Abstract
After more than half of century since the Warburg effect was described, this atypical metabolism has been standing true for almost every type of cancer, exhibiting higher glycolysis and lactate metabolism and defective mitochondrial ATP production. This phenomenon had attracted many scientists to the problem of elucidating the mechanism of, and reason for, this effect. Several models based on oncogenic studies have been proposed, such as the accumulation of mitochondrial gene mutations, the switch from oxidative phosphorylation respiration to glycolysis, the enhancement of lactate metabolism, and the alteration of glycolytic genes. Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear. Although there are some pharmacological compounds, such as 2-deoxy-D-glucose, dichloroacetic acid, and 3-bromopyruvate, therapeutic strategies, including diet, have been developed based on targeting the Warburg effect. In this review, we will revisit the Warburg effect to determine how much scientists currently understand about this phenomenon and how we can treat the cancer based on targeting metabolism.
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Warburg, O. (1915) Notizen zur Entwickelungsphysiologie des Seeigeleies. Arch. f. d. ges. Physiol., 160, 324–332.
Warburg, O. (1923) Versuche an überlebendem Carcinom-Gewebe (Methoden). Biochem. Zeitschr., 142, 317–333.
Warburg, O. (1924) Verbesserte Methode zur Messung der Atmung und Glykolyse. Biochem. Zeitschr., 152, 51–63.
Warburg, O. (1956) On the origin of cancer cells. Science, 123, 309–314.
Warburg, O. (1956) On respiratory impairment in cancer cells. Science, 124, 269–270.
Chance, B. and Castor, L.N. (1952) Some patterns of the respiratory pigments of ascites tumors of mice. Science, 116, 200–202.
Weinhouse, S. (1956) On respiratory impairment in cancer cells. Science, 124, 267–269.
Hanahan, D. and Weinberg, R.A. (2000) The hallmarks of cancer. Cell, 100, 57–70.
Yeung, S.J., Pan, J. and Lee, M.H. (2008) Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell. Mol. Life Sci., 65, 3981–3999.
Gatenby, R.A. and Gillies, R.J. (2004) Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer, 4, 891–899.
Brand, K.A. and Hermfisse, U. (1997) Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J., 11, 388–395.
Spitz, D.R., Sim, J.E., Ridnour, L.A., Galoforo, S.S. and Lee, Y.J. (2000) Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? Ann. N. Y. Acad. Sci., 899, 349–362.
Elf, S.E. and Chen, J. (2014) Targeting glucose metabolism in patients with cancer. Cancer, 120, 774–780.
Hamanaka, R.B. and Chandel, N.S. (2009) Mitochondrial reactive oxygen species regulate hypoxic signaling. Curr. Opin. Cell Biol., 21, 894–899.
Hatefi, Y. (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu. Rev. Biochem., 54, 1015–1069.
Boguski, M.S., Lowe, T.M. and Tolstoshev, C.M. (1993) dbEST--database for “expressed sequence tags”. Nat. Genet., 4, 332–333.
Altenberg, B. and Greulich, K.O. (2004) Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics, 84, 1014–1020.
Nachmansohn, D. (1979) German-Jewish Pioneers in Science, Springer, New York, pp. 1900–1933.
Koppenol, W.H., Bounds, P.L. and Dang, C.V. (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer, 11, 325–337.
Parsons, D.W., Jones, S., Zhang, X., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.M., Gallia, G.L., Olivi, A., McLendon, R., Rasheed, B.A., Keir, S., Nikolskaya, T., Nikolsky, Y., Busam, D.A., Tekleab, H., Diaz, L.A., Jr., Hartigan, J., Smith, D.R., Strausberg, R.L., Marie, S.K., Shinjo, S.M., Yan, H., Riggins, G.J., Bigner, D.D., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V.E. and Kinzler, K.W. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science, 321, 1807–1812.
Bayley, J.P. and Devilee, P. (2010) Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Curr. Opin. Genet. Dev., 20, 324–329.
Baysal, B.E., Willett-Brozick, J.E., Lawrence, E.C., Drovdlic, C.M., Savul, S.A., McLeod, D.R., Yee, H.A., Brackmann, D.E., Slattery, W.H., 3rd, Myers, E.N., Ferrell, R.E. and Rubinstein, W.S. (2002) Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J. Med. Genet., 39, 178–183.
Baysal, B.E. (2007) A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia. PLoS ONE, 2, e436.
Tomlinson, I.P., Alam, N.A., Rowan, A.J., Barclay, E., Jaeger, E.E., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R.R., Olpin, S., Bevan, S., Barker, K., Hearle, N., Houlston, R.S., Kiuru, M., Lehtonen, R., Karhu, A., Vilkki, S., Laiho, P., Eklund, C., Vierimaa, O., Aittomaki, K., Hietala, M., Sistonen, P., Paetau, A., Salovaara, R., Herva, R., Launonen, V., Aaltonen, L.A. and Multiple Leiomyoma Consortium (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet., 30, 406–410.
Semenza, G.L. (2012) Hypoxia-inducible factors in physiology and medicine. Cell, 148, 399–408.
Martin-Puig, S., Temes, E., Olmos, G., Jones, D.R., Aragones, J. and Landazuri, M.O. (2004) Role of iron (II)-2-oxoglutarate-dependent dioxygenases in the generation of hypoxia-induced phosphatidic acid through HIF-1/2 and von Hippel-Lindau-independent mechanisms. J. Biol. Chem., 279, 9504–9511.
Chen, H. and Costa, M. (2009) Iron- and 2-oxoglutarate-dependent dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity. Biometals, 22, 191–196.
Isaacs, J.S., Jung, Y.J., Mole, D.R., Lee, S., Torres-Cabala, C., Chung, Y.L., Merino, M., Trepel, J., Zbar, B., Toro, J., Ratcliffe, P.J., Linehan, W.M. and Neckers, L. (2005) HIF over-expression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell, 8, 143–153.
King, A., Selak, M.A. and Gottlieb, E. (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene, 25, 4675–4682.
Goda, N. and Kanai, M. (2012) Hypoxia-inducible factors and their roles in energy metabolism. Int. J. Hematol., 95, 457–463.
Kim, J.W., Tchernyshyov, I., Semenza, G.L. and Dang, C.V. (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab., 3, 177–185.
Semenza, G.L., Roth, P.H., Fang, H.M. and Wang, G.L. (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem., 269, 23757–23763.
Gordan, J.D., Thompson, C.B. and Simon, M.C. (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell, 12, 108–113.
Selak, M.A., Armour, S.M., MacKenzie, E.D., Boulahbel, H., Watson, D.G., Mansfield, K.D., Pan, Y., Simon, M.C., Thompson, C.B. and Gottlieb, E. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7, 77–85.
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.H., Ito, S., Yang, C., Wang, P., Xiao, M.T., Liu, L.X., Jiang, W.Q., Liu, J., Zhang, J.Y., Wang, B., Frye, S., Zhang, Y., Xu, Y.H., Lei, Q.Y., Guan, K.L., Zhao, S.M. and Xiong, Y. (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell, 19, 17–30.
Matoba, S., Kang, J.G., Patino, W.D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P.J., Bunz, F. and Hwang, P.M. (2006) p53 regulates mitochondrial respiration. Science, 312, 1650–1653.
Capuano, F., Guerrieri, F. and Papa, S. (1997) Oxidative phosphorylation enzymes in normal and neoplastic cell growth. J. Bioenerg. Biomembr., 29, 379–384.
Lopez-Rios, F., Sanchez-Arago, M., Garcia-Garcia, E., Ortega, A.D., Berrendero, J.R., Pozo-Rodriguez, F., Lopez-Encuentra, A., Ballestin, C. and Cuezva, J.M. (2007) Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res., 67, 9013–9017.
Reitman, Z.J. and Yan, H. (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J. Natl. Cancer Inst., 102, 932–941.
Gross, S., Cairns, R.A., Minden, M.D., Driggers, E.M., Bittinger, M.A., Jang, H.G., Sasaki, M., Jin, S., Schenkein, D.P., Su, S.M., Dang, L., Fantin, V.R. and Mak, T.W. (2010) Cancer- associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med., 207, 339–344.
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., Ding, J., Lei, Q., Guan, K.L. and Xiong, Y. (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science, 324, 261–265.
Cavalli, L.R., Varella-Garcia, M. and Liang, B.C. (1997) Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth Differ., 8, 1189–1198.
Tan, A.S., Baty, J.W., Dong, L.F., Bezawork-Geleta, A., Endaya, B., Goodwin, J., Bajzikova, M., Kovarova, J., Peterka, M., Yan, B., Pesdar, E.A., Sobol, M., Filimonenko, A., Stuart, S., Vondrusova, M., Kluckova, K., Sachaphibulkij, K., Rohlena, J., Hozak, P., Truksa, J., Eccles, D., Haupt, L.M., Griffiths, L.R., Neuzil, J. and Berridge, M.V. (2015) Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab., 21, 81–94.
Okar, D.A., Manzano, A., Navarro-Sabate, A., Riera, L., Bartrons, R. and Lange, A.J. (2001) PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate. Trends Biochem. Sci., 26, 30–35.
Bensaad, K., Tsuruta, A., Selak, M.A., Vidal, M.N., Nakano, K., Bartrons, R., Gottlieb, E. and Vousden, K.H. (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126, 107–120.
Green, D.R. and Chipuk, J.E. (2006) p53 and metabolism: Inside the TIGAR. Cell, 126, 30–32.
Shim, H., Dolde, C., Lewis, B.C., Wu, C.S., Dang, G., Jungmann, R.A., Dalla-Favera, R. and Dang, C.V. (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl. Acad. Sci. U.S.A., 94, 6658–6663.
Fantin, V.R., 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, 425–434.
Cardone, R.A., Casavola, V. and Reshkin, S.J. (2005) The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat. Rev. Cancer, 5, 786–795.
Opavsky, R., Pastorekova, S., Zelnik, V., Gibadulinova, A., Stanbridge, E.J., Zavada, J., Kettmann, R. and Pastorek, J. (1996) Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics, 33, 480–487.
Ivanov, S., Liao, S.Y., Ivanova, A., Danilkovitch-Miagkova, A., Tarasova, N., Weirich, G., Merrill, M.J., Proescholdt, M.A., Oldfield, E.H., Lee, J., Zavada, J., Waheed, A., Sly, W., Lerman, M.I. and Stanbridge, E.J. (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am. J. Pathol., 158, 905–919.
Robertson, N., Potter, C. and Harris, A.L. (2004) Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res., 64, 6160–6165.
Secomb, T.W., Hsu, R., Dewhirst, M.W., Klitzman, B. and Gross, J.F. (1993) Analysis of oxygen transport to tumor tissue by microvascular networks. Int. J. Radiat. Oncol. Biol. Phys., 25, 481–489.
Heldin, C.H., Rubin, K., Pietras, K. and Ostman, A. (2004) High interstitial fluid pressure - an obstacle in cancer therapy. Nat. Rev. Cancer, 4, 806–813.
Vaupel, P., Fortmeyer, H.P., Runkel, S. and Kallinowski, F. (1987) Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats. Cancer Res., 47, 3496–3503.
Minchenko, O., Opentanova, I. and Caro, J. (2003) Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family (PFKFB-1-4) expression in vivo. FEBS Lett., 554, 264–270.
Minchenko, O.H., Ogura, T., Opentanova, I.L., Minchenko, D.O. and Esumi, H. (2005) Splice isoform of 6-phosphofructo- 2-kinase/fructose-2,6-bisphosphatase-4: expression and hypoxic regulation. Mol. Cell. Biochem., 280, 227–234.
Acker, T. and Plate, K.H. (2002) A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology. J. Mol. Med., 80, 562–575.
Semenza, G.L. (2000) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol., 35, 71–103.
Barthel, A., Okino, S.T., Liao, J., Nakatani, K., Li, J., Whitlock, J.P., Jr. and Roth, R.A. (1999) Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem., 274, 20281–20286.
Taha, C., Liu, Z., Jin, J., Al-Hasani, H., Sonenberg, N. and Klip, A. (1999) Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. Role of mammalian target of rapamycin, protein kinase b, and phosphatidylinositol 3-kinase in GLUT1 mRNA translation. J. Biol. Chem., 274, 33085–33091.
Majewski, N., Nogueira, V., Bhaskar, P., Coy, P.E., Skeen, J.E., Gottlob, K., Chandel, N.S., Thompson, C.B., Robey, R.B. and Hay, N. (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell, 16, 819–830.
Majewski, N., Nogueira, V., Robey, R.B. and Hay, N. (2004) Akt inhibits apoptosis downstream of BID cleavage via a glucose- dependent mechanism involving mitochondrial hexokinases. Mol. Cell. Biol., 24, 730–740.
Bauer, D.E., Hatzivassiliou, G., Zhao, F., Andreadis, C. and Thompson, C.B. (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene, 24, 6314–6322.
Deberardinis, R.J., Lum, J.J. and Thompson, C.B. (2006) Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J. Biol. Chem., 281, 37372–37380.
Albanell, J., Dalmases, A., Rovira, A. and Rojo, F. (2007) mTOR signalling in human cancer. Clin. Transl. Oncol., 9, 484–493.
Chiang, G.G. and Abraham, R.T. (2007) Targeting the mTOR signaling network in cancer. Trends Mol. Med., 13, 433–442.
Martin, D.E. and Hall, M.N. (2005) The expanding TOR signaling network. Curr. Opin. Cell Biol., 17, 158–166.
Hudson, C.C., Liu, M., Chiang, G.G., Otterness, D.M., Loomis, D.C., Kaper, F., Giaccia, A.J. and Abraham, R.T. (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol. Cell. Biol., 22, 7004–7014.
Mathupala, S.P., Rempel, A. and Pedersen, P.L. (1997) Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J. Bioenerg. Biomembr., 29, 339–343.
Dang, C.V., Lewis, B.C., Dolde, C., Dang, G. and Shim, H. (1997) Oncogenes in tumor metabolism, tumorigenesis, and apoptosis. J. Bioenerg. Biomembr., 29, 345–354.
Dang, C.V. and Semenza, G.L. (1999) Oncogenic alterations of metabolism. Trends Biochem. Sci., 24, 68–72.
Lu, H., Forbes, R.A. and Verma, A. (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem., 277, 23111–23115.
Kim, J.W., Gao, P., Liu, Y.C., Semenza, G.L. and Dang, C.V. (2007) Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol., 27, 7381–7393.
Schwartzenberg-Bar-Yoseph, F., Armoni, M. and Karnieli, E. (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res., 64, 2627–2633.
Kawauchi, K., Araki, K., Tobiume, K. and Tanaka, N. (2008) p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nat. Cell Biol., 10, 611–618.
Kondoh, H., Lleonart, M.E., Gil, J., Wang, J., Degan, P., Peters, G., Martinez, D., Carnero, A. and Beach, D. (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res., 65, 177–185.
Beckert, S., Farrahi, F., Aslam, R.S., Scheuenstuhl, H., Konigsrainer, A., Hussain, M.Z. and Hunt, T.K. (2006) Lactate stimulates endothelial cell migration. Wound Repair Regen., 14, 321–324.
Vegran, F., Boidot, R., Michiels, C., Sonveaux, P. and Feron, O. (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res., 71, 2550–2560.
Draoui, N. and Feron, O. (2011) Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis. Model. Mech., 4, 727–732.
Hirschhaeuser, F., Sattler, U.G. and Mueller-Klieser, W. (2011) Lactate: a metabolic key player in cancer. Cancer Res., 71, 6921–6925.
Kurtoglu, M., Maher, J.C. and Lampidis, T.J. (2007) Differential toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy- D-glucose in hypoxic and normoxic tumor cells. Antioxid. Redox Signal., 9, 1383–1390.
Bandugula, V.R. and N, R.P. (2013) 2-Deoxy-D-glucose and ferulic acid modulates radiation response signaling in non-small cell lung cancer cells. Tumour Biol., 34, 251–259.
Giammarioli, A.M., Gambardella, L., Barbati, C., Pietraforte, D., Tinari, A., Alberton, M., Gnessi, L., Griffin, R.J., Minetti, M. and Malorni, W. (2012) Differential effects of the glycolysis inhibitor 2-deoxy-D-glucose on the activity of pro-apoptotic agents in metastatic melanoma cells, and induction of a cytoprotective autophagic response. Int. J. Cancer, 131, E337–E347.
Ralser, M., Wamelink, M.M., Struys, E.A., Joppich, C., Krobitsch, S., Jakobs, C. and Lehrach, H. (2008) A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth. Proc. Natl. Acad. Sci. U.S.A., 105, 17807–17811.
Urakami, K., Zangiacomi, V., Yamaguchi, K. and Kusuhara, M. (2013) Impact of 2-deoxy-D-glucose on the target metabolome profile of a human endometrial cancer cell line. Biomed. Res., 34, 221–229.
Robinson, G.L., Dinsdale, D., Macfarlane, M. and Cain, K. (2012) Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL. Oncogene, 31, 4996–5006.
Zagorodna, O., Martin, S.M., Rutkowski, D.T., Kuwana, T., Spitz, D.R. and Knudson, C.M. (2012) 2-Deoxyglucose-induced toxicity is regulated by Bcl-2 family members and is enhanced by antagonizing Bcl-2 in lymphoma cell lines. Oncogene, 31, 2738–2749.
Golding, J.P., Wardhaugh, T., Patrick, L., Turner, M., Phillips, J.B., Bruce, J.I. and Kimani, S.G. (2013) Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy. Br. J. Cancer, 109, 976–982.
Kim, S.M., Yun, M.R., Hong, Y.K., Solca, F., Kim, J.H., Kim, H.J. and Cho, B.C. (2013) Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation. Mol. Cancer Ther., 12, 2145–2156.
Wood, T.E., Dalili, S., Simpson, C.D., Hurren, R., Mao, X., Saiz, F.S., Gronda, M., Eberhard, Y., Minden, M.D., Bilan, P.J., Klip, A., Batey, R.A. and Schimmer, A.D. (2008) A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death. Mol. Cancer Ther., 7, 3546–3555.
Yamaguchi, R., Janssen, E., Perkins, G., Ellisman, M., Kitada, S. and Reed, J.C. (2011) Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy. PLoS ONE, 6, e24102.
Maher, J.C., Wangpaichitr, M., Savaraj, N., Kurtoglu, M. and Lampidis, T.J. (2007) Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Mol. Cancer Ther., 6, 732–741.
Raez, L.E., Papadopoulos, K., Ricart, A.D., Chiorean, E.G., Dipaola, R.S., Stein, M.N., Rocha Lima, C.M., Schlesselman, J.J., Tolba, K., Langmuir, V.K., Kroll, S., Jung, D.T., Kurtoglu, M., Rosenblatt, J. and Lampidis, T.J. (2013) A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother. Pharmacol., 71, 523–530.
Stacpoole, P.W. (1969) Review of the pharmacologic and therapeutic effects of diisopropylammonium dichloroacetate (DIPA). J. Clin. Pharmacol. J. New Drugs, 9, 282–291.
Stacpoole, P.W. and Felts, J.M. (1970) Diisopropylammonium dichloroacetate (DIPA) and sodium dichloracetate (DCA): effect on glucose and fat metabolism in normal and diabetic tissue. Metabolism, 19, 71–78.
Whitehouse, S. and Randle, P.J. (1973) Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate (Short Communication). Biochem. J., 134, 651–653.
Stacpoole, P.W., Moore, G.W. and Kornhauser, D.M. (1978) Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N. Engl. J. Med., 298, 526–530.
Stacpoole, P.W. (1989) The pharmacology of dichloroacetate. Metabolism, 38, 1124–1144.
Bersin, R.M. and Stacpoole, P.W. (1997) Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am. Heart J., 134, 841–855.
Stacpoole, P.W., Harman, E.M., Curry, S.H., Baumgartner, T.G. and Misbin, R.I. (1983) Treatment of lactic acidosis with dichloroacetate. N. Engl. J. Med., 309, 390–396.
Stacpoole, P.W., Wright, E.C., Baumgartner, T.G., Bersin, R.M., Buchalter, S., Curry, S.H., Duncan, C.A., Harman, E.M., Henderson, G.N., Jenkinson, S., et al. (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N. Engl. J. Med., 327, 1564–1569.
Stacpoole, P.W., Kerr, D.S., Barnes, C., Bunch, S.T., Carney, P.R., Fennell, E.M., Felitsyn, N.M., Gilmore, R.L., Greer, M., Henderson, G.N., Hutson, A.D., Neiberger, R.E., O’Brien, R.G., Perkins, L.A., Quisling, R.G., Shroads, A.L., Shuster, J.J., Silverstein, J.H., Theriaque, D.W. and Valenstein, E. (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics, 117, 1519–1531.
Stacpoole, P.W., Gilbert, L.R., Neiberger, R.E., Carney, P.R., Valenstein, E., Theriaque, D.W. and Shuster, J.J. (2008) Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics, 121, e1223–e1228.
Berendzen, K., Theriaque, D.W., Shuster, J. and Stacpoole, P.W. (2006) Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion, 6, 126–135.
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. and De Vivo, D.C. (2006) Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology, 66, 324–330.
Zhou, Z.H., McCarthy, D.B., O’Connor, C.M., Reed, L.J. and Stoops, J.K. (2001) The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proc. Natl. Acad. Sci. U.S.A., 98, 14802–14807.
Smolle, M., Prior, A.E., Brown, A.E., Cooper, A., Byron, O. and Lindsay, J.G. (2006) A new level of architectural complexity in the human pyruvate dehydrogenase complex. J. Biol. Chem., 281, 19772–19780.
Brautigam, C.A., Wynn, R.M., Chuang, J.L., Machius, M., Tomchick, D.R. and Chuang, D.T. (2006) Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex. Structure, 14, 611–621.1
Bowker-Kinley, M.M., Davis, W.I., Wu, P., Harris, R.A. and Popov, K.M. (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem. J., 329, 191–196.
Huang, B., Wu, P., Popov, K.M. and Harris, R.A. (2003) Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney. Diabetes, 52, 1371–1376.
Motojima, K. and Seto, K. (2003) Fibrates and statins rapidly and synergistically induce pyruvate dehydrogenase kinase 4 mRNA in the liver and muscles of mice. Biol. Pharm. Bull., 26, 954–958.
Hsieh, M.C., Das, D., Sambandam, N., Zhang, M.Q. and Nahle, Z. (2008) Regulation of the PDK4 isozyme by the Rb-E2F1 complex. J. Biol. Chem., 283, 27410–27417.
Velpula, K.K., Bhasin, A., Asuthkar, S. and Tsung, A.J. (2013) Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect. Cancer Res., 73, 7277–7289.
Heshe, D., Hoogestraat, S., Brauckmann, C., Karst, U., Boos, J. and Lanvers-Kaminsky, C. (2011) Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs. Cancer Chemother. Pharmacol., 67, 647–655.
Roche, T.E., Baker, J.C., Yan, X., Hiromasa, Y., Gong, X., Peng, T., Dong, J., Turkan, A. and Kasten, S.A. (2001) Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Prog. Nucleic Acid Res. Mol. Biol., 70, 33–75.
Bao, H., Kasten, S.A., Yan, X. and Roche, T.E. (2004) Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP. Biochemistry, 43, 13432–13441.
Kato, M., Li, J., Chuang, J.L. and Chuang, D.T. (2007) Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure, 15, 992–1004.
Klyuyeva, A., Tuganova, A. and Popov, K.M. (2007) Amino acid residues responsible for the recognition of dichloroacetate by pyruvate dehydrogenase kinase 2. FEBS Lett., 581, 2988–2992.
Li, J., Kato, M. and Chuang, D.T. (2009) Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J. Biol. Chem., 284, 34458–34467.
Evans, O.B. and Stacpoole, P.W. (1982) Prolonged hypolactatemia and increased total pyruvate dehydrogenase activity by dichloroacetate. Biochem. Pharmacol., 31, 1295–1300.
Curry, S.H., Chu, P.I., Baumgartner, T.G. and Stacpoole, P.W. (1985) Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate. Clin. Pharmacol. Ther., 37, 89–93.
Stacpoole, P.W., Nagaraja, N.V. and Hutson, A.D. (2003) Efficacy of dichloroacetate as a lactate-lowering drug. J. Clin. Pharmacol., 43, 683–691.
Morten, K.J., Caky, M. and Matthews, P.M. (1998) Stabilization of the pyruvate dehydrogenase E1alpha subunit by dichloroacetate. Neurology, 51, 1331–1335.
Han, Z., Berendzen, K., Zhong, L., Surolia, I., Chouthai, N., Zhao, W., Maina, N., Srivastava, A. and Stacpoole, P.W. (2008) A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate. Mol. Genet. Metab., 93, 381–387.
Ishida, N., Kitagawa, M., Hatakeyama, S. and Nakayama, K. (2000) Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability. J. Biol. Chem., 275, 25146–25154.
Lu, K.P., Liou, Y.C. and Zhou, X.Z. (2002) Pinning down proline-directed phosphorylation signaling. Trends Cell Biol., 12, 164–172.
Virshup, D.M., Eide, E.J., Forger, D.B., Gallego, M. and Harnish, E.V. (2007) Reversible protein phosphorylation regulates circadian rhythms. Cold Spring Harb. Symp. Quant. Biol., 72, 413–420.
Moretto-Zita, M., Jin, H., Shen, Z., Zhao, T., Briggs, S.P. and Xu, Y. (2010) Phosphorylation stabilizes Nanog by promoting its interaction with Pin1. Proc. Natl. Acad. Sci. U.S.A., 107, 13312–13317.
Ozlu, N., Akten, B., Timm, W., Haseley, N., Steen, H. and Steen, J.A. (2010) Phosphoproteomics. Wiley Interdiscip. Rev. Syst. Biol. Med., 2, 255–276.
Thomas, L.W., Lam, C. and Edwards, S.W. (2010) Mcl-1; the molecular regulation of protein function. FEBS Lett., 584, 2981–2989.
Geschwind, J.F., Georgiades, C.S., Ko, Y.H. and Pedersen, P.L. (2004) Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev. Anticancer Ther., 4, 449–457.
Buijs, M., Vossen, J.A., Geschwind, J.F., Ishimori, T., Engles, J.M., Acha-Ngwodo, O., Wahl, R.L. and Vali, M. (2009) Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer. Invest. New Drugs, 27, 120–123.
Ko, Y.H., Smith, B.L., Wang, Y., Pomper, M.G., Rini, D.A., Torbenson, M.S., Hullihen, J. and Pedersen, P.L. (2004) Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem. Biophys. Res. Commun., 324, 269–275.
Danial, N.N., Gramm, C.F., Scorrano, L., Zhang, C.Y., Krauss, S., Ranger, A.M., Datta, S.R., Greenberg, M.E., Licklider, L.J., Lowell, B.B., Gygi, S.P. and Korsmeyer, S.J. (2003) BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature, 424, 952–956.
Ganapathy-Kanniappan, S., Geschwind, J.F., Kunjithapatham, R., Buijs, M., Vossen, J.A., Tchernyshyov, I., Cole, R.N., Syed, L.H., Rao, P.P., Ota, S. and Vali, M. (2009) Glyceraldehyde- 3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death. Anticancer Res., 29, 4909–4918.
Ihrlund, L.S., Hernlund, E., Khan, O. and Shoshan, M.C. (2008) 3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Mol. Oncol., 2, 94–101.
Vali, M., Vossen, J.A., Buijs, M., Engles, J.M., Liapi, E., Ventura, V.P., Khwaja, A., Acha-Ngwodo, O., Ganapathy-Kanniappan, S., Syed, L., Wahl, R.L. and Geschwind, J.F. (2008) Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study. J. Pharmacol. Exp. Ther., 327, 32–37.
Xu, R.H., Pelicano, H., Zhou, Y., Carew, J.S., Feng, L., Bhalla, K.N., Keating, M.J. and Huang, P. (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res., 65, 613–621.
Blagosklonny, M.V. (2010) Linking calorie restriction to longevity through sirtuins and autophagy: any role for TOR. Cell Death Dis., 1, e12.
Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., Michaud, M., Madeo, F., Tavernarakis, N. and Kroemer, G. (2010) Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis., 1, e10.
Willcox, D.C., Willcox, B.J., Todoriki, H. and Suzuki, M. (2009) The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load. J. Am. Coll. Nutr., 28 Suppl, 500S-516S.
Ho, V.W., Leung, K., Hsu, A., Luk, B., Lai, J., Shen, S.Y., Minchinton, A.I., Waterhouse, D., Bally, M.B., Lin, W., Nelson, B.H., Sly, L.M. and Krystal, G. (2011) A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res., 71, 4484–4493.
Bowker, S.L., Majumdar, S.R., Veugelers, P. and Johnson, J.A. (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care, 29, 254–258.
Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., Alessi, D.R. and Morris, A.D. (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ, 330, 1304–1305.
Nicklin, P., Bergman, P., Zhang, B., Triantafellow, E., Wang, H., Nyfeler, B., Yang, H., Hild, M., Kung, C., Wilson, C., Myer, V.E., MacKeigan, J.P., Porter, J.A., Wang, Y.K., Cantley, L.C., Finan, P.M. and Murphy, L.O. (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 136, 521–534.
Venkateswaran, V. and Klotz, L.H. (2010) Diet and prostate cancer: mechanisms of action and implications for chemoprevention. Nat. Rev. Urol., 7, 442–453.
Nomura, D.K., Long, J.Z., Niessen, S., Hoover, H.S., Ng, S.W. and Cravatt, B.F. (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell, 140, 49–61.
Hursting, S.D., Lavigne, J.A., Berrigan, D., Perkins, S.N. and Barrett, J.C. (2003) Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu. Rev. Med., 54, 131–152.
El Mjiyad, N., Caro-Maldonado, A., Ramirez-Peinado, S. and Munoz-Pinedo, C. (2011) Sugar-free approaches to cancer cell killing. Oncogene, 30, 253–264.
Lee, C. and Longo, V.D. (2011) Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene, 30, 3305–3316.
Wallace, D.C. (2012) Mitochondria and cancer. Nat. Rev. Cancer, 12, 685–698.
Galluzzi, L., Kepp, O. and Kroemer, G. (2012) Mitochondria: master regulators of danger signalling. Nat. Rev. Mol. Cell Biol., 13, 780–788.
Cheon, J.M., Kim, D.I. and Kim, K.S. (2015) Insulin sensitivity improvement of fermented Korean Red Ginseng (Panax ginseng) mediated by insulin resistance hallmarks in old-aged ob/ob mice. J. Ginseng Res., 39, 331–337.
Kim, A.Y., Kwak, J.H., Je, N.K., Lee, Y.H. and Jung, Y.S. (2015) Epithelial-mesenchymal transition is associated with acquired resistance to 5-fluorocuracil in HT-29 colon cancer cells. Toxicol. Res., 31, 151–156.
Kim, I.S., Yang, S.Y., Han, J.H., Jung, S.H., Park, H.S. and Myung, C.S. (2015) Differential gene expression in GPR40-overexpressing pancreatic beta-cells treated with linoleic acid. Korean J. Physiol. Pharmacol., 19, 141–149.
Li, Y., Park, J., Piao, L., Kong, G., Kim, Y., Park, K.A., Zhang, T., Hong, J., Hur, G.M., Seok, J.H., Choi, S.W., Yoo, B.C., Hemmings, B.A., Brazil, D.P., Kim, S.H. and Park, J. (2013) PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage. Cell. Signal., 25, 74–84.
Na, C.H., Hong, J.H., Kim, W.S., Shanta, S.R., Bang, J.Y., Park, D., Kim, H.K. and Kim, K.P. (2015) Identification of protein markers specific for papillary renal cell carcinoma using imaging mass spectrometry. Mol. Cells, 38, 624–629.
Liu, Y., Cao, Y., Zhang, W., Bergmeier, S., Qian, Y., Akbar, H., Colvin, R., Ding, J., Tong, L., Wu, S., Hines, J. and Chen, X. (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. Mol. Cancer Ther., 11, 1672–1682.
Chan, D.A., Sutphin, P.D., Nguyen, P., Turcotte, S., Lai, E.W., Banh, A., Reynolds, G.E., Chi, J.T., Wu, J., Solow-Cordero, D.E., Bonnet, M., Flanagan, J.U., Bouley, D.M., Graves, E.E., Denny, W.A., Hay, M.P. and Giaccia, A.J. (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med., 3, 94ra70.
Anastasiou, D., Yu, Y., Israelsen, W.J., Jiang, J.K., Boxer, M.B., Hong, B.S., Tempel, W., Dimov, S., Shen, M., Jha, A., Yang, H., Mattaini, K.R., Metallo, C.M., Fiske, B.P., Courtney, K.D., Malstrom, S., Khan, T.M., Kung, C., Skoumbourdis, A.P., Veith, H., Southall, N., Walsh, M.J., Brimacombe, K.R., Leister, W., Lunt, S.Y., Johnson, Z.R., Yen, K.E., Kunii, K., Davidson, S.M., Christofk, H.R., Austin, C.P., Inglese, J., Harris, M.H., Asara, J.M., Stephanopoulos, G., Salituro, F.G., Jin, S., Dang, L., Auld, D.S., Park, H.W., Cantley, L.C., Thomas, C.J. and Vander Heiden, M.G. (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat. Chem. Biol., 8, 839–847.
Kung, C., Hixon, J., Choe, S., Marks, K., Gross, S., Murphy, E., DeLaBarre, B., Cianchetta, G., Sethumadhavan, S., Wang, X., Yan, S., Gao, Y., Fang, C., Wei, W., Jiang, F., Wang, S., Qian, K., Saunders, J., Driggers, E., Woo, H.K., Kunii, K., Murray, S., Yang, H., Yen, K., Liu, W., Cantley, L.C., Vander Heiden, M.G., Su, S.M., Jin, S., Salituro, F.G. and Dang, L. (2012) Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem. Biol., 19, 1187–1198.
Le, A., Cooper, C.R., Gouw, A.M., Dinavahi, R., Maitra, A., Deck, L.M., Royer, R.E., Vander Jagt, D.L., Semenza, G.L. and Dang, C.V. (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl. Acad. Sci. U.S.A., 107, 2037–2042.
Bhardwaj, R., Sharma, P.K., Jadon, S.P. and Varshney, R. (2012) A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces cell cycle arrest and apoptosis selectively in irradiated human malignant cells. Tumour Biol., 33, 1021–1030.
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. and Dewhirst, M.W. (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest., 118, 3930–3942.
Michelakis, E.D., Webster, L. and Mackey, J.R. (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer, 99, 989–994.
Strum, S.B., Adalsteinsson, O., Black, R.R., Segal, D., Peress, N.L. and Waldenfels, J. (2013) Case report: Sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin’s lymphoma after disease progression with rituximab-CHOP. J. Bioenerg. Biomembr., 45, 307–315.
Addie, M., Ballard, P., Buttar, D., Crafter, C., Currie, G., Davies, B.R., Debreczeni, J., Dry, H., Dudley, P., Greenwood, R., Johnson, P.D., Kettle, J.G., Lane, C., Lamont, G., Leach, A., Luke, R.W., Morris, J., Ogilvie, D., Page, K., Pass, M., Pearson, S. and Ruston, L. (2013) Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J. Med. Chem., 56, 2059–2073.
Lin, J., Sampath, D., Nannini, M.A., Lee, B.B., Degtyarev, M., Oeh, J., Savage, H., Guan, Z., Hong, R., Kassees, R., Lee, L.B., Risom, T., Gross, S., Liederer, B.M., Koeppen, H., Skelton, N.J., Wallin, J.J., Belvin, M., Punnoose, E., Friedman, L.S. and Lin, K. (2013) Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin. Cancer Res., 19, 1760–1772.
Dumble, M., Crouthamel, M.C., Zhang, S.Y., Schaber, M., Levy, D., Robell, K., Liu, Q., Figueroa, D.J., Minthorn, E.A., Seefeld, M.A., Rouse, M.B., Rabindran, S.K., Heerding, D.A. and Kumar, R. (2014) Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS ONE, 9, e100880.
Hirai, H., Sootome, H., Nakatsuru, Y., Miyama, K., Taguchi, S., Tsujioka, K., Ueno, Y., Hatch, H., Majumder, P.K., Pan, B.S. and Kotani, H. (2010) MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol. Cancer Ther., 9, 1956–1967.
Chen, X., Qian, Y. and Wu, S. (2015) The Warburg effect: evolving interpretations of an established concept. Free Radic. Biol. Med., 79, 253–263.
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Tran, Q., Lee, H., Park, J. et al. Targeting Cancer Metabolism - Revisiting the Warburg Effects. Toxicol Res. 32, 177–193 (2016). https://doi.org/10.5487/TR.2016.32.3.177
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DOI: https://doi.org/10.5487/TR.2016.32.3.177