Biochemistry (Moscow)

, Volume 81, Issue 2, pp 65–79 | Cite as

Cellular energetics as a target for tumor cell elimination

  • P. V. Maximchik
  • A. V. Kulikov
  • B. D. Zhivotovsky
  • V. G. GogvadzeEmail author


Investigation of cancer cell metabolism has revealed variability of the metabolic profiles among different types of tumors. According to the most classical model of cancer bioenergetics, malignant cells primarily use glycolysis as the major metabolic pathway and produce large quantities of lactate with suppressed oxidative phosphorylation even in the presence of ample oxygen. This is referred to as aerobic glycolysis, or the Warburg effect. However, a growing number of recent studies provide evidence that not all cancer cells depend on glycolysis, and, moreover, oxidative phosphorylation is essential for tumorigenesis. Thus, it is necessary to consider distinctive patterns of cancer metabolism in each specific case. Chemoresistance of cancer cells is associated with decreased sensitivity to different types of antitumor agents. Stimulation of apoptosis is a major strategy for elimination of cancer cells, and therefore activation of mitochondrial functions with direct impact on mitochondria to destabilize them appears to be an important approach to the induction of cell death. Consequently, the design of combination therapies using acclaimed cytotoxic agents directed to induction of apoptosis and metabolic agents affecting cancer cell bioenergetics are prospective strategies for antineoplastic therapy.

Key words

tumor cells bioenergetics mitochondria Warburg effect glycolysis 



adenine nucleotide translocase


a-tocopheryl succinate


cyclophilin D






hypoxia inducible factor




mitochondrial outer membrane (permeabilization)


mitochondrial permeability transition (pore)


oxidative phosphorylation


reactive oxygen species


voltage-dependent anion channel.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hanahan, D., and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation, Cell, 144, 646–674.PubMedCrossRefGoogle Scholar
  2. 2.
    Lunt, S. Y., and Heiden, M. V. (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation, Annu. Rev. Cell Dev. Biol., 27, 441–464.PubMedCrossRefGoogle Scholar
  3. 3.
    Tennant, D. A., Duran, R. V., Boulahbel, H., and Gottlieb, E. (2009) Metabolic transformation in cancer, Carcinogenesis, 30, 1269–1280.PubMedCrossRefGoogle Scholar
  4. 4.
    Funes, J. M., Quintero, M., Henderson, S., Martinez, D., Qureshi, U., Westwood, C., Clements, M. O., Bourboulia, D., Pedley, R. B., Moncada, S., and Boshoff, C. (2007) Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production, Proc. Natl. Acad. Sci. USA, 104, 6223–6228.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Moreno-Sanchez, R., Rodriguez-Enriquez, S., MarinHernandez, A., and Saavedra, E. (2007) Energy metabolism in tumor cells, FEBS J., 274, 1393–1418.PubMedCrossRefGoogle Scholar
  6. 6.
    Rodriguez-Enriquez, S., Carreno-Fuentes, L., GallardoPerez, J. C., Saavedra, E., Quezada, H., Vega, A., MarinHernandez, A., Olin-Sandoval, V., Torres-Marquez, M. E., and Moreno-Sanchez, R. (2010) Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma, Int. J. Biochem. Cell Biol., 42, 1744–1751.PubMedCrossRefGoogle Scholar
  7. 7.
    Barbosa, I. A., Machado, N. G., Skildum, A. J., Scott, P. M., and Oliveira, P. J. (2012) Mitochondrial remodeling in cancer metabolism and survival: potential for new therapies, Biochim. Biophys. Acta, 1826, 238–254.PubMedGoogle Scholar
  8. 8.
    Ralph, S. J., Rodriguez-Enriquez, S., Neuzil, J., and Moreno-Sanchez, R. (2010) Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger, Mol. Aspects Med., 31, 29–59.PubMedCrossRefGoogle Scholar
  9. 9.
    Vaughn, A., and Deshmukh, M. (2008) Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c, Nat. Cell Biol., 10, 1477–1483.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Cairns, R. A., Harris, I. S., and Mak, T. W. (2011) Regulation of cancer cell metabolism, Nat. Rev. Cancer, 11, 85–95.PubMedCrossRefGoogle Scholar
  11. 11.
    Gao, P., Tchernyshyov, I., Chang, T., and Lee, Y. (2009) cMyc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism, Nature, 458, 762–765.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Wise, D. R., Deberardinis, R. J., Mancuso, A., Sayed, N., Zhang, X., Pfeiffer, H. K., Nissim, I., Daikhin, E., Yudkoff, M., Mcmahon, S. B., and Thompson, C. B. (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, PNAS, 105, 18782–18787.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Dang, C. V. (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism, Cancer Res., 70, 859–862.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Jose, C., Bellance, N., and Rossignol, R. (2011) Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochim. Biophys. Acta, 1807, 552–561.PubMedCrossRefGoogle Scholar
  15. 15.
    Mazurek, S., Michel, A., and Eigenbrodt, E. (1997) Effect of extracellular AMP on cell proliferation and metabolism of breast cancer cell lines with high and low glycolytic rates, J. Biol. Chem., 272, 4941–4952.PubMedCrossRefGoogle Scholar
  16. 16.
    Rossignol, R., Gilkerson, R., and Aggeler, R. (2004) Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells, Cancer Res., 64, 985–993.PubMedCrossRefGoogle Scholar
  17. 17.
    Moreadith, R., and Lehninger, A. (1984) Purification, kinetic behavior, and regulation of NAD(P)+ malic enzyme of tumor mitochondria, J. Biol. Chem., 259, 6222–6227.PubMedGoogle Scholar
  18. 18.
    Mandella, R., and Sauer, L. (1975) The mitochondrial malic enzymes. I. Submitochondrial localization and purification and properties of the NAD(P)+-dependent enzyme from adrenal cortex, J. Biol. Chem., 250, 5877–5884.PubMedGoogle Scholar
  19. 19.
    Brand, R. M., Lyons, R. H., and Midgley, A. R. (1994) Understanding the dynamics of cellular responsiveness to modifications of metabolic substrates in perifusion, J. Cell. Physiol., 160, 10–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Zu, X. L., and Guppy, M. (2004) Cancer metabolism: facts, fantasy, and fiction, Biochem. Biophys. Res. Commun., 313, 459–465.PubMedCrossRefGoogle Scholar
  21. 21.
    Vander Heiden, M. G., Cantley, L. C., and Thompson, C. B. (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science, 324, 1029–1033.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Gorlach, A., and Acker, H. (1994) pO2and pH-gradients in multicellular spheroids and their relationship to cellular metabolism and radiation sensitivity of malignant human tumor cells, Biochim. Biophys. Acta, 1227, 105–112.PubMedCrossRefGoogle Scholar
  23. 23.
    Sutherland, R. (1998) Tumor hypoxia and gene expression, Acta Oncol., 37, 567–574.PubMedCrossRefGoogle Scholar
  24. 24.
    Vaupel, P., Kallinowski, F., and Okunieff, P. (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review, Cancer Res., 49, 6449–6465.Google Scholar
  25. 25.
    Matsumoto, A., Matsumoto, S., Sowers, A., Koscielniak, J., Trigg, N., Kuppusamy, P., Mitchell, J., Subramanian, S., Krishna, M., and Matsumoto, K. (2005) Absolute oxygen tension (pO2) in murine fatty and muscle tissue as determined by EPR, Magn. Reson. Med., 54, 1530–1535.PubMedCrossRefGoogle Scholar
  26. 26.
    Schroeder, T., Yuan, H., Viglianti, B., Peltz, C., Asopa, S., Vujaskovic, Z., and Dewhirst, M. (2005) Spatial heterogeneity and oxygen dependence of glucose consumption in R3230Ac and fibrosarcomas of the Fischer 344 rat, Cancer Res., 65, 5163–5171.PubMedCrossRefGoogle Scholar
  27. 27.
    Mason, M. G., Nicholls, P., Wilson, M. T., and Cooper, C. E. (2006) Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase, Proc. Natl. Acad. Sci. USA, 103, 708–713.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Gnaiger, E., Lassnig, B., Kuznetsov, A., Riege, A. G., and Margreiter, R. (1998) Mitochondrial oxygen affinity, respiratory flux control and excess capacity of cytochrome c oxidase, J. Exp. Biol., 201, 1129–1139.PubMedGoogle Scholar
  29. 29.
    Pecina, P., Gnaiger, E., Zeman, J., Pronicka, E., and Houstek, T. (2004) Decreased affinity for oxygen of cytochromec oxidase in Leigh syndrome caused by SURF1 mutations, Am. J. Physiol. Cell Physiol., 287, C1384–C1388.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Pollard, P. J., Wortham, N. C., and Tomlinson, I. P. M. (2003) The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase, Ann. Med., 35, 632–639.PubMedCrossRefGoogle Scholar
  32. 32.
    Robey, I. F., Lien, A. D., Welsh, S. J., Baggett, B. K., and Gillies, R. J. (2005) Hypoxia-inducible factor-1α and the glycolytic phenotype in tumors, Neoplasia, 7, 324–330.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Kroemer, G. (2006) Mitochondria in cancer, Oncogene, 25, 4630–4632.PubMedCrossRefGoogle Scholar
  34. 34.
    Yeunga, S. J., Pand, J., and Leec, 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.CrossRefGoogle Scholar
  35. 35.
    Shaw, R. J. (2006) Glucose metabolism and cancer, Curr. Opin. Cell Biol., 18, 598–608.PubMedCrossRefGoogle Scholar
  36. 36.
    Parlo, R., and Coleman, P. (1984) Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol, J. Biol. Chem., 259, 9997–10003.PubMedGoogle Scholar
  37. 37.
    Briscoe, D., Fiskum, G., Holleran, A., and Kelleher, J. (1994) Acetoacetate metabolism in AS-30D hepatoma cells, Mol. Cell Biochem., 136, 131–137.PubMedCrossRefGoogle Scholar
  38. 38.
    Dietzen, D., and Davis, E. (1993) Oxidation of pyruvate, malate, citrate, and cytosolic reducing equivalents by AS-30D hepatoma mitochondria, Arch. Biochem. Biophys., 305, 91–102.Google Scholar
  39. 39.
    Schmitt, S., Schulz, S., Schropp, E.-M., Eberhagen, C., Simmons, A., Beisker, W., Aichler, M., and Zischka, H. (2014) Why to compare absolute numbers of mitochondria, Mitochondrion, 19 (Pt. A), 113–123.PubMedCrossRefGoogle Scholar
  40. 40.
    Pedersen, P. (1978) Tumor mitochondria and the bioenergetics of cancer cells, Prog. Exp. Tumor Res., 22, 190–274.PubMedCrossRefGoogle Scholar
  41. 41.
    LaNoue, K., Hemington, J., Ohnishi, T., Morris, H., and Williamson, J. (1974) Defects in anion and electron transport in Morris hepatoma mitochondria, Horm. Cancer, 131–167.Google Scholar
  42. 42.
    Lichtor, T., and Dohrmann, G. (1987) Oxidative metabolism and glycolysis in benign brain tumors, Neurosurgery, 67, 336–340.CrossRefGoogle Scholar
  43. 43.
    Melo, R., Stevan, F., Campello, A., Carnieri, E., and de Oliveira, M. (1998) Occurrence of the Crabtree effect in HeLa cells, Cell Biochem. Funct., 16, 99–105.PubMedCrossRefGoogle Scholar
  44. 44.
    Sauer, L. (1977) On the mechanism of the Crabtree effect in mouse ascites tumor cells, J. Cell Physiol., 93, 313–316.PubMedCrossRefGoogle Scholar
  45. 45.
    Sussman, I., Erecinska, M., and Wilson, D. (1980) Regulation of cellular energy metabolism: the Crabtree effect, Biochim. Biophys. Acta, 591, 209–223.PubMedCrossRefGoogle Scholar
  46. 46.
    Seshagiri, P., and Bavister, B. (1991) Glucose and phosphate inhibit respiration and oxidative metabolism in cultured hamster eight-cell embryos: evidence for the “Crabtree effect”, Mol. Reprod. Dev., 30, 105–111.PubMedCrossRefGoogle Scholar
  47. 47.
    Yang, X., Borg, L., and Eriksson, U. (1997) Altered metabolism and superoxide generation in neural tissue of rat embryos exposed to high glucose, Am. J. Physiol., E173–E180.Google Scholar
  48. 48.
    Rodriguez-Enriquez, S., Juarez, O., Rodriguez-Zavala, J. S., and Moreno-Sanchez, R. (2001) Multisite control of the Crabtree effect in ascites hepatoma cells, Eur. J. Biochem., 268, 2512–2519.PubMedCrossRefGoogle Scholar
  49. 49.
    Covian, R., and Moreno-Sanchez, R. (2001) Role of protonatable groups of bovine heart bc1 complex in ubiquinol binding and oxidation, Eur. J. Biochem., 268, 5783–5790.PubMedCrossRefGoogle Scholar
  50. 50.
    Tsujimoto, Y., Ikegaki, N., and Croce, C. M. (1987) Characterization of the protein product of bcl-2, the gene involved in human follicular lymphoma, Oncogene, 2, 3–7.PubMedGoogle Scholar
  51. 51.
    Belmar, J., and Fesik, S. W. (2014) Small molecule Mcl-1 inhibitors for the treatment of cancer, Pharmacol. Ther., 145, 76–84.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Dutta, S., Gulla, S., Chen, T. S., Fire, E., Grant, R. A., and Keating, A. E. (2010) Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL, J. Mol. Biol., 398, 747–762.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Moldoveanu, T., Follis, A. V., Kriwacki, R. W., and Green, D. R. (2014) Many players in BCL-2 family affairs, Trends Biochem. Sci., 39, 101–111.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Chen, L., Willis, S., Wei, A., Smith, B., Fletcher, J., Hinds, M., Colman, P., Day, C., Adams, J., and Huang, D. (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function, Mol. Cell, 17, 393–403.PubMedCrossRefGoogle Scholar
  55. 55.
    Biasutto, L., Dong, L.-F., Zoratti, M., and Neuzil, J. (2010) Mitochondrially targeted anti-cancer agents, Mitochondrion, 10, 670–681.PubMedCrossRefGoogle Scholar
  56. 56.
    Gogvadze, V., Orrenius, S., and Zhivotovsky, B. (2008) Mitochondria in cancer cells: what is so special about them? Trends Cell Biol., 18, 165–173.PubMedCrossRefGoogle Scholar
  57. 57.
    Hartman, M., and Czyz, M. (2012) Pro-apoptotic activity of BH3-only proteins and BH3 mimetics: from theory to potential cancer therapy, Anticancer Agents Med. Chem., 12, 966–981.PubMedCrossRefGoogle Scholar
  58. 58.
    Gogvadze, V., Robertson, J. D., Zhivotovsky, B., and Orrenius, S. (2001) Cytochrome c release occurs via Ca2+dependent and Ca2+-independent mechanisms that are regulated by Bax, J. Biol. Chem., 276, 19066–19071.PubMedCrossRefGoogle Scholar
  59. 59.
    Armstrong, J. S. (2006) The role of the mitochondrial permeability transition in cell death, Mitochondrion, 6, 225–234.PubMedCrossRefGoogle Scholar
  60. 60.
    Narita, M., Shimizu, S., Ito, T., Chittenden, T., Lutz, R. J., Matsuda, H., and Tsujimoto, Y. (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria, Proc. Natl. Acad. Sci. USA, 95, 14681–14686.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Brenner, C., Cadiou, H., Vieira, H. L., Zamzami, N., Marzo, I., Xie, Z., Leber, B., Andrews, D., Duclohier, H., Reed, J. C., and Kroemer, G. (2000) Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator, Oncogene, 19, 329–336.PubMedCrossRefGoogle Scholar
  62. 62.
    Crompton, M., Barksby, E., Johnson, N., and Capano, M. (2002) Mitochondrial intermembrane junctional complexes and their involvement in cell death, Biochimie, 84, 143–152.PubMedCrossRefGoogle Scholar
  63. 63.
    Marzo, I., Brenner, C., Zamzami, N., Jurgensmeier, J. M., Susin, S. A., Vieira, H. L., Prevost, M. C., Xie, Z., Matsuyama, S., Reed, J. C., and Kroemer, G. (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis, Science, 281, 2027–2031.PubMedCrossRefGoogle Scholar
  64. 64.
    Rostovtseva, T. K., Antonsson, B., Suzuki, M., Youle, R. J., Colombini, M., and Bezrukov, S. M. (2004) Bid, but not Bax, regulates VDAC channels, J. Biol. Chem., 279, 13575–13583.PubMedCrossRefGoogle Scholar
  65. 65.
    Green, D. R., and Kroemer, G. (2004) The pathophysiology of mitochondrial cell death, Science, 305, 626–629.PubMedCrossRefGoogle Scholar
  66. 66.
    Arora, K. K., and Pedersen, P. L. (1988) Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP, J. Biol. Chem., 263, 17422–17428.PubMedGoogle Scholar
  67. 67.
    Vander Heiden, M. G., Li, X. X., Gottleib, E., Hill, R. B., Thompson, C. B., and Colombini, M. (2001) Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane, J. Biol. Chem., 276, 19414–19419.PubMedCrossRefGoogle Scholar
  68. 68.
    Tan, W., and Colombini, M. (2007) VDAC closure increases calcium ion flux, Biochim. Biophys. Acta, 29, 2510–2515.CrossRefGoogle Scholar
  69. 69.
    Shulga, N. (2009) Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism, Cell Cycle, 8, 3355–3364.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Mathupala, S., Ko, Y., and Pedersen, P. (2012) Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria, Oncogene, 25, 4777–4786.CrossRefGoogle Scholar
  71. 71.
    Pastorino, J., and Hoek, J. (2008) Regulation of hexokinase binding to VDAC, J. Bioenerg. Biomembr., 40, 171–182.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Schindler, A., and Foley, E. (2013) Hexokinase 1 blocks apoptotic signals at the mitochondria, Cell. Signal., 25, 2685–2692.PubMedCrossRefGoogle Scholar
  73. 73.
    Robey, R. B., and Hay, N. (2006) Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt, Oncogene, 25, 4683–4696.Google Scholar
  74. 74.
    Shinohara, Y., Ishida, T., Hino, M., Yamazaki, N., Baba, Y., and Terada, H. (2000) Characterization of porin isoforms expressed in tumor cells, Eur. J. Biochem., 267, 6067–6073.PubMedCrossRefGoogle Scholar
  75. 75.
    Kennedy, S. G., Kandel, E. S., Cross, T. K., and Hay, N. (1999) Akt/protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria, Mol. Cell. Biol., 19, 5800–5810.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Yamaguchi, A., Tamatani, M., Matsuzaki, H., Namikawa, K., Kiyama, H., Vitek, M. P., Mitsuda, N., and Tohyama, M. (2001) Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53, J. Biol. Chem., 276, 5256–5264.PubMedCrossRefGoogle Scholar
  77. 77.
    Del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R., and Nunez, G. (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt, Science, 278, 687–699.PubMedCrossRefGoogle Scholar
  78. 78.
    Franke, T. F., Hornik, C. P., Segev, L., Shostak, G. A., and Sugimoto, C. (2003) PI3K/Akt and apoptosis: size matters, Oncogene, 22, 8983–8998.PubMedCrossRefGoogle Scholar
  79. 79.
    Gogvadze, V., Zhivotovsky, B., and Orrenius, S. (2010) The Warburg effect and mitochondrial stability in cancer cells, Mol. Aspects Med., 31, 60–74.PubMedCrossRefGoogle Scholar
  80. 80.
    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.PubMedCrossRefGoogle Scholar
  81. 81.
    Mookherjee, P., and Quintanilla, R. (2007) Mitochondrialtargeted active Akt protects SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic cell death, J. Cell Biochem., 102, 196–210.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Weinberg, S. E., and Chandel, N. S. (2015) Targeting mitochondria metabolism for cancer therapy, Nat. Publ. Gr., 11, 9–15.Google Scholar
  83. 83.
    Neuzil, J., Dong, L. F., Rohlena, J., Truksa, J., and Ralph, S. J. (2013) Classification of mitocans, anti-cancer drugs acting on mitochondria, Mitochondrion, 13, 199–208.Google Scholar
  84. 84.
    Lea, M. A., Qureshi, M. S., Buxhoeveden, M., Gengel, N., Kleinschmit, J., and DesBordes, C. (2013) Regulation of the proliferation of colon cancer cells by compounds that affect glycolysis, including 3-bromopyruvate, 2-deoxyglucose and biguanides, Anticancer Res., 33, 401–407.PubMedGoogle Scholar
  85. 85.
    Loar, P., Wahl, H., Kshirsagar, M., Gossner, G., Griffith, K., and Liu, J. R. (2010) Inhibition of glycolysis enhances cisplatin-induced apoptosis in ovarian cancer cells, Am. J. Obstet. Gynecol., 202, 1–8.CrossRefGoogle Scholar
  86. 86.
    Maher, J. C., Krishan, A., and Lampidis, T. J. (2004) Greater cell cycle inhibition and cytotoxicity induced by 2deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions, Cancer Chemother. Pharmacol., 53, 116–122.PubMedCrossRefGoogle Scholar
  87. 87.
    Sullivan, E. J., Kurtoglu, M., Brenneman, R., Liu, H., and Lampidis, T. J. (2014) Targeting cisplatin-resistant human tumor cells with metabolic inhibitors, Cancer Chemother. Pharmacol., 73, 417–427.PubMedCrossRefGoogle Scholar
  88. 88.
    Birsoy, K., Wang, T., Possemato, R., Yilmaz, O., Koch, C., Chen, W., Hutchins, A., Gultekin, Y., Peterson, T., Carette, J., Brummelkamp, T., Clish, C., and Sabatini, D. M. (2012) MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors, Changes, 29, 997–1003.Google Scholar
  89. 89.
    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.PubMedCrossRefGoogle Scholar
  90. 90.
    Xu, R., Pelicano, H., and Zhou, Y. (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia, 65, 613–621.Google Scholar
  91. 91.
    Ralph, S. J., Low, P., Dong, L., Lawen, A., and Neuzil, J. (2006) Mitocans: mitochondrial targeted anti-cancer drugs as improved therapies and related patent documents, Recent Pat. Anticancer Drug Discov., 1, 327–346.PubMedCrossRefGoogle Scholar
  92. 92.
    Zu, X. L., and Guppy, M. (2004) Cancer metabolism: facts, fantasy, and fiction, Biochem. Biophys. Res. Commun., 313, 459–465.PubMedCrossRefGoogle Scholar
  93. 93.
    Dang, C. V., and Semenza, G. L. (1999) Oncogenic alterations of metabolism, Trends Biochem. Sci., 24, 68–72.PubMedCrossRefGoogle Scholar
  94. 94.
    Griguer, C. E., Oliva, C. R., and Gillespie, G. Y. (2005) Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines, J. Neurooncol., 74, 123–133.PubMedCrossRefGoogle Scholar
  95. 95.
    Mathupala, S. P., Ko, Y. H., and Pedersen, P. L. (2010) The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies, Biochim. Biophys. Acta–Bioenergetics, 1797, 1225–1230.CrossRefGoogle Scholar
  96. 96.
    Solaini, G., Sgarbi, G., and Baracca, A. (2011) Oxidative phosphorylation in cancer cells, Biochim. Biophys. Acta, 1807, 534–542.PubMedCrossRefGoogle Scholar
  97. 97.
    Reitzer, L., Wice, B., and Kennell, D. (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells, J. Biol. Chem., 254, 2669–2676.PubMedGoogle Scholar
  98. 98.
    Fuchs, B. C., and Bode, B. P. (2006) Stressing out over survival: glutamine as an apoptotic modulator, J. Surg. Res., 131, 26–40.PubMedCrossRefGoogle Scholar
  99. 99.
    Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., and Lazebnik, Y. (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells, J. Cell Biol., 178, 93–105.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Ladurner, A. G. (2006) Rheostat control of gene expression by metabolites, Mol. Cell, 24, 1–11.PubMedCrossRefGoogle Scholar
  101. 101.
    Jonas, E. A., Hickman, J. A., Chachar, M., Polster, B. M., Brandt, T. A., Fannjiang, Y., Ivanovska, I., Basanez, G., Kinnally, K. W., Zimmerberg, J., Hardwick, J. M., and Kaczmarek, L. K. (2004) Proapoptotic N-truncated BCLxL protein activates endogenous mitochondrial channels in living synaptic terminals, Proc. Natl. Acad. Sci. USA, 101, 13590–13595.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Baggetto, L. G. (1992) Deviant energetic metabolism of glycolytic cancer cells, Biochimie, 74, 959–974.PubMedCrossRefGoogle Scholar
  103. 103.
    Newsholme, E., Crabtree, B., and Ardawi, M. (1985) The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells, Biosci. Rep., 400, 393–400.CrossRefGoogle Scholar
  104. 104.
    Kruspig, B., Zhivotovsky, B., and Gogvadze, V. (2014) Mitochondrial substrates in cancer: drivers or passengers? Mitochondrion, 19, Pt. A, 8–19.PubMedCrossRefGoogle Scholar
  105. 105.
    Smolkova, K., Plecita-Hlavata, L., Bellance, N., Benard, G., Rossignol, R., and Jezek, P. (2011) Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells, Int. J. Biochem. Cell Biol., 43, 950–968.PubMedCrossRefGoogle Scholar
  106. 106.
    Bonnet, S., Archer, S. L., Allalunis-Turner, J., Haromy, A., Beaulieu, C., Thompson, R., Lee, C. T., Lopaschuk, G. D., Puttagunta, L., Bonnet, S., Harry, G., Hashimoto, K., Porter, C. J., Andrade, M. A., Thebaud, B., and Michelakis, E. D. (2007) A mitochondria–K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth, Cancer Cell, 11, 37–51.PubMedCrossRefGoogle Scholar
  107. 107.
    Cai, P., Boor, P. J., Khan, M., Kaphalia, B. S., Ansari, G. A., and Konig, R. (2007) Immunoand hepato-toxicity of dichloroacetic acid in MRL+/+ and B6C3F1 mice, J. Immunotoxicol., 4, 107–115.PubMedCrossRefGoogle Scholar
  108. 108.
    Moungjaroen, J., Nimmannit, U., Callery, P. S., Wang, L., Azad, N., Lipipun, V., Chanvorachote, P., and Rojanasakul, Y. (2006) Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 downregulation, J. Pharmacol. Exp. Ther., 319, 1062–1069.PubMedCrossRefGoogle Scholar
  109. 109.
    Simbula, G., Columbano, A., Ledda-Columbano, G. M., Sanna, L., Deidda, M., Diana, A., and Pibiri, M. (2007) Increased ROS generation and p53 activation in alphalipoic acid-induced apoptosis of hepatoma cells, Apoptosis, 12, 113–123.PubMedCrossRefGoogle Scholar
  110. 110.
    Feron, O. (2009) Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells, Radiother. Oncol., 92, 329–333.PubMedCrossRefGoogle Scholar
  111. 111.
    Dong, L., Low, P., Dyason, J., and Wang, X. (2008) αTocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II, Oncogene, 27, 4324–4335.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Baggetto, L., and Testa-Parussini, R. (1990) Role of acetoin on the regulation of intermediate metabolism of Ehrlich ascites tumor mitochondria: its contribution to membrane cholesterol enrichment modifying passive proton permeability, Arch. Biochem. Biophys., 283, 241–248.PubMedCrossRefGoogle Scholar
  113. 113.
    Kruspig, B., Nilchian, A., Bejarano, I., Orrenius, S., Zhivotovsky, B., and Gogvadze, V. (2012) Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression, Cell. Mol. Life Sci., 69, 2091–2099.PubMedCrossRefGoogle Scholar
  114. 114.
    Truksa, J., Dong, L.-F., Rohlena, J., Stursa, J., Vondrusova, M., Goodwin, J., Nguyen, M., Kluckova, K., Rychtarcikova, Z., Lettlova, S., Spacilova, J., Stapelberg, M., Zoratti, M., and Neuzil, J. (2015) Mitochondrially targeted vitamin E succinate modulates expression of mitochondrial DNA transcripts and mitochondrial biogenesis, Antioxid. Redox Signal., 22, 883–900.PubMedCrossRefGoogle Scholar
  115. 115.
    Liu, Z., Zhang, Y., Zhang, Q., Zhao, S., Wu, C., Cheng, X., Jiang, C., Jiang, Z., and Liu, H. (2014) 3Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway, Anticancer Drugs, 25, 447–455.PubMedCrossRefGoogle Scholar
  116. 116.
    Macchioni, L., Davidescu, M., and Roberti, R. (2014) The energy blockers 3-bromopyruvate and lonidamine: effects on bioenergetics of brain mitochondria, J. Bioenerg. Biomembr., 46, 389–394.PubMedCrossRefGoogle Scholar
  117. 117.
    Pereira da Silva, A. P., El-Bacha, T., Kyaw, N., dos Santos, R. S., da Silva, W. S., Almeida, F. C. L., Da Poian, A. T., and Galina, A. (2009) Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate, Biochem. J., 417, 717–726.PubMedCrossRefGoogle Scholar
  118. 118.
    Cardaci, S., Rizza, S., Filomeni, G., Bernardini, R., Bertocchi, F., Mattei, M., Paci, M., Rotilio, G., and Ciriolo, M. R. (2012) Glutamine deprivation enhances antitumor activity of 3-bromopyruvate through the stabilization of monocarboxylate transporter-1, Cancer Res., 72, 4526–4536.PubMedCrossRefGoogle Scholar
  119. 119.
    Van Delft, M. F., Wei, A. H., Mason, K. D., Vandenberg, C. J., Chen, L., Czabotar, P. E., Willis, S. N., Scott, C. L., Day, C. L., Adams, J. M., Roberts, A. W., and Huang, D. C. S. (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized, Cancer Cell, 10, 389–399.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Fulda, S., Galluzzi, L., and Kroemer, G. (2010) Targeting mitochondria for cancer therapy, Nat. Rev. Drug. Discov., 9, 447–464.PubMedCrossRefGoogle Scholar
  121. 121.
    Lessene, G., Czabotar, P. E., and Colman, P. M. (2008) BCL-2 family antagonists for cancer therapy, Nat. Rev. Drug Discov., 7, 989–1000.PubMedCrossRefGoogle Scholar
  122. 122.
    Albershardt, T. C., Salerni, B. L., Soderquist, R. S., Bates, D. J., Pletnev, A. A., Kisselev, A. F., and Eastman, A. (2011) Multiple BH3 mimetics antagonize antiapoptotic MCL-1 protein by inducing the endoplasmic reticulum stress response and upregulating BH3-only protein NOXA, J. Biol. Chem., 286, 24882–24895.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Billard, C. (2013) BH3 mimetics: status of the field and new developments, Mol. Cancer Ther., 12, 1691–1700.PubMedCrossRefGoogle Scholar
  124. 124.
    Zhang, Z., Song, T., Zhang, T., Gao, J., Wu, G., An, L., and Du, G. (2010) A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1, J. Cancer, 128, 1724–1735.Google Scholar
  125. 125.
    Soderquist, R., Pletnev, A. A., Danilov, A. V., and Eastman, A. (2013) The putative BH3 amimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA, Apoptosis, 19, 201–209.Google Scholar
  126. 126.
    Zhong, J. T., Xu, Y., Yi, H. W., Su, J., Yu, H. M., Xiang, X. Y., Li, X. N., Zhang, Z. C., and Sun, L. K. (2012) The BH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin 1 interaction in human glioma U251 cells, Cancer Lett., 323, 180–187.PubMedCrossRefGoogle Scholar
  127. 127.
    Song, T., Li, X., Chang, X., Liang, X., Zhao, Y., and Wu, G. Y. (2013) 3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) derivatives as panBcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1, Bioorg. Med. Chem., 21, 11–20.PubMedCrossRefGoogle Scholar
  128. 128.
    Song, T., Chen, Q., Li, X., Chai, G., and Zhang, Z. C. (2013) Correction to 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1)-based molecules as potent, dual inhibitors of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1): structure-based design and structure–activity relationship studies, J. Med. Chem., 56, 9366–9367.CrossRefGoogle Scholar
  129. 129.
    Ponassi, R., Biasotti, B., Tomati, V., Bruno, S., Poggi, A., Malacarne, D., Cimoli, G., Salis, A., Pozzi, S., Miglino, M., Damonte, G., Cozzini, P., Spyraki, F., Campanini, B., Bagnasco, L., Castagnino, N., Tortolina, L., Mumot, A., Frassoni, F., Daga, A., Cilli, M., Piccardi, F., Monfardini, I., Perugini, M., Zoppoli, G., D’Arrigo, C., Pesenti, R., and Parodi, S. (2008) A novel Bim-BH3derived Bcl-XL inhibitor: biochemical characterization, in vitro, in vivo and ex vivo anti-leukemic activity, Cell Cycle, 7, 3211–3224.PubMedCrossRefGoogle Scholar
  130. 130.
    Ghiotto, F., Fais, F., Tenca, C., Tomati, V., Morabito, F., Casciaro, S., Mumot, A., Zoppoli, G., Ciccone, E., Parodi, S., and Bruno, S. (2009) Apoptosis of B-cell chronic lymphocytic leukemia cells induced by a novel BH3 peptidomimetic, Cancer Biol. Ther., 8, 263–271.PubMedCrossRefGoogle Scholar
  131. 131.
    Cheng, G., Zielonka, J., Dranka, B. P., McAllister, D., Mackinnon, A. C., Jr., Joseph, J., and Kalyanaraman, B. (2012) Mitochondria targeted drugs synergize with 2deoxyglucose to trigger breast cancer cell death, Cancer Res., 72, 2634–2644.PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Sahra, I. B., Laurent, K., Giuliano, S., Larbret, F., Ponzio, G., Gounon, P., Le Marchand-Brustel, Y., Giorgetti-Peraldi, S., Cormont, M., Bertolotto, C., Deckert, M., Auberger, P., Tanti, J. F., and Bost, F. (2010) Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells, Cancer Res., 70, 2465–2475.PubMedCrossRefGoogle Scholar
  133. 133.
    Zhai, X., Yang, Y., Wan, J., Zhu, R., and Wu, Y. (2013) Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells, Oncol. Rep., 30, 2983–2991.PubMedGoogle Scholar
  134. 134.
    Meynet, O., Beneteau, M., Jacquin, M. A., Pradelli, L. A., Cornille, A., Carles, M., and Ricci, J.-E. (2012) Glycolysis inhibition targets Mcl-1 to restore sensitivity of lymphoma cells to ABT-737-induced apoptosis, Leukemia, 26, 1145–1147.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2016

Authors and Affiliations

  • P. V. Maximchik
    • 1
  • A. V. Kulikov
    • 1
  • B. D. Zhivotovsky
    • 1
    • 2
  • V. G. Gogvadze
    • 1
    • 2
    Email author
  1. 1.Faculty of Basic MedicineLomonosov Moscow State UniversityMoscowRussia
  2. 2.Institute of Environmental MedicineKarolinska InstitutetStockholmSweden

Personalised recommendations