Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeting metabolic transformation for cancer therapy

Key Points

  • The metabolism observed in tumours is different from that of the normal tissues from which the tumours are derived. This altered metabolic phenotype allows cancer cells to accommodate increased metabolic demands and adapt to environmental changes.

  • Specific alterations in metabolic pathways may generate opportunities to design new therapeutic approaches.

  • Metabolic alterations in cancer can be driven by changes in signalling pathways involving kinases such as PI3K and mTOR, and transcription factors, including hypoxia inducible factor and MYC. These are important targets for cancer therapy in general and cancer metabolism in particular.

  • Cancer cells increase their rate of glucose and glutamine metabolism for bioenergetic and anabolic purposes. These important external carbon sources are diverted to generate DNA, proteins and lipids that are required for cancer cell growth.

  • Cancer-specific isoforms of enzymes involved in energy metabolism, anabolism and adaptation to low oxygen may be new druggable targets for cancer therapy with potentially improved therapeutic indices compared with current therapy.

Abstract

Cancer therapy has long relied on the rapid proliferation of tumour cells for effective treatment. However, the lack of specificity in this approach often leads to undesirable side effects. Many reports have described various 'metabolic transformation' events that enable cancer cells to survive, suggesting that metabolic pathways might be good targets. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways of tumours. This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Targeting tumour metabolism.

References

  1. 1

    DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell. Metab. 7, 11–20 (2008).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Tennant, D. A., Duran, R. V., Boulahbel, H. & Gottlieb, E. Metabolic transformation in cancer. Carcinogenesis 30, 1269–1280 (2009).

    CAS  Article  Google Scholar 

  3. 3

    King, A. & Gottlieb, E. Glucose metabolism and programmed cell death: an evolutionary and mechanistic perspective. Curr. Opin. Cell Biol. 21, 885–893 (2009).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Pizer, E. S., Lax, S. F., Kuhajda, F. P., Pasternack, G. R. & Kurman, R. J. Fatty acid synthase expression in endometrial carcinoma: correlation with cell proliferation and hormone receptors. Cancer 83, 528–537 (1998).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Rashid, A. et al. Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am. J. Pathol. 150, 201–208 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008). This paper is the first to report the link between germline IDH1 mutations and glioma.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genet. 30, 406–410 (2002).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell. Metab. 3, 177–185 (2006).

    Article  Google Scholar 

  12. 12

    Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Atsumi, T. et al. High expression of inducible 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 62, 5881–5887 (2002).

    CAS  PubMed  Google Scholar 

  14. 14

    Moeller, B. J. et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8, 99–110 (2005).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550–562 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Cushman, S. W. & Wardzala, L. J. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. J. Biol. Chem. 255, 4758–4762 (1980).

    CAS  PubMed  Google Scholar 

  17. 17

    Suzuki, K. & Kono, T. Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc. Natl Acad. Sci. USA 77, 2542–2545 (1980).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Deprez, J., Vertommen, D., Alessi, D. R., Hue, L. & Rider, M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J. Biol. Chem. 272, 17269–17275 (1997).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Majewski, N. et al. 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 (2004).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Shackelford, D. B. & Shaw, R. J. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Gualberto, A. & Pollak, M. Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28, 3009–3021 (2009).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med. 14, 1351–1356 (2008). This paper describes the anti-tumour effects of a dual PI3K and mTOR inhibitor, suggesting a new therapeutic approach.

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Brachmann, S., Fritsch, C., Maira, S. M. & Garcia-Echeverria, C. PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr. Opin. Cell Biol. 21, 194–198 (2009).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Libby, G. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 1620–1625 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Anisimov, V. N. et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp. Gerontol. 40, 685–693 (2005).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Dowling, R. J., Zakikhani, M., Fantus, I. G., Pollak, M. & Sonenberg, N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 67, 10804–10812 (2007).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Jiralerspong, S. et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol. 27, 3297–3302 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Ewald, B., Sampath, D. & Plunkett, W. Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 27, 6522–6537 (2008).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Tong, X., Zhao, F. & Thompson, C. B. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr. Opin. Genet. Dev. 19, 32–37 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Salway, J. G. Metabolism at a Glance 20–21 (Blackwell Publishing, Oxford, UK, 2004).

    Google Scholar 

  33. 33

    Newsholme, E. A. & Board, M. Application of metbolic-control logic to fuel utilization and its significance in tumor cells. Adv. Enzyme Regul. 31, 225–246 (1985).

    Article  Google Scholar 

  34. 34

    Gambhir, S. S. Molecular imaging of cancer with positron emission tomography. Nature Rev. Cancer 2, 683–693 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Warburg, O. Metabolism of tumours. Biochem. Zeitschr. 142, 317–333 (1923).

    CAS  Google Scholar 

  36. 36

    Ely, J. O. 2-deoxy-d-glucose as an inhibitor of cancerous growth in animals. J. Franklin Inst. 258, 157–160 (1954).

    CAS  Article  Google Scholar 

  37. 37

    Maschek, G. et al. 2-deoxy-D-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res. 64, 31–34 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Rosbe, K. W., Brann, T. W., Holden, S. A., Teicher, B. A. & Frei, E. Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro. Cancer Chemother. Pharmacol. 25, 32–36 (1989).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Singh, D. et al. Optimizing cancer radiotherapy with 2-deoxy-d-glucose dose escalation studies in patients with glioblastoma multiforme. Strahlenther. Onkol. 181, 507–514 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    De Lena, M. et al. Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study. Eur. J. Cancer 37, 364–368 (2001).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Di Cosimo, S. et al. Lonidamine: efficacy and safety in clinical trials for the treatment of solid tumors. Drugs Today (Barc) 39, 157–174 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Oudard, S. et al. Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J. Neurooncol. 63, 81–86 (2003).

    PubMed  Article  Google Scholar 

  43. 43

    Papaldo, P. et al. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J. Clin. Oncol. 21, 3462–3468 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Cao, X. et al. Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother. Pharmacol. 59, 495–505 (2007).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Devi, M. A. & Das, N. P. In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett. 69, 191–196 (1993).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Kobori, M., Shinmoto, H., Tsushida, T. & Shinohara, K. Phloretin-induced apoptosis in B16 melanoma 4A5 cells by inhibition of glucose transmembrane transport. Cancer Lett. 119, 207–212 (1997).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Nelson, J. A. & Falk, R. E. The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res. 13, 2287–2292 (1993).

    CAS  PubMed  Google Scholar 

  48. 48

    Cao, X. et al. Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor. Clin. Cancer Res. 14, 1831–1839 (2008).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Ko, Y. H. et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem. Biophys. Res. Commun. 324, 269–275 (2004).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Coy, J. F., Dressler, D., Wilde, J. & Schubert, P. Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Clin. Lab. 51, 257–273 (2005).

    CAS  PubMed  Google Scholar 

  51. 51

    Langbein, S. et al. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br. J. Cancer 94, 578–585 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Zhang, S., Yang, J. H., Guo, C. K. & Cai, P. C. Gene silencing of TKTL1 by RNAi inhibits cell proliferation in human hepatoma cells. Cancer Lett. 253, 108–114 (2007).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Xu, X., Zur Hausen, 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 124, 1330–1337 (2009).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Clem, B. et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther. 7, 110–120 (2008).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Mazurek, S., Boschek, C. B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300–308 (2005).

    CAS  Article  Google Scholar 

  56. 56

    Eigenbrodt, E., Reinacher, M., Scheefers-Borchel, U., Scheefers, H. & Friis, R. Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. Crit. Rev. Oncog. 3, 91–115 (1992).

    CAS  PubMed  Google Scholar 

  57. 57

    Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181–186 (2008).

    CAS  Article  Google Scholar 

  58. 58

    Deberardinis, R. J. & Cheng, T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. 59

    Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell. Metab. 3, 187–197 (2006). This paper, with reference11, describes a mechanism by which hypoxic cells adapt their means of generating ATP.

    CAS  Article  PubMed  Google Scholar 

  60. 60

    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 9, 425–434 (2006). The first demonstration of the importance of LDHA on tumour metabolism.

    CAS  Article  Google Scholar 

  61. 61

    Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007). This paper was the first to suggest that a PDK1 inhibitor could be used to treat cancer.

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Sun, R. C. et al. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res. Treat 120, 253–260 (2009).

    PubMed  Article  CAS  Google Scholar 

  63. 63

    McFate, T. et al. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J. Biol. Chem. 283, 22700–22708 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Pearson, H. Cancer patients opt for unapproved drug. Nature 446, 474–475 (2007).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Stuwe, L. et al. pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution. J. Physiol. 585, 351–360 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66

    Wong, P., Kleemann, H. W. & Tannock, I. F. Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. Br. J. Cancer 87, 238–245 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930–3942 (2008). The first demonstration that inhibition of 'lactate-swapping' between normoxic and hypoxic cells could retard tumour growth.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Thornton, S. N. Letter [online] (2009).

  69. 69

    Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B. & Gillies, R. J. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Gillies, R. J. & Gatenby, R. A. Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev. 26, 311–317 (2007).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Bhujwalla, Z. M. et al. Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn. Reson. Med. 41, 897–903 (1999).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Martinez-Zaguilan, R. et al. Acidic pH enhances the invasive behavior of human melanoma cells. Clin. Exp. Metastasis 14, 176–186 (1996).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Baumann, F. et al. Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol. 11, 368–380 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Robey, I. F. et al. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 69, 2260–2268 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Chiche, J. et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 69, 358–368 (2009).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Supuran, C. T. Indisulam: an anticancer sulfonamide in clinical development. Expert Opin. Investig Drugs 12, 283–287 (2003).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Supuran, C. T., Briganti, F., Tilli, S., Chegwidden, W. R. & Scozzafava, A. Carbonic anhydrase inhibitors: sulfonamides as antitumor agents? Bioorg. Med. Chem. 9, 703–714 (2001).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Winum, J. Y. et al. Carbonic anhydrase inhibitors. Inhibition of isoforms I, II, IV, VA, VII, IX, and XIV with sulfonamides incorporating fructopyranose-thioureido tails. Bioorg. Med. Chem. Lett. 17, 2685–2691 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Supuran, C. T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Rev. Drug Discov. 7, 168–181 (2008).

    CAS  Article  Google Scholar 

  80. 80

    DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007). This paper makes the important observation of increased glutamine usage by tumour cells to feed the TCA cycle.

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Szeliga, M. & Obara-Michlewska, M. Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem. Int. 55, 71–75 (2009).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Samid, D., Yeh, A. & Prasanna, P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood 80, 1576–1581 (1992).

    CAS  PubMed  Google Scholar 

  83. 83

    Brusilow, S. W. et al. Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N. Engl. J. Med. 310, 1630–1634 (1984).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Simell, O., Sipila, I., Rajantie, J., Valle, D. L. & Brusilow, S. W. Waste nitrogen excretion via amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance. Pediatr. Res. 20, 1117–1121 (1986).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Samid, D. et al. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. Cancer Res. 54, 891–895 (1994).

    CAS  PubMed  Google Scholar 

  86. 86

    Samid, D., Shack, S. & Myers, C. E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J. Clin. Invest. 91, 2288–2295 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009). This paper was the first to demonstrate a link between MYC and glutamine metabolism.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Rosenfeld, H. & Roberts, J. Enhancement of antitumor activity of glutamine antagonists 6-diazo-5-oxo-L-norleucine and acivicin in cell culture by glutaminase-asparaginase. Cancer Res. 41, 1324–1328 (1981).

    CAS  PubMed  Google Scholar 

  89. 89

    Weber, G., Lui, M. S., Natsumeda, Y. & Faderan, M. A. Salvage capacity of hepatoma 3924A and action of dipyridamole. Adv. Enzyme Regul. 21, 3953–3969 (1983).

    Google Scholar 

  90. 90

    Masetti, R. & Pession, A. First-line treatment of acute lymphoblastic leukemia with pegasparaginase. Biologics 3, 359–368 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Haskell, C. M. & Canellos, G. P. l-asparaginase resistance in human leukemia—asparagine synthetase. Biochem. Pharmacol. 18, 2578–2580 (1969).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Haskell, C. M. et al. L-asparaginase: therapeutic and toxic effects in patients with neoplastic disease. N. Engl. J. Med. 281, 1028–1034 (1969).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Bunpo, P. et al. The GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent, L-asparaginase. J. Biol. Chem. 284, 32742–32749 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    Zeidan, A., Wang, E. S. & Wetzler, M. Pegasparaginase: where do we stand? Expert Opin. Biol. Ther. 9, 111–119 (2009).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Wheatley, D. N. Controlling cancer by restricting arginine availability--arginine-catabolizing enzymes as anticancer agents. Anticancer Drugs 15, 825–833 (2004).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Feun, L. & Savaraj, N. Pegylated arginine deiminase: a novel anticancer enzyme agent. Expert Opin. Investig Drugs 15, 815–822 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Ni, Y., Schwaneberg, U. & Sun, Z. H. Arginine deiminase, a potential anti-tumor drug. Cancer Lett. 261, 1–11 (2008).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Izzo, F. et al. Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J. Clin. Oncol. 22, 1815–1822 (2004).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005). An important demonstration that the inhibition of the fatty acid synthesis pathway can decrease tumour growth.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100

    Alo, P. L. et al. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77, 474–482 (1996).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Funabashi, H. et al. Binding site of cerulenin in fatty acid synthetase. J. Biochem. 105, 751–755 (1989).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Pizer, E. S., Chrest, F. J., DiGiuseppe, J. A. & Han, W. F. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res. 58, 4611–4615 (1998).

    CAS  PubMed  Google Scholar 

  103. 103

    Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Vazquez, M. J. et al. Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the β-ketoacyl reductase reaction. FEBS J. 275, 831556–831567 (2008).

    Article  CAS  Google Scholar 

  105. 105

    Li, J. N. et al. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 61, 1493–1499 (2001).

    CAS  PubMed  Google Scholar 

  106. 106

    Pizer, E. S. et al. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 60, 213–218 (2000).

    CAS  PubMed  Google Scholar 

  107. 107

    Vazquez-Martin, A., Colomer, R., Brunet, J. & Menendez, J. A. Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting 'HER2 super-expression' occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. Int. J. Oncol. 31, 769–776 (2007).

    CAS  PubMed  Google Scholar 

  108. 108

    Vazquez-Martin, A., Ropero, S., Brunet, J., Colomer, R. & Menendez, J. A. Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. Oncol. Rep. 18, 973–980 (2007).

    CAS  PubMed  Google Scholar 

  109. 109

    Mera, P. et al. C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochem. Pharmacol. 77, 1084–1095 (2009).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Nebeling, L. C., Miraldi, F., Shurin, S. B. & Lerner, E. Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J. Am. Coll. Nutr. 14, 202–208 (1995). Although it is a case report, this paper is the first to suggest that the ketogenic diet may produce clinical improvement in some cancer patients.

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Otto, C. et al. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 8, 122 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112

    Seyfried, T. N. & Mukherjee, P. Targeting energy metabolism in brain cancer: review and hypothesis. Nutr. Metab. (Lond.) 2, 30 (2005).

    Article  CAS  Google Scholar 

  113. 113

    Seyfried, T. N., Kiebish, M., Mukherjee, P. & Marsh, J. Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets. Epilepsia 49 (Suppl. 8), 114–116 (2008).

    PubMed  Article  Google Scholar 

  114. 114

    Zhou, W. et al. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr. Metab. (Lond.) 4, 5 (2007).

    Article  CAS  Google Scholar 

  115. 115

    Chu-Shore, C. J. & Thiele, E. A. Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet. Brain Dev. 12 May 2009 (doi:10.1016/j.braindev.2009.04.009).

  116. 116

    Gottlieb, E. & Tomlinson, I. P. Mitochondrial tumour suppressors: a genetic and biochemical update. Nature Rev. Cancer 5, 857–866 (2005).

    CAS  Article  Google Scholar 

  117. 117

    Welsh, S., Williams, R., Kirpatrick, D. & Powis, G. PX-478, a potent inhibitor of hypoxia inducible factor-1 (HIF-1) and antitumor agent. Eur. J. Cancer 38, 294 (2002).

    Google Scholar 

  118. 118

    Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G. & Powis, G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1α. Mol. Cancer Ther. 3, 233–244 (2004).

    CAS  PubMed  Article  Google Scholar 

  119. 119

    Koh, M. Y. et al. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α. Mol. Cancer Ther. 7, 90–100 (2008).

    CAS  PubMed  Article  Google Scholar 

  120. 120

    Jordan, B. F. et al. Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1α using PX-478. Neoplasia 7, 475–485 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121

    Jordan, B. F. et al. Metabolite changes in HT-29 xenograft tumors following HIF-1α inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR Biomed. 18, 430–439 (2005).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Lee, K. et al. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc. Natl Acad. Sci. USA 106, 17910–17915 (2009).

    CAS  PubMed  Article  Google Scholar 

  123. 123

    Rabbani, Z. N. et al. Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP5+, via suppression of oxidative stress in a mouse model of breast tumor. Free Radic Biol. Med. 47, 992–1004 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124

    McKeown, S. R., Cowen, R. L. & Williams, K. J. Bioreductive drugs: from concept to clinic. Clin. Oncol. (R. Coll. Radiol.) 19, 427–442 (2007).

    CAS  Article  Google Scholar 

  125. 125

    Greco, O., Patterson, A. V. & Dachs, G. U. Can gene therapy overcome the problem of hypoxia in radiotherapy? J. Radiat. Res. 41, 201–212 (2000).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Jain, R. K. & Forbes, N. S. Can engineered bacteria help control cancer? Proc. Natl Acad. Sci. USA 98, 14748–14750 (2001).

    CAS  PubMed  Article  Google Scholar 

  127. 127

    Liu, S. C., Minton, N. P., Giaccia, A. J. & Brown, J. M. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther. 9, 291–296 (2002).

    CAS  Article  Google Scholar 

  128. 128

    Altomare, D. A. & Testa, J. R. Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455–7464 (2005).

    CAS  Article  Google Scholar 

  129. 129

    Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130

    Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007). Temsirolimus, a rapalogue, is shown in Phase III clinical trials to improve survival compared with interferon-α therapy.

    CAS  Article  Google Scholar 

  131. 131

    Witzig, T. E. et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol. 23, 5347–5356 (2005).

    CAS  PubMed  Article  Google Scholar 

  132. 132

    Rizell, M. et al. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int. J. Clin. Oncol. 13, 66–70 (2008).

    CAS  PubMed  Article  Google Scholar 

  133. 133

    Galanis, E. et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294–5304 (2005).

    CAS  PubMed  Article  Google Scholar 

  134. 134

    Chan, S. et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 23, 5314–5322 (2005).

    CAS  PubMed  Article  Google Scholar 

  135. 135

    Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    CAS  Article  Google Scholar 

  136. 136

    Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 6, 1122–1128 (2004).

    CAS  PubMed  Article  Google Scholar 

  137. 137

    Manning, B. D. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J. Cell Biol. 167, 399–403 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    Fan, Q. W. et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 67, 7960–7965 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139

    Marone, R. et al. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol. Cancer Res. 7, 601–613 (2009).

    CAS  PubMed  Article  Google Scholar 

  140. 140

    Molckovsky, A. & Siu, L. L. First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting. J. Hematol. Oncol. 1, 20 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141

    Farber, S. & Diamond, L. K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 238, 787–793 (1948).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Olson, R. E. Oxidation of C14-labeled carbohydrate intermediates in tumor and normal tissue. Cancer Res. 11, 571–584 (1951).

    CAS  PubMed  Google Scholar 

  143. 143

    Zamecnik, P. C., Loftfield, R. B., Stephenson, M. L. & Steele, J. M. Studies on the carbohydrate and protein metabolism of the rat hepatoma. Cancer Res. 11, 592–602 (1951).

    CAS  PubMed  Google Scholar 

  144. 144

    Ely, J. O. 2-deoxy-D-glucose as an inhibitor of cancerous growth in animals. J. Franklin Inst. 258, 157–160 (1954).

    CAS  Article  Google Scholar 

  145. 145

    Thomlinson R. H. & Gray, L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549 (1955).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146

    Landau, B. R., Laszlo, J., Stengle, J. & Burk, D. Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-D-glucose. J. Natl Cancer Inst. 21, 485–494 (1958).

    CAS  PubMed  Google Scholar 

  147. 147

    Roberts, E. & Simonsen, D. G. in Amino Acids, Proteins and Cancer Biochemistry (ed. Edsall, I. T.) 127–145 (Academic, New York, 1960).

    Google Scholar 

  148. 148

    Weinhouse, S. Glycolysis, respiration and anomalous gene expression in experimental hepatomas. Cancer Res. 32, 2007–2016 (1972).

    CAS  PubMed  Google Scholar 

  149. 149

    Som, P. et al. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J. Nucl. Med. 21, 670–675 (1980).

    CAS  PubMed  Google Scholar 

  150. 150

    Wang, G. L. & Semenza, G. L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237 (1995).

    CAS  Article  PubMed  Google Scholar 

  151. 151

    Sabers, C. J. et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815–822 (1995).

    CAS  PubMed  Article  Google Scholar 

  152. 152

    Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA. 94, 6658–6663 (1997). This is the first paper to show that MYC in tumours can also impinge on glycolytic control.

    CAS  PubMed  Article  Google Scholar 

  153. 153

    Sabatini, D. M., Erdjument-Bromage, H., Tempst, P. & Snyder, S.H. RAFT1 A mammalian protein that binds to FKBP12 in a rapamycindependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154

    Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank C. Frezza, J. Swinnen and S. Mazurek for their input and advice on the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Eyal Gottlieb.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary 

5-fluorouracil

BEZ235

cytarabine

DCA

everolimus

metformin

methotrexate

paclitaxel

PX-478

rapamycin

temsirolimus

trastuzumab

TLN-232

XL765

FURTHER INFORMATION

Eyal Gottlieb's homepage

Glossary

Glycolysis

The pathway leading from intracellular glucose directly to pyruvate, resulting in the generation of two moles of pyruvate, ATP and NADH from one mole of glucose.

Glutaminolysis

The process by which glutamine is metabolised to α-ketoglutarate by glutamate.

Pentose phosphate pathway

A bypass of glycolysis with both biosynthetic and antioxidant outcomes. It can generate NADPH and/or ribose-5-phosphate, which can be used for glutathione reduction and anabolic processes.

Tricarboxylic acid cycle

A set of interconnected pathways in the mitochondrial matrix. It produces reducing equivalents (NADH and FADH2) for the electron transport chain and precursors for amino acid and fatty acid synthesis.

Pasteur effect

First used to describe the inhibitory effect of oxygen on yeast fermentation. It is now described as the inhibition of glycolysis by mitochondria-generated ATP that is observed in eukaryotic cells.

Warburg effect

Originally described as the large increase in aerobic production of lactate by cancer cells and suggested to be a consequence of defects in oxidative phosphorylation. Today, it is defined as an increase in 'aerobic glycolysis' that is not necessarily correlated with permanent mitochondrial dysfunction.

Anapleurosis

From the Greek 'ana' meaning 'up' and 'plerotikos' meaning 'to fill', this term describes the replenishment of TCA cycle intermediates.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tennant, D., Durán, R. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10, 267–277 (2010). https://doi.org/10.1038/nrc2817

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing