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Warburg and Krebs and related effects in cancer

  • Judith E. Unterlass (a1) and Nicola J. Curtin (a2)


Warburg and coworkers' observation of altered glucose metabolism in tumours has been neglected for several decades, which, in part, was because of an initial misinterpretation of the basis of their finding. Following the realisation that genetic alterations are often linked to metabolism, and that the tumour micro-environment imposes different demands on cancer cells, has led to a reinvestigation of cancer metabolism in recent years. Increasing our understanding of the drivers and consequences of the Warburg effect in cancer and beyond will help to identify new therapeutic strategies as well as to identify new prognostic and therapeutic biomarkers. Here we discuss the initial findings of Warburg and coworkers regarding cancer cell glucose metabolism, how these studies came into focus again in recent years following the discovery of metabolic oncogenes, and the therapeutic potential that lies within targeting the altered metabolic phenotype in cancer. In addition, another essential nutrient in cancer metabolism, glutamine, will be discussed.


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Author for correspondence: Judith E. Unterlass, E-mail:


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Current address: Evotec (France), 195 route d'Espagne, BP13669, F-31036 Toulouse Cedex, France.



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1.Altenberg, B and Greulich, KO (2004) Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84, 10141020.
2.Muir, A and Vander Heiden, MG (2018) The nutrient environment affects therapy. Science 360, 962963.
3.Warburg, O (1925) Über den Stoffwechsel der Carcinomzelle. Klinische Wochenschrift 4, 534536.
4.Warburg, OH (1915) Notizen zur Entwicklungsphysiologie des Seeigeleies. Pflügers Archiv – European Journal of Physiology 160, 324332.
5.Warburg, O and Minami, S (1923) Versuche am überlebenden Carcinomgewebe. Klinische Wochenschrift 2, 776777.
6.Warburg, O, Posener, K and Negelein, E (1924) Über den Stoffwechsel der Carcinomzelle. Biochemische Zeitschrift 152, 309344.
7.Warburg, O (1924) Verbesserte Methode zur Messung der Atmung und Glykole. Biochemische Zeitschrift 152, 5163.
8.Cori, CF and Cori, GT (1925) The carbohydrate metabolism of tumors: i. the free sugar, lactic acid, and glycogen content of malignant tumors. Journal of Biological Chemistry 64, 1122.
9.Cori, CF and Cori, GT (1925) The carbohydrate metabolism of tumors: ii. changes in the sugar, lactic acid, and co2-combining power of blood passing through a tumor. Journal of Biological Chemistry 65, 397405.
10.Warburg, OH and Ernst, H (1952) Versuche mit Ascites-Tumorzellen. Zeitschrift für Naturforschung 7b, 193194.
11.Warburg, O (1956) On respiratory impairment in cancer cells. Science 124, 269270.
12.Warburg, O (1956) On the origin of cancer cells. Science 123, 309314.
13.Weinhouse, S (1956) On respiratory impairment in cancer cells. Science 124, 267269.
14.Racker, E and Spector, M (1981) Warburg effect revisited: merger of biochemistry and molecular biology. Science 213, 303307.
15.Cooper, GM (2000) The mechanism of oxidative phosphorylation. In The Cell: A Molecular Approach, 2nd edition. Sunderland (MA): Sinauer Associates. Available from
16.Hanahan, D and Weinberg, R (2011) Hallmarks of cancer: the next generation. Cell 144, 646674.
17.Stehelin, D et al. (1976) DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170173.
18.Tabin, CJ et al. (1982) Mechanism of activation of a human oncogene. Nature 300, 143.
19.Nowell, PC (1976) The clonal evolution of tumor cell populations. Science 194, 2328.
20.Greaves, M (2015) Evolutionary determinants of cancer. Cancer Discovery 5, 806820.
21.Sever, R and Brugge, JS (2015) Signal transduction in cancer. Cold Spring Harbor Perspectives in Medicine 5(4), a006098.
22.Jackson, RC et al. (1980) Purine and pyrimidine nucleotide patterns of normal, differentiating, and regenerating liver and of hepatomas in rats. Cancer Research 40, 1286.
23.Natsumeda, Y et al. (1984) Enzymic capacities of purine de novo and salvage pathways for nucleotide synthesis in normal and neoplastic tissues. Cancer Research 44, 2475.
24.Tomlinson, IP et al. (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genetics 30, 406410.
25.Baysal, BE et al. (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848851.
26.Parsons, DW et al. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321, 18071812.
27.Yan, H et al. (2009) IDH1 and IDH2 mutations in gliomas. New England Journal of Medicine 360, 765773.
28.Mardis, ER et al. (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. New England Journal of Medicine 361, 10581066.
29.Dang, L, Yen, K and Attar, EC (2016) IDH mutations in cancer and progress toward development of targeted therapeutics. Annals of Oncology 27, 599608.
30.Dang, L et al. (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739.
31.Ward, PS et al. (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations Is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225234.
32.Noushmehr, H et al. (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510522.
33.Turcan, S et al. (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479.
34.Figueroa, ME et al. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553567.
35.Xu, W et al. (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 1730.
36.Watanabe, T et al. (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. The American Journal of Pathology 174, 11491153.
37.Lai, A et al. (2011) Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. Journal of Clinical Oncology 29, 44824490.
38.Johnson, BE et al. (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343, 189193.
39.Lass, U et al. (2012) Clonal analysis in recurrent astrocytic, oligoastrocytic and oligodendroglial tumors implicates IDH1- mutation as common tumor initiating event. PLoS ONE 7, e41298.
40.Kosmider, O et al. (2010) Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24, 1094.
41.Pardanani, A et al. (2010) IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 24, 1146.
42.Kats, L et al. (2014) Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell 14, 329341.
43.Chen, C et al. (2013) Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes & Development 27, 19741985.
44.Sasaki, M et al. (2012) D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes & Development 26, 20382049.
45.Rohle, D et al. (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626630.
46.Davis, JL, Fallon, HJ and Morris, HP (1970) Two enzymes of serine metabolism in rat liver and hepatomas. Cancer Research 30, 29172920.
47.Snell, K and Weber, G (1986) Enzymic imbalance in serine metabolism in rat hepatomas. The Biochemical Journal 233, 617620.
48.Snell, K et al. (1988) Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. British Journal of Cancer 57, 8790.
49.Locasale, JW et al. (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genetics 43, 869.
50.Possemato, R et al. (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346.
51.Pollari, S et al. (2011) Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Research and Treatment 125, 421430.
52.Adams, CM (2007) Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids. Journal of Biological Chemistry 282, 1674416753.
53.Nilsson, LM et al. (2012) Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis. PLoS Genetics 8, e1002573.
54.Ding, J et al. (2013) The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metabolism 18, 896907.
55.Beroukhim, R et al. (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463, 899.
56.DeNicola, GM et al. (2015) NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nature Genetics 47, 1475.
57.Chen, J et al. (2013) Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth. Oncotarget 4, 25022511.
58.Grant, GA (2018) D-3-Phosphoglycerate dehydrogenase. Frontiers in Molecular Biosciences 5, 110110.
59.Mattaini, KR et al. (2015) An epitope tag alters phosphoglycerate dehydrogenase structure and impairs ability to support cell proliferation. Cancer & Metabolism 3, 5.
60.Fan, J et al. (2015) Human phosphoglycerate dehydrogenase produces the oncometabolite d-2-hydroxyglutarate. ACS Chemical Biology 10, 510516.
61.Samanta, D et al. (2016) PHGDH expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis. Cancer Research 76, 44304442.
62.Liu, J et al. (2013) Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. Journal of Neuro-Oncology 111, 245255.
63.Murphy, JP et al. (2018) The NAD + salvage pathway supports PHGDH-driven serine biosynthesis. Cell Reports 24, 23812391, e5.
64.Meyer, N and Penn, LZ (2008) Reflecting on 25 years with MYC. Nature Reviews Cancer 8, 976990.
65.Kim, JW et al. (2004) Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Molecular and Cellular Biology 24, 59235936.
66.Le, A et al. (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism 15, 110121.
67.Osthus, RC et al. (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. Journal of Biological Chemistry 275, 2179721800.
68.Shen, L et al. (2015) Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proceedings of the National Academy of Sciences of the United States of America 112, 54255430.
69.David, CJ et al. (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364368.
70.Sun, L et al. (2015) cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Research 25, 429.
71.Shim, H et al. (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proceedings of the National Academy of Sciences 94, 66586663.
72.Doherty, JR et al. (2014) Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Research 74, 908920.
73.Sonveaux, P et al. (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE 7, e33418.
74.Lu, H, Forbes, RA and Verma, A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. Journal of Biological Chemistry 277, 23111–5.
75.Maxwell, PH, Pugh, CW and Ratcliffe, PJ (2001) Activation of the HIF pathway in cancer. Current Opinion in Genetics & Development 11, 293299.
76.Sun, Q et al. (2011) Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America 108, 41294134.
77.Maxwell, PH et al. (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271275.
78.Gimenez-Roqueplo, A-P et al. (2001) The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. The American Journal of Human Genetics 69, 11861197.
79.Pollard, PJ et al. (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Human Molecular Genetics 14, 22312239.
80.Maxwell, PH et al. (1997) Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America 94, 81048109.
81.Semenza, GL et al. (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. Journal of Biological Chemistry 269, 2375723763.
82.Kim, J-W et al. (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism 3, 177185.
83.Iurlaro, R, Leon-Annicchiarico, CL and Munoz-Pinedo, C (2014) Regulation of cancer metabolism by oncogenes and tumor suppressors. Methods in Enzymology 542, 5980.
84.Cole, AJ et al. (2017) Comprehensive analyses of somatic TP53 mutation in tumors with variable mutant allele frequency. Scientific Data 4, 170120–20.
85.Schwartzenberg-Bar-Yoseph, F, Armoni, M and Karnieli, E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Research 64, 26272633.
86.Kawauchi, K et al. (2008) P53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nature Cell Biology 10, 611618.
87.Bensaad, K et al. (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107120.
88.Boidot, R et al. (2012) Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Research 72, 939948.
89.Contractor, T and Harris, CR (2012) P53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Research 72, 560567.
90.Liu, K et al. (2016) Parkin regulates the activity of pyruvate kinase M2. Journal of Biological Chemistry 291, 1030710317.
91.Matoba, S et al. (2006) P53 regulates mitochondrial respiration. Science 312, 16501653.
92.Stambolsky, P et al. (2006) Regulation of AIF expression by p53. Cell Death & Differentiation 13, 21402149.
93.Bergstrom, J et al. (1974) Intracellular free amino acid concentration in human muscle tissue. Journal of Applied Physiology 36, 693697.
94.Krebs, HA (1935) Metabolism of amino-acids: the synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. Biochemical Journal 29, 19511969.
95.Lacey, JM and Wilmore, DW (1990) Is glutamine a conditionally essential amino acid? Nutrition Reviews 48, 297309.
96.Krebs, H (1980) 18 – special lecture: glutamine metabolism in the animal body. In Mora, J and Palacios, R (eds), Glutamine: Metabolism, Enzymology, and Regulation. New York: Academic Press, pp. 319329.
97.DeBerardinis, RJ and Cheng, T (2010) Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313324.
98.Eagle, H (1955) Nutrition needs of mammalian cells in tissue culture. Science 122, 501514.
99.Abu Aboud, O et al. (2017) Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging. Cancer Research 77, 67466758.
100.Son, J et al. (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101105.
101.Lampa, M et al. (2017) Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition. PLoS ONE 12, e0185092.
102.Bhutia, YD and Ganapathy, V (2016) Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochimica et Biophysica Acta 1863, 25312539.
103.van Geldermalsen, M et al. (2016) ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 35, 32013208.
104.Wang, Q et al. (2014) Targeting glutamine transport to suppress melanoma cell growth. International Journal of Cancer 135, 10601071.
105.Ren, P et al. (2015) ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation. The Journal of Pathology 235, 90100.
106.Huang, F et al. (2014) Upregulated SLC1A5 promotes cell growth and survival in colorectal cancer. International Journal of Clinical and Experimental Pathology 7, 60066014.
107.Commisso, C et al. (2013) Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633637.
108.Mates, JM, Campos-Sandoval, JA and Marquez, J (2018) Glutaminase isoenzymes in the metabolic therapy of cancer. Biochimica et Biophysica Acta, Reviews on Cancer 1870, 158164.
109.Martin-Rufian, M et al. (2012) Mammalian glutaminase Gls2 gene encodes two functional alternative transcripts by a surrogate promoter usage mechanism. PLoS ONE 7, e38380.
110.Cassago, A et al. (2012) Mitochondrial localization and structure-based phosphate activation mechanism of glutaminase C with implications for cancer metabolism. Proceedings of the National Academy of Sciences of the United States of America 109, 10921097.
111.van den Heuvel, AP et al. (2012) Analysis of glutamine dependency in non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth. Cancer Biology & Therapy 13, 11851194.
112.Huang, F et al. (2014) Expression of glutaminase is upregulated in colorectal cancer and of clinical significance. International Journal of Clinical and Experimental Pathology 7, 10931100.
113.Pan, T et al. (2015) Elevated expression of glutaminase confers glucose utilization via glutaminolysis in prostate cancer. Biochemical and Biophysical Research Communications 456, 452458.
114.Moreadith, RW and Lehninger, AL (1984) The pathways of glutamate and glutamine oxidation by tumor cell mitochondria. Role of mitochondrial NAD(P) + -dependent malic enzyme. Journal of Biological Chemistry 259, 62156221.
115.Coloff, JL et al. (2016) Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. Cell Metabolism 23, 867880.
116.Gaglio, D et al. (2011) Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Molecular Systems Biology 7, 523.
117.Wise, DR et al. (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proceedings of the National Academy of Sciences of the United States of America 105, 18782–7.
118.Gao, P et al. (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762765.
119.Bott, AJ et al. (2015) Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation. Cell Metabolism 22, 10681077.
120.Hu, W et al. (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proceedings of the National Academy of Sciences of the United States of America 107, 74557460.
121.DeBerardinis, RJ et al. (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proceedings of the National Academy of Sciences of the United States of America 104, 1934519350.
122.Yang, C et al. (2014) Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Molecular Cell 56, 414424.
123.Metallo, CM et al. (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380384.
124.Hatzivassiliou, G et al. (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311321.
125.Yuneva, M et al. (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. Journal of Cell Biology 178, 93105.
126.Jiang, L et al. (2016) Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255258.
127.Conti, PS et al. (1996) PET and [18F]-FDG in oncology: a clinical update. Nuclear Medicine and Biology 23, 717735.
128.Zhu, L et al. (2017) Metabolic imaging of glutamine in cancer. Journal of Nuclear Medicine 58, 533537.
129.Li, C et al. (2018) Preclinical study of an (18)F-labeled glutamine derivative for cancer imaging. Nuclear Medicine and Biology 64–65, 3440.
130.Farber, S et al. (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). New England Journal of Medicine 238, 787793.
131.Purcell, WT and Ettinger, DS (2003) Novel antifolate drugs. Current Oncology Reports 5, 114125.
132.Gonen, N and Assaraf, YG (2012) Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resistance Updates 15, 183210.
133.Karran, P and Attard, N (2008) Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nature Reviews Cancer 8, 24.
134.Longley, DB, Harkin, DP and Johnston, PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nature Reviews Cancer 3, 330338.
135.Parker, WB (2009) Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chemical Reviews 109, 28802893.
136.Labak, CM et al. (2016) Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment. American Journal of Cancer Research 6, 15991608.
137.Flaig, TW et al. (2007) A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Investigational New Drugs 25, 139146.
138.Woodward, GE and Hudson, MT (1954) The effect of 2-desoxy-d-glucose on glycolysis and respiration of tumor and normal tissues. Cancer Research 14, 599605.
139.Wick, AN et al. (1957) Localization of the primary metabolic block produced by 2-deoxyglucose. Journal of Biological Chemistry 224, 963969.
140.Crane, RK and Sols, A (1954) The non-competitive inhibition of brain hexokinase by glucose-6-phosphate and related compounds. Journal of Biological Chemistry 210, 597606.
141.Voss, M et al. (2018) Rescue of 2-deoxyglucose side effects by ketogenic diet. International Journal of Molecular Sciences 19, 2462.
142.Zhang, D et al. (2014) 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Letters 355, 176183.
143.Goldman, RD, Kaplan, NO and Hall, TC (1964) Lactic dehydrogenase in human neoplastic tissues. Cancer Research 24(3 Part 1), 389399.
144.Xie, H et al. (2014) Targeting lactate dehydrogenase-a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metabolism 19(5), 795809.
145.Fantin, VR, St-Pierre, J and Leder, P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6), 425434.
146.Rani, R and Kumar, V (2016) Recent Update on Human Lactate Dehydrogenase Enzyme 5 (hLDH5) Inhibitors: A Promising Approach for Cancer Chemotherapy. Journal of Medicinal Chemistry 59(2), 487496.
147.Wang, J et al. (2015) AT-101 inhibits hedgehog pathway activity and cancer growth. Cancer Chemotherapy and Pharmacology 76(3), 461469.
148.Izumi, H et al. (2011) Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Science 102(5), 10071013.
149.Sonveaux, P et al. (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. Journal of Clinical Investigation 118, 39303942.
150.Quanz, M et al. (2018) Preclinical efficacy of the novel monocarboxylate transporter 1 inhibitor BAY-8002 and associated markers of resistance. Molecular Cancer Therapeutics 17, 22852296.
151.Curtis, NJ et al. (2017) Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity. Oncotarget 8, 6921969236.
152.Polanski, R et al. (2014) Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clinical Cancer Research 20, 926937.
153.Benjamin, D et al. (2016) Syrosingopine sensitizes cancer cells to killing by metformin. Science Advances 2, e1601756.
154.Benjamin, D et al. (2018) Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD + depletion in cancer cells. Cell Reports 25, 30473058, e4.
155.Kourelis, TV and Siegel, RD (2012) Metformin and cancer: new applications for an old drug. Medical Oncology (Northwood, London, England) 29, 13141327.
156.Liu, Y et al. (2012) A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Molecular Cancer Therapeutics 11, 16721682.
157.Chan, DA et al. (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Science Translational Medicine 3, 94ra70.
158.Popovici-Muller, J et al. (2018) Discovery of AG-120 (Ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Medicinal Chemistry Letters 9, 300305.
159.Shih, AH et al. (2014) AG-221, a small molecule mutant IDH2 inhibitor, remodels the epigenetic state of IDH2-mutant cells and induces alterations in self-renewal/differentiation in IDH2-mutant AML model in vivo. Blood 124, 437437.
160.Dhillon, S (2018) Ivosidenib: first global approval. Drugs 78, 15091516.
161.Dugan, J and Pollyea, D (2018) Enasidenib for the treatment of acute myeloid leukemia. Expert Review of Clinical Pharmacology 11, 755760.
162.Raineri, S and Mellor, J (2018) IDH1: linking metabolism and epigenetics. Frontiers in Genetics 9(493), 18.
163.Buege, MJ, DiPippo, AJ and DiNardo, CD (2018) Evolving treatment strategies for elderly leukemia patients with IDH mutations. Cancers (Basel) 10 (6), 120.
164.Pacold, ME et al. (2016) A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nature Chemical Biology 12, 452.
165.Mullarky, E et al. (2016) Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proceedings of the National Academy of Sciences 113, 17781783.
166.Wang, Q et al. (2017) Rational design of selective allosteric inhibitors of PHGDH and serine synthesis with anti-tumor activity. Cell Chemical Biology 24, 5565.
167.Unterlass, JE et al. (2016) Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer. Oncotarget 9, 1313913153.
168.Fuller, N et al. (2016) An improved model for fragment-based lead generation at AstraZeneca. Drug Discovery Today 21, 12721283.
169.Esslinger, CS, Cybulski, KA and Rhoderick, JF (2005) Ngamma-aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site. Bioorganic & Medicinal Chemistry 13, 11111118.
170.Hassanein, M et al. (2015) Targeting SLC1a5-mediated glutamine dependence in non-small cell lung cancer. International Journal of Cancer 137, 15871597.
171.Bolzoni, M et al. (2016) Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target. Blood 128, 667679.
172.Wang, Q et al. (2015) Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. The Journal of Pathology 236, 278289.
173.Broer, A, Rahimi, F and Broer, S (2016) Deletion of amino acid transporter ASCT2 (SLC1A5) reveals an essential role for transporters SNAT1 (SLC38A1) and SNAT2 (SLC38A2) to sustain glutaminolysis in cancer cells. Journal of Biological Chemistry 291, 1319413205.
174.Chiu, M et al. (2017) GPNA inhibits the sodium-independent transport system L for neutral amino acids. Amino Acids 49, 13651372.
175.Grewer, C and Grabsch, E (2004) New inhibitors for the neutral amino acid transporter ASCT2 reveal its Na + -dependent anion leak. Journal of Physiology 557(Pt 3), 747759.
176.van Geldermalsen, M et al. (2018) Benzylserine inhibits breast cancer cell growth by disrupting intracellular amino acid homeostasis and triggering amino acid response pathways. BMC Cancer 18, 689.
177.Colas, C et al. (2015) Ligand discovery for the alanine-serine-cysteine transporter (ASCT2, SLC1A5) from homology modeling and virtual screening. PLoS Computational Biology 11, e1004477.
178.Newcomb, RW (2002) Patent US6451828B1, Selective inhibition of glutaminase by bis-thiadiazoles.
179.DeLaBarre, B et al. (2011) Full-length human glutaminase in complex with an allosteric inhibitor. Biochemistry 50, 1076410770.
180.Robinson, MM et al. (2007) Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochemical Journal 406, 407414.
181.Gross, MI et al. (2014) Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Molecular Cancer Therapeutics 13, 890901.
182.Liang, Y, Bromley, SD and Orford, K (2018) Patent WO2018039442A1, Treatment of cancer with inhibitors of glutaminase.
183.Wang, JB et al. (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207219.
184.Stalnecker, CA et al. (2015) Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells. Proceedings of the National Academy of Sciences of the United States of America 112, 394399.
185.Li, C et al. (2006) Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. Journal of Biological Chemistry 281, 1021410221.
186.Qing, G et al. (2012) ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631644.
187.Yang, C et al. (2009) Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Research 69, 79867993.
188.Jin, L et al. (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27, 257270.
189.Reed, HT et al. (1985) Amino-oxyacetic acid as a palliative in tinnitus. Archives of Otolaryngology 111, 803805.
190.Guth, PS et al. (1990) Evaluation of amino-oxyacetic acid as a palliative in tinnitus. Annals of Otology Rhinology & Laryngology 99, 7479.
191.Perry, TL et al. (1980) Failure of aminooxyacetic acid therapy in Huntington disease. Neurology 30(7 Pt 1), 772775.
192.Thornburg, JM et al. (2008) Targeting aspartate aminotransferase in breast cancer. Breast Cancer Research 10, R84.
193.Korangath, P et al. (2015) Targeting glutamine metabolism in breast cancer with aminooxyacetate. Clinical Cancer Research 21, 32633273.


Warburg and Krebs and related effects in cancer

  • Judith E. Unterlass (a1) and Nicola J. Curtin (a2)


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