Journal of Bioenergetics and Biomembranes

, Volume 39, Issue 1, pp 1–12

The cancer cell’s “power plants” as promising therapeutic targets: An overview

Introduction

Abstract

This introductory article to the review series entitled “The Cancer Cell’s Power Plants as Promising Therapeutic Targets” is written while more than 20 million people suffer from cancer. It summarizes strategies to destroy or prevent cancers by targeting their energy production factories, i.e., “power plants.” All nucleated animal/human cells have two types of power plants, i.e., systems that make the “high energy” compound ATP from ADP and Pi. One type is “glycolysis,” the other the “mitochondria.” In contrast to most normal cells where the mitochondria are the major ATP producers (>90%) in fueling growth, human cancers detected via Positron Emission Tomography (PET) rely on both types of power plants. In such cancers, glycolysis may contribute nearly half the ATP even in the presence of oxygen (“Warburg effect”). Based solely on cell energetics, this presents a challenge to identify curative agents that destroy only cancer cells as they must destroy both of their power plants causing “necrotic cell death” and leave normal cells alone. One such agent, 3-bromopyruvate (3-BrPA), a lactic acid analog, has been shown to inhibit both glycolytic and mitochondrial ATP production in rapidly growing cancers (Ko et al., Cancer Letts., 173, 83–91, 2001), leave normal cells alone, and eradicate advanced cancers (19 of 19) in a rodent model (Ko et al., Biochem. Biophys. Res. Commun., 324, 269–275, 2004). A second approach is to induce only cancer cells to undergo “apoptotic cell death.” Here, mitochondria release cell death inducing factors (e.g., cytochrome c). In a third approach, cancer cells are induced to die by both apoptotic and necrotic events. In summary, much effort is being focused on identifying agents that induce “necrotic,” “apoptotic” or apoptotic plus necrotic cell death only in cancer cells. Regardless how death is inflicted, every cancer cell must die, be it fast or slow.

Keywords

Bioenergetics Warburg Warburg effect Cancer Anti-cancer agents Cancer therapy 3-bromopyruvate 3-BrPA Cell death Necrosis Apoptosis Energy metabolism Power plants Glycolysis Mitochondria Cytochrome c 

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References

  1. Aisenberg AC (1961) The glycolysis and respiration of tumors. Academic Press, New York and London Part II: The Oxidative Metabolism of Tumors, pp 156–157Google Scholar
  2. Allison PD (1995) In: Survival analysis using SAS, A practical guide, Chapter 3, SAS Publishing, Cary, North Carolina, pp 30–32Google Scholar
  3. Andre N, Rome A, Carre M (2006) Archives de Pediatrie 13:69–75PubMedCrossRefGoogle Scholar
  4. Arora KK, Pedersen PL (1988) J Biol Chem 263:17422–17428PubMedGoogle Scholar
  5. Arunkumar A, Vijayababu MR, Gunadharini N, Krishnamoorthy G, Arunakaran J (2006) Cancer Lett. Epub ahead of printGoogle Scholar
  6. Athanasiou A, Smith PA, Vakilpour S, Kumaran NM, Turner AE, Bagiokou D, Layfield R, Ray DE, Westwell AD, Alexander SP, Kendall DA, Lobo DN, Watson SA, Lophatanon A, Muir KA, Guo DA, Bates TE (2007) Biochem Biophys Res Commun 354:50–55PubMedCrossRefGoogle Scholar
  7. Badros A, Goloubeva O, Fenton R, Rapoport AP, Akpek G, Harris C, Ruehle K, Westphal S, Meisenberg B (2006) Clin Lymphoma Myeloma 7:210–216PubMedCrossRefGoogle Scholar
  8. Barna G, Sebestyen A, Weischede S, Petak I, Mihalik R, Formelli F, Kopper L (2005) Anticancer Res 25:4179–4185PubMedGoogle Scholar
  9. Bleday R, Weiss MJ, Salem RR, Wilson RE, Chen LB, Steele G Jr (1986) Arch Surg 121:1272–1275PubMedCrossRefGoogle Scholar
  10. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) Cancer Cell 11:37–51PubMedCrossRefGoogle Scholar
  11. Bouchier-Hayes L, Lartigue L, Newmeyer DD (2005) J Clin Invest 115:2640–2647PubMedCrossRefGoogle Scholar
  12. Britten CD, Rowinsky EK, Baker SD, Weiss GR, Smith L, Stephenson J, Rothenberg M, Smetzer L, Cramer J, Collins W, VonHoff DD, Eckhardt SG (2000) Clin Cancer Res 6:42–49PubMedGoogle Scholar
  13. Bustamante E, Pedersen PL (1977) Proc Natl Acad Sci (USA) 74:3735–3739CrossRefADSGoogle Scholar
  14. Campas C, Cosialls AM, Barragan M, Iglesias-Serret D, Santidrian AF, Coll-Mulet L, de Frias M, Domingo A, Pons G, Gil J (2006) Exp Hematol 34:1663–1669Google Scholar
  15. Carter BZ, Mak DH, Schober WD, McQueen T, Harris D, Estrov Z, Evans RL, Andreeff M (2006) Blood 108:630–637PubMedCrossRefGoogle Scholar
  16. Cereghetti GM, Scorrano L (2006) Oncogene 25:4717–4724PubMedCrossRefGoogle Scholar
  17. Chen BJ (2001) Leuk Lymphoma 42:253–265PubMedGoogle Scholar
  18. Chen J, Ramos J, Sirisawad M, Miller R, Naumovski L (2005) Apoptosis 10:1131–1142PubMedCrossRefGoogle Scholar
  19. Chen LB (1989) Methods Cell Biol 29:103–123PubMedCrossRefGoogle Scholar
  20. Cherry SR (2006) J Nuc Med 47:1735–1745Google Scholar
  21. Chitambar CR, Wereley JP, Matsuyama SM (2006) Cancer Ther 5:2834–2843CrossRefGoogle Scholar
  22. Dancy J, Sausville EA (2003) Nat Rev Drug Discov 2:296–313CrossRefGoogle Scholar
  23. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A (2007) J Clin Invest 117:112–121PubMedCrossRefGoogle Scholar
  24. Di Cosimo S, Ferretti G, Papaldo P, Carlini P, Fabi A, Cognetti F (2003) Drugs Today (Barc) 39:157–174CrossRefGoogle Scholar
  25. Don AS, Hogg PJ (2004) Trends Mol Med 10:372–378PubMedCrossRefGoogle Scholar
  26. Efferth T (2006) Curr Drug Targets 7:407–421PubMedCrossRefGoogle Scholar
  27. Eggermont AM (2006) J Clin Oncol 24:4673–4674PubMedCrossRefGoogle Scholar
  28. El-Mahdy MA, Zhu Q, Wang QE, Wani G, Wani AA (2005) Int J Cancer 117:409–417PubMedCrossRefGoogle Scholar
  29. Elshimali YI, Grody WW (2006) Diagn Mol Pathol 15:187–194PubMedCrossRefGoogle Scholar
  30. Engel M, Mazurek S, Eingenbrodt E, Welter CJ (2004) J Biol Chem 279:35803–35812PubMedCrossRefGoogle Scholar
  31. Fang J, Quinones QJ, Holman TL, Morowitz MJ, Wang Q, Zhao H, Sivo F, Maris JM, Wahl ML (2006) Mol Pharm 70:2108–2115CrossRefGoogle Scholar
  32. Farber S (1950) Am J Dis Child 79:961–962PubMedGoogle Scholar
  33. Fischer OM, Streit S, Hart S, Ullrich A (2003) Curr Opin Chem Biol 7:490–495PubMedCrossRefGoogle Scholar
  34. Fleming A (1929) Br J Exp Pathol 10:226–236Google Scholar
  35. Foubister V (2002) DDT 7:934–935PubMedGoogle Scholar
  36. Frankel SR (2003) Semin Oncol 30:300–3004PubMedCrossRefGoogle Scholar
  37. Gali-Muhtasib H, Diab-Assaf M, Boltze C, Al-Hmaira J, Hartig R, Roessner A, Schneider-Stock R (2004) Int J Oncol 25:858–866Google Scholar
  38. Galluzzi L, Larochette N, Zamzami N, Kroemer G (2006) Oncogene 25:4812–4830PubMedCrossRefGoogle Scholar
  39. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Cancer Res 62:3903–3913Google Scholar
  40. Goodsell DS (2004) The Oncologist 9:226–227PubMedCrossRefGoogle Scholar
  41. Greville G (1969) Curr Top Bioenerg 3:1–78MathSciNetGoogle Scholar
  42. Hosler JP, Ferguson-Miller S, Mills DA (2006) Annu Rev Biochem 75:165–187PubMedCrossRefGoogle Scholar
  43. Issat T, Jakobisiak M, Golab J (2006) Oncol Rep 16: 1273–1276PubMedGoogle Scholar
  44. Jiang X, Wang X (2004) Annu Rev Biochem 73:87–106PubMedCrossRefGoogle Scholar
  45. Johnson JH, Belt JA, Dubinsky WP, Zimniak A, Racker E(1980) Biochemistry 19:3836–3840Google Scholar
  46. Johnson LV, Johnson ML, Chen LB (1980) Proc Natl Acad Sci (USA) 77:990–994CrossRefADSGoogle Scholar
  47. Kerkela R, Grazette L, Yacobi R, Iliescu C, Pattern R, Beahm C, Walters G, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, A Van Hatten R, Alroy J, Durand J-B, Force T (2006) Nat Med 12:908–916PubMedCrossRefGoogle Scholar
  48. Kerr JF, Wyllie AH, Currie AR (1972) Br J Cancer 26:239–257PubMedGoogle Scholar
  49. Ko JK, Leung WC, Ho WK, Chiu P (2006) Eur J Pharmacol [Epub ahead of print]Google Scholar
  50. Ko YH, Pedersen PL, Geschwind (2001) Cancer Lett 173:83–91Google Scholar
  51. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Biochem Biophys Res Commun 324:269–275PubMedCrossRefGoogle Scholar
  52. Koya K, Li Y, Wang H, Ukai T, Tatsukta N, Kawakami M, Shishido, Chen LB (1996) Cancer Res 56:538–543Google Scholar
  53. LeBras M, Borgne-Sanchez A, Touat Z, El Dein OS, Deniaud A, Maillier E, Lecellier G, Rebouilat D, Lemaire C, Kroemer G, Jacotot E, Brenner C (2006) Cancer Res 66:9143–9152Google Scholar
  54. Li YC, Fung KP, Kwok TT, Lee CY, Suen YK, Kong SK (2002) Life Sci 71:2729–2740PubMedCrossRefGoogle Scholar
  55. Malhi H, Gores GJ, Lemasters JJ (2006) Hepatology 43:S31–S44PubMedCrossRefGoogle Scholar
  56. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) Science 298:1912–1934PubMedCrossRefADSGoogle Scholar
  57. Marcinkowska A, Malarska A, Saczko J, Chwilkowska A, Wysocka T, Drag-Zalesinska M, Wysocka T, Banas T (2001) Folia Histochem Cytobiol 39(Suppl 2):177–178PubMedGoogle Scholar
  58. Mathupala SP, Ko YH, Pedersen PL (2006) Oncogene 25:4777–4786PubMedCrossRefGoogle Scholar
  59. Mathupala SP, Parajuli P, Sloan AE (2004) Neurosurgery 55:1410–1419PubMedCrossRefGoogle Scholar
  60. McGuire JJ (2003) Curr Pharm Design 9:2593–2613CrossRefGoogle Scholar
  61. Mitchell P (1961) Nature 191:144–148PubMedCrossRefADSGoogle Scholar
  62. Nakashima RA, Paggi MG, Pedersen PL (1984) Cancer Res 44:5702–5706PubMedGoogle Scholar
  63. Nakashima RA, Managan PS, Colombini M, Pedersen PL (1986) Biochemistry 25:1015–1021PubMedCrossRefGoogle Scholar
  64. Neuzil J, Wang X-F, Dong L-F, Low P, Ralph SJ (2006) FEBS Lett 580:5125–5129PubMedCrossRefGoogle Scholar
  65. Niizuma H, Nakamura Y, Ozaki T, Nakanishi H, Ohira M, Isogai E, Kageyama H, Imaizumi M, Nakagawara A (2006) Oncogene 25:5046–5055PubMedCrossRefGoogle Scholar
  66. Oh KW, Qian T, Brenner DA, Lemaster JJ (2003) Toxicol Sci 73:44–52PubMedCrossRefGoogle Scholar
  67. Palozza P, Serini S, Torsello A, Dinicuolo F, Maggiano N, Ranelletti FO, Wolf FI, Calviello G (2003) Nutr Cancer 47:76–87PubMedCrossRefGoogle Scholar
  68. Panichakul T, Intachote P, Wongkajorsilp A, Sripa B, Sirisinha S (2006) Anticancer Res 26(1A):259–265PubMedGoogle Scholar
  69. Pastorino JG, Shulga N, Hoek JB (2002) J Biol Chem 277:7610–7618PubMedCrossRefGoogle Scholar
  70. Pedersen PL (1978) Prog Exp Tumor Res 22:190–274PubMedGoogle Scholar
  71. Pelicano H, Martin DS, Xu R-H, Huang P (2006) Oncogene 25:4633–4646PubMedCrossRefGoogle Scholar
  72. Perchellet EM, Wang Y, Weber RL, Lou K, Hua DH, Perchellet JP (2004) Anticancer Drugs 15:929–946PubMedCrossRefGoogle Scholar
  73. Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, A Van Hatten R, Alroy J, Durand J-B, Force T (2006) Nat Med 12:908–916PubMedCrossRefGoogle Scholar
  74. Pisano M, Pagnan G, Loi M, Mura ME, Tilocca MG, Palmieri G, Fabbri D, Dettori MA, Delogus G, Ponzoni M, Rozzo C (2007) Mol Cancer 6:8Google Scholar
  75. Qin J, Xie LP, Zheng XY, Wang YB, Bai Y, Shen HF, Li LC, Dahiya R (2007) Biochem Biophys Res Commun 354:852–857PubMedCrossRefGoogle Scholar
  76. Rall TW, Sutherland EW (1958) J Biol Chem 232:1065–1076PubMedGoogle Scholar
  77. Richards GM, Mehta MP (2007) Expert Opin Pharmacother 8:351–359PubMedCrossRefGoogle Scholar
  78. Roccaro AM, Hideshima T, Richardson PG, Russo D, Ribatti D, Vacca A, Dammacco F, Anderson KC (2006) Curr Pharm Biotechnol 7:441–448PubMedCrossRefGoogle Scholar
  79. Rzeski W, Stepulak A, Szymanski M, Sifringer M, Kaczor J, Wejksza K, Zdzisinka B, Kandefer-Szerszen M (2006) Naunyn Schmiedebergs Arch Pharmol 374:11–20CrossRefGoogle Scholar
  80. Sancho P, Galeano E, Nieto E, Delgado MD, Garcia-Perez AI (2007) Leukema Research (On Line)Google Scholar
  81. Schreiber JR, Balcavage WX, Morris HP, Pedersen PL (1970) Cancer Res 30:2497–2501PubMedGoogle Scholar
  82. Shen PF (2004) Front Biosci 9:2663–2670PubMedCrossRefGoogle Scholar
  83. Shields AF (2006) Mol Imaging Biol 8:141–150PubMedCrossRefGoogle Scholar
  84. Spencer TL, Lehninger AL (1976) Biochem J 154:405–414PubMedGoogle Scholar
  85. Strebhardt K, Ullrich A (2006) N Eng J Med 355:2481–2482CrossRefGoogle Scholar
  86. Sun X, Wong JR, Song K, Hu J, Garlid KD, Chen LB (1994) Cancer Res 54:1465–1471PubMedGoogle Scholar
  87. Sutherland EW, Rall TW (1958) J Biol Chem 232:1077–1092PubMedGoogle Scholar
  88. Tang L, Jin T, Zeng X, Wang JS (2005) J Nutr 135:287–290PubMedGoogle Scholar
  89. Wang Y, Perchellet EM, Ward MM, Lou K, Zhao H, Battina SK, Wiredu B, Hua DH, Perchellet JP (2006b) Int J Oncol 28:161–172MATHGoogle Scholar
  90. Wang XS, Yang W, Tao SJ, Li K, Li M, Dong JH, Wang MH (2006a) Yakuqaku Zasshi 126:979–990CrossRefGoogle Scholar
  91. Warburg O (1930) The metabolism of tumors. Constable, LondonGoogle Scholar
  92. Weber G (1968) Naturwissenschaften 55:418–429PubMedCrossRefGoogle Scholar
  93. Weber G (2001) Biochem (Mosc) 66(10):1164–1173CrossRefGoogle Scholar
  94. Weber G, Lea MA (1966) Adv Enzyme Regul 4:115–145PubMedCrossRefGoogle Scholar
  95. Weinhouse S (1972) Cancer Res 32:2007–2016PubMedGoogle Scholar
  96. Weiss MJ, Wong JR, Ha CS, Bleday R, Salem RR, Steele GD Jr, Chen LB (1987) Proc Natl Acad Sci 84:5444–5448PubMedCrossRefADSGoogle Scholar
  97. Weiss MJ, Wong JR, Ha CS, Bleday R, Salem RR, Steele GD Jr (1988) Annu Rev Cell Biol 4:155–181Google Scholar
  98. Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P (2005) Leukemia 19:2153–2158PubMedCrossRefGoogle Scholar
  99. Zhang XD, Deslandes E, Villedieu M, Poulain L, Duval M, Gauduchon P, Schwartz L, Icard P (2006) Anticancer Res 26: 3561–3566PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Biological ChemistryJohns Hopkins University, School of MedicineBaltimoreUSA

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