.; Mankoff, D.A.; Shankar, L.; Larson, S.M.; Sigman, C.C.; Schilsky, R.L.; Sullivan, D.C. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin. Cancer Res., 2005, 11, 2785-2808.
19. Kurhanewicz, J.; Bok, R.; Nelson, S.J.; Vigneron, D.B. Current and potential applications of clinical 13C MR spectroscopy. J. Nucl. Med., 2008, 49, 341-344.
20. Golman, K.; Zandt, R.I.; Lerche, M.; Pehrson, R.; Ardenkjaer-Larsen, J.H. Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res., 2006, 66, 10855-10860.
21. Albers, M.J.; Bok, R.; Chen, A.P.; Cunningham, C.H.; Zierhut, M.L.; Zhang, V.Y.; Kohler, S.J.; Tropp, J.; Hurd, R.E.; Yen, Y.F.; Nelson, S.J.; Vigneron, D.B.; Kurhanewicz, J. Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. Cancer Res., 2008, 68, 8607-8615.
22. Walenta, S.; Chau, T.V.; Schroeder, T.; Lehr, H.A.; Kunz-Schughart, L.A.; Fuerst, A.; Mueller-Klieser, W. Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists? J. Cancer Res. Clin. Oncol., 2003, 129, 321-326.
23. Tessem, M.B.; Swanson, M.G.; Keshari, K.R.; Albers, M.J.; Joun, D.; Tabatabai, Z.L.; Simko, J.P.; Shinohara, K.; Nelson, S.J.; Vigneron, D.B.; Gribbestad, I.S.; Kurhanewicz, J. Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR-MAS spectroscopy of biopsy tissues. Magn. Reson. Med., 2008, 60, 510-516.
24. Mueller-Klieser, W.; Walenta, S. Geographical mapping of metabolites in biological tissue with quantitative bioluminescence and single photon imaging. Histochem. J., 1993, 25, 407-420.
25. Sattler, U.G.; Walenta, S.; Mueller-Klieser, W. A bioluminescence technique for quantitative and structure-associated imaging of pyruvate. Lab. Invest., 2007, 87, 84-92.
26. Brizel, D.M.; Schroeder, T.; Scher, R.L.; Walenta, S.; Clough, R.W.; Dewhirst, M.W.; Mueller-Klieser, W. Elevated tumor lactate concentrations predict for an increased risk of metastases in headand-neck cancer. Int. J. Radiat. Oncol. Biol. Phys., 2001, 51, 349-353.
27. Walenta, S.; Wetterling, M.; Lehrke, M.; Schwickert, G.; Sundfor, K.; Rofstad, E.K.; Mueller-Klieser, W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res., 2000, 60, 916-921.
28. Quennet, V.; Yaromina, A.; Zips, D.; Rosner, A.; Walenta, S.; Baumann, M.; Mueller-Klieser, W. Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice. Radiother. Oncol., 2006, 81, 130-135.
29. Gorlach, A.; Acker, H. The relationship of radiation sensitivity and microenvironment of human tumor cells in multicellular spheroid tissue culture. Adv. Exp. Med. Biol., 1994, 345, 343-350.
30. Yaromina, A.; Zips, D.; Thames, H.D.; Eicheler, W.; Krause, M.; Rosner, A.; Haase, M.; Petersen, C.; Raleigh, J.A.; Quennet, V.; Walenta, S.; Mueller-Klieser, W.; Baumann, M. Pimonidazole labeling and response to fractionated irradiation of five human squamous cell carcinoma (hSCC) lines in nude mice: the need for a multivariate approach in biomarker studies. Radiother. Oncol., 2006, 81, 122-129.
31. Groussard, C.; Morel, I.; Chevanne, M.; Monnier, M.; Cillard, J.; Delamarche, A. Free radical scavenging and antioxidant effects of lactate ion: an in vitro study. J. Appl. Physiol., 2000, 89, 169-175.
32. Yen, T.C.; See, L.C.; Lai, C.H.; Yah-Huei, C.W.; Ng, K.K.; Ma, S.Y.; Lin, W.J.; Chen, J.T.; Chen, W.J.; Lai, C.R.; Hsueh, S. 18FFDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression. J. Nucl. Med., 2004, 45, 22-29.
33. Endo, M.; Tateishi, U.; Seki, K.; Yamaguchi, U.; Nakatani, F.; Kawai, A.; Chuman, H.; Beppu, Y. Prognostic implications of glucose transporter protein-1 (glut-1) overexpression in bone and softtissue sarcomas. Jpn. J. Clin. Oncol., 2007, 37, 955-960.
34. Kunkel, M.; Moergel, M.; Stockinger, M.; Jeong, J.H.; Fritz, G.; Lehr, H.A.; Whiteside, T.L. Overexpression of GLUT-1 is associated with resistance to radiotherapy and adverse prognosis in squamous cell carcinoma of the oral cavity. Oral Oncol., 2007, 43, 796-803.
35. Gu, J.; Yamamoto, H.; Fukunaga, H.; Danno, K.; Takemasa, I.; Ikeda, M.; Tatsumi, M.; Sekimoto, M.; Hatazawa, J.; Nishimura, T.; Monden, M. Correlation of GLUT-1 overexpression, tumor size, and depth of invasion with 18F-2-fluoro-2-deoxy-D-glucose uptake by positron emission tomography in colorectal cancer. Dig. Dis. Sci., 2006, 51, 2198-2205.
36. Cantuaria, G.; Fagotti, A.; Ferrandina, G.; Magalhaes, A.; Nadji, M.; Angioli, R.; Penalver, M.; Mancuso, S.; Scambia, G. GLUT-1 expression in ovarian carcinoma: association with survival and response to chemotherapy. Cancer, 2001, 92, 1144-1150.
37. Mazurek, S.; Boschek, C.B.; Hugo, F.; Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol., 2005, 15, 300-308.
38. Kaura, B.; Bagga, R.; Patel, F.D. Evaluation of the Pyruvate Kinase isoenzyme tumor (Tu M2-PK) as a tumor marker for cervical carcinoma. J. Obstet. Gynaecol. Res., 2004, 30, 193-196.
39. Kim, C.W.; Kim, J.I.; Park, S.H.; Han, J.Y.; Kim, J.K.; Chung, K.W.; Sun, H.S. [Usefulness of plasma tumor M2-pyruvate kinase in the diagnosis of gastrointestinal cancer]. Korean J. Gastroenterol., 2003, 42, 387-393.
40. Hardt, P.D.; Mazurek, S.; Toepler, M.; Schlierbach, P.; Bretzel, R.G.; Eigenbrodt, E.; Kloer, H.U. Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer. Br. J. Cancer, 2004, 91, 980-984.
41. Hegele, A.; Varga, Z.; Kosche, B.; Stief, T.; Heidenreich, A.; Hofmann, R. Pyruvate kinase type tumor M2 in urological malignancies. Urol. Int., 2003, 70, 55-58.
42. Ervens, J.; Fuchs, H.; Niemann, V.T.; Hoffmeister, B. Pyruvate kinase isoenzyme M2 is not of diagnostic relevance as a marker for oral cancer. J. Craniomaxillofac. Surg., 2008, 36, 89-94.
43. Staib, P.; Hoffmann, M.; Schinkothe, T. Plasma levels of tumor M2-pyruvate kinase should not be used as a tumor marker for hematological malignancies and solid tumors. Clin. Chem. Lab. Med., 2006, 44, 28-31.
44. Koukourakis, M.I.; Giatromanolaki, A.; Sivridis, E.; Gatter, K.C.; Harris, A.L. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway-a report of the Tumour Angiogenesis Research Group. J. Clin. Oncol., 2006, 24, 4301-4308.
45. Koukourakis, M.I.; Giatromanolaki, A.; Sivridis, E.; Bougioukas, G.; Didilis, V.; Gatter, K.C.; Harris, A.L. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br. J. Cancer, 2003, 89, 877-885.
46. Giatromanolaki, A.; Sivridis, E.; Gatter, K.C.; Turley, H.; Harris, A.L.; Koukourakis, M.I. Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis. Gynecol. Oncol., 2006, 103, 912-918.
47. Kolev, Y.; Uetake, H.; Takagi, Y.; Sugihara, K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann. Surg. Oncol., 2008, 15, 2336-2344.
48. Jacobs, E.L.; Haskell, C.M. Clinical use of tumor-markers in oncology. Curr. Probl. Cancer, 1991, 15, 299-350.
49. Lagerwaard, F.J.; Levendag, P.C.; Nowak, P.J.C.M.; Eijkenboom, W.M.H.; Hanssens, P.E.J.; Schmitz, P.I.M. Identification of prognostic factors in patients with brain metastases: A review of 1292 patients. Int. J. Radiat. Oncol. Biol. Phys., 1999, 43, 795-803.
50. Culine, S. Prognostic factors in unknown primary cancer. Semin. Oncol., 2009, 36, 60-64.
51. Koukourakis, M.I.; Kontomanolis, E.; Giatromanolaki, A.; Sivridis, E.; Liberis, V. Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases. Gynecol. Obstet. Invest., 2009, 67, 162-168.
52. Argilés, J.M.; López-Soriano, F.J. The energy-state of tumorbearing rats. J. Biol. Chem., 1991, 266, 2978-2982.
53. Durig, J.; Fiedler, W.; deWit, M.; Steffen, M.; Hossfeld, D.K. Lactic acidosis and hypoglycemia in a patient with high-grade non-Hodgkin's lymphoma and elevated circulating TNF-alpha. Ann. Hematol., 1996, 72, 97-99.
54. 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, S.W.; Kreutz, M. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood, 2007, 109, 3812-3819.
55. Merezhinskaya, N.; Fishbein, W.N. Monocarboxylate transporters: Past, present, and future. Histol. Histopathol., 2009, 24, 243-264.
56. Pinheiro, C.; Longatto, A.; Scapulatempo, C.; Ferreira, L.; Martins, S.; Pellerin, L.; Rodrigues, M.; Alves, V.A.F.; Schmitt, F.; Baltazar, F. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch., 2008, 452, 139-146.
57. Vaupel, P.; Mayer, A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev., 2007, 26, 225-239.
58. Volker, H.U.; Scheich, M.; Schmausser, B.; Kammerer, U.; Eck, M. Overexpression of transketolase TKTL1 is associated with shorter survival in laryngeal squamous cell carcinomas. Eur. Arch. Otorhinolaryngol., 2007, 264, 1431-1436.
59. Zhang, S.; Yue, J.X.; Yang, J.H.; Cai, P.C.; Kong, W.J. Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: a potential therapeutic target in nasopharyngeal carcinoma. Cancer Biol. Ther., 2008, 7, 517-522.
60. Langbein, S.; Zerilli, M.; Zur, H.A.; Staiger, W.; Rensch-Boschert, K.; Lukan, N.; Popa, J.; Ternullo, M.P.; Steidler, A.; Weiss, C.; Grobholz, R.; Willeke, F.; Alken, P.; Stassi, G.; Schubert, P.; Coy, J.F. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br. J. Cancer, 2006, 94, 578-585.
61. Foldi, M.; Stickeler, E.; Bau, L.; Kretz, O.; Watermann, D.; Gitsch, G.; Kayser, G.; Zur, H.A.; Coy, J.F. Transketolase protein TKTL1 overexpression: A potential biomarker and therapeutic target in breast cancer. Oncol. Rep., 2007, 17, 841-845.
62. Cuezva, J.M.; Ortega, A.D.; Willers, I.; Sanchez-Cenizo, L.; Aldea, M.; Sanchez-Arago, M. The tumor suppressor function of mitochondria: Translation into the clinics. Biochim. Biophys. Acta, 2009, (Epub ahead of peirnt).
63. Pelicano, H.; Martin, D.S.; Xu, R.H.; Huang, P. Glycolysis inhibition for anticancer treatment. Oncogene, 2006, 25, 4633-4646.
64. Coe, E.L.; Strunk, R.C. The effect of oxamate on glycolysis in intact ascites tumor cells. I. Kinetic evidence for a dual glycolytic system. Biochim. Biophys. Acta, 1970, 208, 189-202.
65. Liu, H.; Savaraj, N.; Priebe, W.; Lampidis, T.J. Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C). Biochem. Pharmacol., 2002, 64, 1745-1751.
66. Fantin, V.R.; St-Pierre, J.; Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell, 2006, 9, 425-434.
67. Young, C.D.; Anderson, S.M. Sugar and fat - that's where it's at: metabolic changes in tumors. Breast Cancer Res., 2008, 10, 202-
68. Behal, R.H.; Buxton, D.B.; Robertson, J.G.; Olson, M.S. Regulation of the pyruvate dehydrogenase multienzyme complex. Annu. Rev. Nutr., 1993, 13, 497-520.
69. Harris, R.A.; Bowker-Kinley, M.M.; Huang, B.; Wu, P. Regulation of the activity of the pyruvate dehydrogenase complex. Adv. Enzyme Regul., 2002, 42, 249-259.
70. Wigfield, S.M.; Winter, S.C.; Giatromanolaki, A.; Taylor, J.; Koukourakis, M.L.; Harris, A.L. PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br. J. Cancer, 2008, 98, 1975-1984.
71. Cairns, R.A.; Papandreou, I.; Sutphin, P.D.; Denko, N.C. Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 9445-9450.
72. Cao, W.; Yacoub, S.; Shiverick, K.T.; Namiki, K.; Sakai, Y.; Porvasnik, S.; Urbanek, C.; Rosser, C.J. Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate, 2008, 68, 1223-1231.
73. Bonnet, S.; Archer, S.L.; lalunis-Turner, J.; Haromy, A.; Beaulieu, C.; Thompson, R.; Lee, C.T.; Lopaschuk, G.D.; Puttagunta, L.; Bonnet, S.; Harry, G.; Hashimoto, K.; Porter, C.J.; Andrade, M.A.; Thebaud, B.; Michelakis, E.D. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell, 2007, 11, 37-51.
74. Sattler, U.G.; Walenta, S.; Mueller-Klieser, W. Lactate and redox status in malignant tumors. Anaesthesist, 2007, 56, 466-469.
75. Salahudeen, A.K.; Clark, E.C.; Nath, K.A. Hydrogen peroxideinduced renal injury. A protective role for pyruvate in vitro and in vivo. J. Clin. Invest., 1991, 88, 1886-1893.
76. O'Donnell-Tormey, J.; Nathan, C.F.; Lanks, K.; DeBoer, C.J.; de la, H.J. Secretion of pyruvate. An antioxidant defense of mammalian cells. J. Exp. Med., 1987, 165, 500-514.
77. Mallet, R.T.; Sun, J. Antioxidant properties of myocardial fuels. Mol. Cell. Biochem., 2003, 253, 103-111.
78. Xu, X.; Zur, H.A.; Coy, J.F.; Lochelt, M. Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells. Int. J. Cancer, 2009, 124, 1330-1337.
79. Boros, L.G.; Puigjaner, J.; Cascante, M.; Lee, W.N.; Brandes, J.L.; Bassilian, S.; Yusuf, F.I.; Williams, R.D.; Muscarella, P.; Melvin, W.S.; Schirmer, W.J. Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. Cancer Res., 1997, 57, 4242-4248.
80. Rais, B.; Comin, B.; Puigjaner, J.; Brandes, J.L.; Creppy, E.; Saboureau, D.; Ennamany, R.; Lee, W.N.; Boros, L.G.; Cascante, M. Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle. FEBS Lett., 1999, 456, 113-118.
81. Stetak, A.; Veress, R.; Ovadi, J.; Csermely, P.; Keri, G.; Ullrich, A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res., 2007, 67, 1602-1608.
82. Keri, G.; Erchegyi, J.; Horvath, A.; Mezo, I.; Idei, M.; Vantus, T.; Balogh, A.; Vadasz, Z.; Bokonyi, G.; Seprodi, J.; Teplan, I.; Csuka, O.; Tejeda, M.; Gaal, D.; Szegedi, Z.; Szende, B.; Roze, C.; Kalthoff, H.; Ullrich, A. A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity. Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 12513-12518.
83. Szende, B.; Keri, G. TT-232: a somatostatin structural derivative as a potent antitumor drug candidate. Anticancer Drugs, 2003, 14, 585-588.
84. Lu, H.; Dalgard, C.L.; Mohyeldin, A.; McFate, T.; Tait, A.S.; Verma, A. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J. Biol. Chem., 2005, 280, 41928-41939.
85. Roudier, E.; Bachelet, C.; Perrin, A. Pyruvate reduces DNA damage during hypoxia and after reoxygenation in hepatocellular carcinoma cells. FEBS J., 2007, 274, 5188-5198.
86. McComb, R.B.; Yushok, W.D. Metabolism Of Ascites Tumor Cells. III. Effect Of 2-Deoxyglucose Phosphorylation On Phosphorous Metabolism. Cancer Res., 1964, 24, 193-197.
87. Lin, X.; Zhang, F.; Bradbury, C.M.; Kaushal, A.; Li, L.; Spitz, D.R.; Aft, R.L.; Gius, D. 2-Deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is mediated via disruptions in thiol metabolism. Cancer Res., 2003, 63, 3413-3417.
88. Coleman, M.C.; Asbury, C.R.; Daniels, D.; Du, J.; ykin-Burns, N.; Smith, B.J.; Li, L.; Spitz, D.R.; Cullen, J.J. 2-deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer. Free Radic. Biol. Med., 2008, 44, 322-331.
89. Ihrlund, L.S.; Hernlund, E.; Khan, O.; Shoshan, M.C. 3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Mol. Oncol., 2008, 2, 94-101.
90. Chang, J.M.; Chung, J.W.; Jae, H.J.; Eh, H.; Son, K.R.; Lee, K.C.; Park, J.H. Local toxicity of hepatic arterial infusion of hexokinase II inhibitor, 3-bromopyruvate: In vivo investigation in normal rabbit model. Acad. Radiol., 2007, 14, 85-92.
91. Bustamante, E.; Pedersen, P.L. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc. Natl. Acad. Sci. U. S. A., 1977, 74, 3735-3739.
92. Pedersen, P.L. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen. J. Bioenerg. Biomembr., 2007, 39, 211-222.
93. Floridi, A.; Paggi, M.G.; Datri, S.; Demartino, C.; Marcante, M.L.; Silvestrini, B.; Caputo, A. Effect of lonidamine on the energymetabolism of ehrlich ascites tumor-cells. Cancer Res., 1981, 41, 4661-4666.
94. Mathupala, S.P.; Colen, C.B.; Parajuli, P.; Sloan, A.E. Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis. J. Bioenerg. Biomembr., 2007, 39, 73-77.
95. Fang, J.; Quinones, Q.J.; Holman, T.L.; Morowitz, M.J.; Wang, Q.; Zhao, H.; Sivo, F.; Maris, J.M.; Wahl, M.L. The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol. Pharmacol., 2006, 70, 2108-2115.
96. Ben-Horin, H.; Tassini, M.; Vivi, A.; Navon, G.; Kaplan, O. Mechanism of action of the antineoplastic drug lonidamine: 31P and 13C nuclear magnetic resonance studies. Cancer Res., 1995, 55, 2814-2821.
97. Wahl, M.L.; Owen, J.A.; Burd, R.; Herlands, R.A.; Nogami, S.S.; Rodeck, U.; Berd, D.; Leeper, D.B.; Owen, C.S. Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol. Cancer Ther., 2002, 1, 617-628.
98. Colen, C.B.; Seraji-Bozorgzad, N.; Marples, B.; Galloway, M.P.; Sloan, A.E.; Mathupala, S.P. Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study. Neurosurgery, 2006, 59, 1313-1323.
99. Mathupala, S.P.; Parajuli, P.; Sloan, A.E. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery, 2004, 55, 1410-1419.
100. Dimmer, K.S.; Friedrich, B.; Lang, F.; Deitmer, J.W.; Broer, S. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J., 2000, 350 Pt 1, 219-227.
101. Laszlo, J.; Harlan, W.R.; Klein, R.F.; Kirshner, N.; Estes, E.H., Jr.; Bogdonoff, M.D. The effect of 2-deoxy-D-glucose infusions on lipid and carbohydrate metabolism in man. J. Clin. Invest., 1961, 40, 171-176.
102. Halestrap, A.P.; Meredith, D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch., 2004, 447, 619-628.
103. Bowker-Kinley, M.M.; Davis, W.I.; Wu, P.F.; Harris, R.A.; Popov, K.M. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem. J., 1998, 329, 191-196.
104. Halestrap, A.P.; Denton, R.M. Specific inhibition of pyruvate transport in rat liver mitochondria and human erythrocytes by alpha-cyano-4- hydroxycinnamate. Biochem. J., 1974, 138, 313-316.
105. Kaufmann, P.; Engelstad, K.; Wei, Y.; Jhung, S.; Sano, M.C.; Shungu, D.C.; Millar, W.S.; Hong, X.; Gooch, C.L.; Mao, X.; Pascual, J.M.; Hirano, M.; Stacpoole, P.W.; DiMauro, S.; De, V. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology, 2006, 66, 324-330.
106. Maranghi, F.; Mantovani, A.; Macri, C.; Romeo, A.; Eleuteri, P.; Leter, G.; Rescia, M.; Spano, M.; Saso, L. Long-term effects of lonidamine on mouse testes. Contraception, 2005, 72, 268-272.
107. Gong, X.D.; Burbridge, S.M.; Lewis, A.C.; Wong, P.Y.D.; Linsdell, P. Mechanism of lonidamine inhibition of the CFTR chloride channel. Br. J. Pharmacol., 2002, 137, 928-936.
108. Thornburg, J.M.; Nelson, K.K.; Clem, B.F.; Lane, A.N.; Arumugam, S.; Simmons, A.; Eaton, J.W.; Telang, S.; Chesney, J. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res., 2008, 10, R84-
109. Crowe, S.F.; Kempton, S. Both ethanol toxicity and thiamine deficiency are necessary to produce long-term memory deficits in the young chick. Pharmacol. Biochem. Behav., 1997, 58, 461-470.
110. Szokoloczi, O.; Schwab, R.; Petak, I.; Orfi, L.; Pap, A.; Eberle, A.N.; Szuts, T.; Keril, G. TT232, a novel signal transduction inhibitory compound in the therapy of cancer and inflammatory diseases. J. Recept. Signal Transduct. Res., 2005, 25, 217-235.
111. Warburg, O. On the origin of cancer cells. Science, 1956, 123, 309-314.
112. Weinhouse, S. On respiratory impairment in cancer cells. Science, 1956, 124, 267-269.
113. Stacpoole, P.W.; Kurtz, T.L.; Han, Z.; Langaee, T. Role of dichloroacetate in the treatment of genetic mitochondrial diseases. Adv. Drug Deliv. Rev., 2008, 60, 1478-1487.
114. Broer, S.; Broer, A.; Schneider, H.P.; Stegen, C.; Halestrap, A.P.; Deitmer, J.W. Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem. J., 1999, 341, 529-535.
115. Behlke, M.A. Progress towards in vivo use of siRNAs. Mol. Ther., 2006, 13, 644-670.
116. Xie, F.Y.; Woodle, M.C.; Lu, P.Y. Harnessing in vivo siRNA delivery for drug discovery and therapeutic development. Drug Discov. Today, 2006, 11, 67-73.
117. Kamlah, F.; Eul, B.G.; Li, S.; Lang, N.; Marsh, L.M.; Seeger, W.; Grimminger, F.; Rose, F.; Hanze, J. Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model. Cancer Gene Ther., 2009, 16, 195-205.
118. Zu, X.L.; Guppy, M. Cancer metabolism: facts, fantasy, and fiction. Biochem. Biophys. Res. Commun., 2004, 313, 459-465.