Advertisement

The Warburg effect and its cancer therapeutic implications

  • Zhao Chen
  • Weiqin Lu
  • Celia Garcia-Prieto
  • Peng Huang
MIni Review

Abstract

Increased aerobic glycolysis in cancer, a phenomenon known as the Warburg effect, has been observed in various tumor cells and represents a major biochemical alteration associated with malignant transformation. Although the exact molecular mechanisms underlying this metabolic change remain to be elucidated, the profound biochemical alteration in cancer cell energy metabolism provides exciting opportunities for the development of therapeutic strategies to preferentially kill cancer cells by targeting the glycolytic pathway. Several small molecules capable of inhibiting glycolysis in experimental systems have been shown to have promising anticancer activity in vitro and in vivo. This review article provides a brief summary of our current understanding of the Warburg effect, the underlying mechanisms, and its influence on the development of therapeutic strategies for cancer treatment.

Keywords

Warburg effect Glycolysis Inhibitor Mitochondria Cancer therapeutics Drug resistance Reactive oxygen species (ROS) Oncogene Hypoxia 

References

  1. Albayrak T, Scherhammer V, Schoenfeld N, Braziulis E, Mund T, Bauer MK, Scheffler IE, Grimm S (2003) Mol Biol Cell 14:3082–3096CrossRefGoogle Scholar
  2. Altenberg B, Greulich KO (2004) Genomics 84:1014–1020CrossRefGoogle Scholar
  3. Arora KK, Pedersen PL (1988) J Biol Chem 263:17422–17428, Nov 25Google Scholar
  4. Barnard JP, Reynafarje B, Pedersen PL (1993) J Biol Chem 268:3654–3661Google Scholar
  5. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) Cell 126:107–120CrossRefGoogle Scholar
  6. Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, Nuzzo F, Giardina G, Danese S, De Lena M, Lorusso V, Farris A, Sarobba MG, DeFabiani E, Bonazzi G, Castiglione F, Bumma C, Moro G, Bruzzi P, Dogliotti L (2002) J Clin Oncol 20:4150–4159CrossRefGoogle Scholar
  7. Biaglow JE, Cerniglia G, Tuttle S, Bakanauskas V, Stevens C, McKenna G (1997) Biochem Biophys Res Commun 235:739–742CrossRefGoogle Scholar
  8. Brand KA, Hermfisse U (1997) FASEB J 11:388–395Google Scholar
  9. Brandon M, Baldi P, Wallace DC (2006) Oncogene 25:4647–4662CrossRefGoogle Scholar
  10. Briasoulis E, Pavlidis N, Terret C, Bauer J, Fiedler W, Schoffski P, Raoul JL, Hess D, Selvais R, Lacombe D, Bachmann P, Fumoleau P (2003) Eur J Cancer 39:2334–2340CrossRefGoogle Scholar
  11. Burgering BM, Coffer PJ (1995) Nature 376:599–602CrossRefGoogle Scholar
  12. Carew JS, Huang P (2002) Molecular Cancer 1:1–12CrossRefGoogle Scholar
  13. Carew JS, Zhou Y, Albitar M, Carew JD, Keating MJ, Huang P (2003) Leukemia 17:1437–1447CrossRefGoogle Scholar
  14. Carew JS, Nawrocki ST, Xu RH, Dunner K, McConkey DJ, Wierda WG, Keating MJ, Huang P (2004) Leukemia 18:1934–1940CrossRefGoogle Scholar
  15. Chesney J (2006) Curr Opin Clin Nutr Metab Care 9:535–539CrossRefGoogle Scholar
  16. Coy JF, Dressler D, Wilde J, Schubert P (2005) Clin Lab 51:257–273Google Scholar
  17. Di Cosimo S, Ferretti G, Papaldo P, Carlini P, Fabi A, Cognetti F (2003) Drugs Today (Barc) 39:157–174CrossRefGoogle Scholar
  18. Fantin VR, St-Pierre J, Leder P (2006) Cancer Cell 9:425–434CrossRefGoogle Scholar
  19. Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Science 235:1492–1495CrossRefGoogle Scholar
  20. Floridi A, Bruno T, Miccadei S, Fanciulli M, Federico A, Paggi MG (1998) Biochem Pharmacol 56:841–849CrossRefGoogle Scholar
  21. Floridi A, Paggi MG, Marcante ML, Silvestrini B, Caputo A, De Martino C (1981) J Natl Cancer Inst 66:497–499Google Scholar
  22. Giaccone G, Smit EF, de Jonge M, Dansin E, Briasoulis E, Ardizzoni A, Douillard JY, Spaeth D, Lacombe D, Baron B, Bachmann P, Fumoleau P (2004) Eur J Cancer 40:667–672CrossRefGoogle Scholar
  23. Gatenby RA, Gillies RJ (2004) Nat Rev Cancer 4:891–899CrossRefGoogle Scholar
  24. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Cancer Res 62:3909–3913Google Scholar
  25. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2004) Cancer Res 64:31–34CrossRefGoogle Scholar
  26. Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ (2004) Clin Cancer Res 10:6661–6668CrossRefGoogle Scholar
  27. Gottlieb E, Tomlinson IP (2005) Nat Rev Cancer 5:857–866CrossRefGoogle Scholar
  28. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Genes Dev 15:2203–2208CrossRefGoogle Scholar
  29. Harris AL (2001) Nat Rev Cancer 2(1):38–47CrossRefGoogle Scholar
  30. Ishii T, Yasuda K, Akatsuka A, Hino O, Hartman PS, Ishii N (2005) Cancer Res 65:203–209Google Scholar
  31. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) Cell Metab 3:177–185CrossRefGoogle Scholar
  32. Ko YH, Pedersen PL, Geschwind JF (2001) Cancer Lett 173:83–91CrossRefGoogle Scholar
  33. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Biochem Biophys Res Commun 324:269–275CrossRefGoogle Scholar
  34. Lampidis TJ, Kurtoglu M, Maher JC, Liu H, Krishan A, Sheft V, Szymanski S, Fokt I, Rudnicki WR, Ginalski K, Lesyng B, Priebe W (2006) Cancer Chemother Pharmacol 58:725–734CrossRefGoogle Scholar
  35. Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C, Grobholz R, Willeke F, Alken P, Stassi G, Schubert P, Coy JF (2006) Br J Cancer 94:578–585CrossRefGoogle Scholar
  36. Liu H, Hu YP, Savaraj N, Priebe W, Lampidis TJ (2001) Biochemistry 40:5542–5547CrossRefGoogle Scholar
  37. Liu H, Savaraj N, Priebe W, Lampidis TJ (2002) Biochem Pharmacol 64:1745–1751CrossRefGoogle Scholar
  38. Maher JC, Krishan A, Lampidis TJ (2004) Cancer Chemother Pharmacol 53:116–122CrossRefGoogle Scholar
  39. Marin-Hernandez A, Rodriguez-Enriquez S, Vital-Gonzalez PA, Flores-Rodriguez FL, Macias-Silva M, Sosa-Garrocho M, Moreno-Sanchez R (2006) FEBS J 273:1975–1988CrossRefGoogle Scholar
  40. Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, De Young LR, Lampidis TJ (2004) Cancer Res 64:31–34CrossRefGoogle Scholar
  41. Mathupala SP, Rempel A, Pedersen PL (1995) J Biol Chem 270:16918–16925CrossRefGoogle Scholar
  42. Mathupala SP, Ko YH, Pedersen PL (2006) Oncogene 25:4777–4786CrossRefGoogle Scholar
  43. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) Science 312:1650–1653CrossRefGoogle Scholar
  44. Nakashima RA, Paggi MG, Pedersen PL (1984) Cancer Res 44:5702–5706Google Scholar
  45. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002) Biochim Biophys Acta 1555:14–20CrossRefGoogle Scholar
  46. Pelicano H, Xu R-H, Du M, Feng L, Sasaki R, Carew JS, Hu Y, Ramdas L, Hu L, Keating MJ, Zhang W, Plunkett W, Huang P (2006a) J Cell Biol 175:913–923Google Scholar
  47. Pelicano H, Martin DS, Xu RH, Huang P (2006b) Oncogene 25:4633–4646CrossRefGoogle Scholar
  48. Rais B, Comin B, Puigjaner J, Brandes JL, Creppy E, Saboureau D, Ennamany R, Lee WN, Boros LG, Cascante M (1999) FEBS Lett 456:113–118CrossRefGoogle Scholar
  49. Ramanathan A, Wang C, Schreiber SL (2005) Proc Natl Acad Sci USA 102:5992–5997CrossRefGoogle Scholar
  50. Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB (2003) Mol Cell Biol 23:7315–7328CrossRefGoogle Scholar
  51. Robey RB, Hay N (2006) Oncogene 25:4683–4696CrossRefGoogle Scholar
  52. Rodriguez-Enriquez S, Torres-Marquez ME, Moreno-Sanchez R (2000) Arch Biochem Biophys 375:21–30CrossRefGoogle Scholar
  53. Rosbe KW, Brann TW, Holden SA, Teicher BA, Frei E III (1989) Cancer Chemother Pharmacol 25:32–36CrossRefGoogle Scholar
  54. Sebastian S, White JA, Wilson JE (1999) J Biol Chem 274:31700–31706CrossRefGoogle Scholar
  55. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Cancer Cell 7:77–85CrossRefGoogle Scholar
  56. Serkova N, Boros LG (2005) Am J Pharmacogenomics 5:293–302CrossRefGoogle Scholar
  57. Shinohara Y, Ichihara J, Terada H (1991) FEBS Lett 291:55–57CrossRefGoogle Scholar
  58. Singh K.K. (2004). Ann N Y Acad Sci. 1019, 260–264CrossRefGoogle Scholar
  59. Singh D, Banerji AK, Dwarakanath BS, Tripathi RP, Gupta JP, Mathew TL, Ravindranath T, Jain V (2005) Strahlenther Onkol 181:507–514CrossRefGoogle Scholar
  60. Sirover MA (2005) J Cell Biochem 95:45–52CrossRefGoogle Scholar
  61. Tian M, Zhang H, Higuchi T, Oriuchi N, Nakasone Y, Takata K, Nakajima N, Mogi K, Endo K (2005) Ann Nucl Med 19:335–338CrossRefGoogle Scholar
  62. Warburg O (1956) Science 123:309–314CrossRefGoogle Scholar
  63. Warburg O, Negelein E (1924) Biochemische Zeitschrift 152:319–344Google Scholar
  64. Wilson JE (2003) J Exp Biol 206:2049–2057CrossRefGoogle Scholar
  65. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P (2005a) Cancer Res 65:613–621CrossRefGoogle Scholar
  66. Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P (2005b) Leukemia 19:2153–2158CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Zhao Chen
    • 1
  • Weiqin Lu
    • 1
  • Celia Garcia-Prieto
    • 1
  • Peng Huang
    • 1
  1. 1.Department of Molecular PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations