Advertisement

Mitochondria as Targets for Cancer Therapy

  • Stephen J. Ralph
  • Jiri Neuzil
Chapter

Introduction: Molecularly Targeted Precision Heralds New-Age Cancer Therapy

Treatments that selectively target and kill cancer cells without affecting normal cells would represent the panacea for cancer. Gleevec (Imatinib) treatment of chronic myelogenous leukaemia (CML) provided the first example that such a feat was indeed possible by targeting the Bcr-Abl tyrosine kinase fusion protein specific to the survival of this type of cancer (O’Hare et al.2006). Together with the development of the monoclonal antibody Herceptin (Trastuzimab), which inhibits the HER2 (erbB2) receptor on breast cancer cells (Hsieh and Moasser2007), the drugs Gleevec and Herceptin have confirmed that the age of molecularly targeted cancer therapeutics has finally arrived.

We are now seeing another exciting time in cancer therapy with a range of compounds in development that selectively target mitochondria in cancer cells. The mitochondria acting as the powerhouses producing cellular energy are potential “powder...

Keywords

Reactive Oxygen Species Production Mitochondrial Outer Membrane Mitochondrial Permeability Transition Mitochondrial Permeability Transition Pore Mitochondrial Permeability Transition Pore 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Adam-Vizi, V. and Chinopoulos, C. 2006. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645.PubMedGoogle Scholar
  2. Alakurtti, S., Makela, T., Koskimies, S. and Yli-Kauhaluoma, J. 2006. Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci 29:1–13.PubMedGoogle Scholar
  3. Albores, R., Neafsey, E.J., Drucker, G., Fields, J.Z. and Collins, M.A. 1990. Mitochondrial respiratory inhibition byN.-methylated β-carboline derivatives structurally resemblingN-methyl-4-phenylpyridine Proc Natl Acad Sci USA87:9368–9372.PubMedGoogle Scholar
  4. Andreyev, A.Y., Kushnareva, Y.E. and Starkov, A.A. 2005. Mitochondrial metabolism of reactive oxygen species. Biochemistry (Moscow) 70:200–214.Google Scholar
  5. Antignani, A. and Youle, R.J. 2006. How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol 18:685–689.PubMedGoogle Scholar
  6. Antonsson, B., Montessuit, S., Sanchez, B. and Martinou, J.C. 2001. Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem 276:11615–11623.PubMedGoogle Scholar
  7. Arner, E.S. and Holmgren, A. 2006. The thioredoxin system in cancer. Semin Cancer Biol 16:420–426.PubMedGoogle Scholar
  8. Bacsi, A., Woodberry, M., Widger, W., Papaconstantinou, J., Mitra, S., Peterson, J.W. and Boldogh, I. 2006. Localization of superoxide anion production to mitochondrial electron transport chain in 3-NPA-treated cells. Mitochondrion 6:235–244.PubMedGoogle Scholar
  9. Baggetto, L.G. 1992. Deviant energetic metabolism of glycolytic cancer cells. Biochimie 74:959–974.PubMedGoogle Scholar
  10. Baggetto, L.G. and Lehninger, A.L. 1987. Isolated tumoral pyruvate dehydrogenase can synthesize acetoin which inhibits pyruvate oxidation as well as other aldehydes. Biochem Biophys Res Commun 145:153–159.PubMedGoogle Scholar
  11. Baggetto, L.G. 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.PubMedGoogle Scholar
  12. Baggetto, L.G., Clottes, E. and Vial, C. 1992. Low mitochondrial proton leak due to high membrane cholesterol content and cytosolic creatine kinase as two features of the deviant bioenergetics of Ehrlich and AS30-D tumor cells. Cancer Res 52:4935–4941.PubMedGoogle Scholar
  13. Bell, E.L. and Chandel, N.S. 2007. Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species. Essays Biochem 43:17–28.PubMedGoogle Scholar
  14. Belogrudov, G.I. 2002. Factor B is essential for ATP synthesis by mitochondria. Arch Biochem Biophys 406:271–274.PubMedGoogle Scholar
  15. Belogrudov, G.I. 2006. Bovine factor B: cloning, expression, and characterization. Arch Biochem Biophys 451:68–78.PubMedGoogle Scholar
  16. Belogrudov, G.I. and Hatefi, Y. 2002. Factor B and the mitochondrial ATP synthase complex. J Biol Chem 277:6097–6103.PubMedGoogle Scholar
  17. Belzacq, A.S., El Hamel, C., Vieira, H.L., Cohen, I., Haouzi, D., Metivier, D., Marchetti, P., Brenner, C. and Kroemer, G. 2001. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20:7579–7587.PubMedGoogle Scholar
  18. Bernal, S.D., Lampidis, T.J., Summerhayes, I.C. and Chen, L.B. 1982. Rhodamine-123 selectively reduces clonal growth of carcinoma cells in vitro. Science 218:1117–1119.PubMedGoogle Scholar
  19. Bernal, S.D., Lampidis, T.J., McIsaac, R.M. and Chen, L.B. 1983. Anticarcinoma activity in vivo of rhodamine 123, a mitochondrial-specific dye. Science 222:169–172.PubMedGoogle Scholar
  20. Berndt, C., Lillig, C.H. and Holmgren, A. 2007. Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am J Physiol 292:H1227–H1236.Google Scholar
  21. Bowman, E.J. and Bowman, B.J. 2005. V-ATPases as drug targets. J Bioenerg Biomembr 37:431–435.PubMedGoogle Scholar
  22. Bowman, E.J., Gustafson, K.R., Bowman, B.J. and Boyd, M.R. 2003. Identification of a new chondropsin class of antitumor compound that selectively inhibits V-ATPases. J Biol Chem 278:44147–44152.PubMedGoogle Scholar
  23. Brahimi-Horn, M.C., Chiche, J. and Pouyssegur, J. 2007. Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19:223–229.PubMedGoogle Scholar
  24. Britten, C.D., Rowinsky, E.K., Baker, S.D., Weiss, G.R., Smith, L., Stephenson, J., Rothenberg, M., Smetzer, L., Cramer, J., Collins, W., Von Hoff, D.D. and Eckhardt, S.G. 2000. A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077. Clin Cancer Res 6:42–49.PubMedGoogle Scholar
  25. Brookes, P.S. 2005. Mitochondrial H+. leak and ROS generation: an odd couple Free Radic Biol Med 38:12–23.2005.PubMedGoogle Scholar
  26. Brooks, G.A. 1998. Mammalian fuel utilization during sustained exercise. Comp Biochem Physiol B120:89–107.Google Scholar
  27. Brooks, G.A. 2000. Intra- and extra-cellular lactate shuttles. Med Sci Sports Exer 32:790–799.Google Scholar
  28. Brooks, G.A. 2002a. Lactate shuttle – between but not within cells? J Physiol 541:333.Google Scholar
  29. Brooks, G.A. 2002b. Lactate shuttles in nature. Biochem Soc Trans 30:258–264.Google Scholar
  30. Brooks, G.A., Brown, M.A., Butz, C.E., Sicurello, J.P. and Dubouchaud, H. 1999a. Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J Appl Physiol 87:1713–1718.Google Scholar
  31. Brooks, G.A., Dubouchaud, H., Brown, M., Sicurello, J.P. and Butz, C.E. 1999b. Role of mitochondrial lactate dehydrogenase and lactate oxidation in the intracellular lactate shuttle. Proc Natl Acad Sci USA 96:1129–1134.Google Scholar
  32. Brown, J.M. and Giaccia, A.J. 1998. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58:1408–1416.PubMedGoogle Scholar
  33. Bustamante, E., Morris, H.P. and Pedersen, P.L. 1981. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 256:8699–8704.PubMedGoogle Scholar
  34. Campian, J.L., Gao, X., Qian, M. and Eaton, J.W. 2007. Cytochrome C oxidase activity and oxygen tolerance. J Biol Chem 282:12430–12438.PubMedGoogle Scholar
  35. Cantley, L.C. 2002. The phosphoinositide 3-kinase pathway. Science 296:1655–1657.PubMedGoogle Scholar
  36. Cape, J.L., Bowman, M.K. and Kramer, D.M. 2007. A semiquinone intermediate generated at the Qo site of the cytochrome bc1 complex: importance for the Q-cycle and superoxide production. Proc Natl Acad Sci USA 104:7887–7892.PubMedGoogle Scholar
  37. Capuano, F., Guerrieri, F. and Papa, S. 1997. Oxidative phosphorylation enzymes in normal and neoplastic cell growth. J Bioenerg Biomembr 29:379–384.PubMedGoogle Scholar
  38. Capuano, F., Varone, D., D’Eri, N., Russo, E., Tommasi, S., Montemurro, S., Prete, F. and Papa, S. 1996. Oxidative phosphorylation and F0.F1 ATP synthase activity of human hepatocellular carcinoma Biochem Mol Biol Int 38:1013–1022.PubMedGoogle Scholar
  39. Cardone, R.A., Casavola, V. and Reshkin, S.J. 2005. The role of disturbed pH dynamics and the Na +/H + exchanger in metastasis. Nat Rev Cancer 5:786–795.PubMedGoogle Scholar
  40. Cartron, P.F., Arokium, H., Oliver, L., Meflah, K., Manon, S. and Vallette, F.M. 2005. Distinct domains control the addressing and the insertion of Bax into mitochondria. J Biol Chem 280:10587–10598.PubMedGoogle Scholar
  41. Chandel, N.S., McClintock, D.S., Feliciano, C.E., Wood, T.M., Melendez, J.A., Rodriguez, A.M., and Schumacker, P.T. 2000. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1. α during hypoxia: a mechanism of O2 sensing J Biol Chem275:25130–25138.PubMedGoogle Scholar
  42. Chang, B.S., Minn, A.J., Muchmore, S.W., Fesik, S.W., Thompson, C.B. 1997. Identification of a novel regulatory domain in Bcl-xL. and Bcl-2 EMBO J 16:968–977.PubMedGoogle Scholar
  43. Chang, K.N., Lee, T.C., Tam, M.F., Chen, Y.C., Lee, L.W., Lee, S.Y., Lin, P.J. and Huang, R.N. 2003. Identification of galectin I and thioredoxin peroxidase II as two arsenic-binding proteins in Chinese hamster ovary cells. Biochem J 371:495–503.PubMedGoogle Scholar
  44. Chang, T.S., Cho, C.S., Park, S., Yu, S., Kang, S.W. and Rhee, S.G. 2004. Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria. J Biol Chem 279:41975–41984.PubMedGoogle Scholar
  45. Chen, L.B. 1988. Mitochondrial membrane potential in living cells. Annu Rev Cell Biol 4:155–181.PubMedGoogle Scholar
  46. Connor, K.M., Subbaram, S., Regan, K.J., Nelson, K.K., Mazurkiewicz, J.E., Bartholomew, P.J., Aplin, A.E., Tai, Y.T., Aguirre-Ghiso, J., Flores, S.C. and Melendez, J.A. 2005. Mitochondrial H2.O2 regulates the angiogenic phenotype via PTEN oxidation J Biol Chem 280:16916–16924.PubMedGoogle Scholar
  47. Costantini, P., Chernyak, B.V., Petronilli, V. and Bernardi, P. 1996. Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites. J Biol Chem 271:6746–6751.PubMedGoogle Scholar
  48. Costantini, P., Belzacq, A.S., Vieira, H.L., Larochette, N., de Pablo, M.A., Zamzami, N., Susin, S.A., Brenner, C. and Kroemer, G. 2000. Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis. Oncogene 19:307–314.PubMedGoogle Scholar
  49. Cuezva, J.M., Ostronoff, L.K., Ricart, J., Lopez de Heredia, M., Di Ligero, C.M. and Izquierdo, J.M. 1997. Mitochondrial biogenesis in the liver during development and oncogenesis. J Bioenerg Biomembr 29:365–377.PubMedGoogle Scholar
  50. Dahout-Gonzalez, C., Nury, H., Trezeguet, V., Lauquin, G.J., Pebay-Peyroula, E. and Brandolin, G. 2006. Molecular, functional, and pathological aspects of the mitochondrial ADP/ATP carrier. Physiology 21:242–249.PubMedGoogle Scholar
  51. D’Alessio, M., De Nicola, M., Coppola, S., Gualandi, G., Pugliese, L., Cerella, C., Cristofanon, S., Civitareale, P., Ciriolo, M.R., Bergamaschi, A., Magrini, A. and Ghibelli, L. 2005. Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. FASEB J 19:1504–1506.PubMedGoogle Scholar
  52. Dalgard, C.L., Lu, H., Mohyeldin, A. and Verma, A. 2004. Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem J 380:419–424.PubMedGoogle Scholar
  53. Davey, G.P., Tipton, K.F. and Murphy, M.P. 1992. Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode. Biochem J 288:439–443.PubMedGoogle Scholar
  54. Davis, S., Weiss, M.J., Wong, J.R., Lampidis, T.J. and Chen, L.B. 1985. Mitochondrial and plasma membrane potentials cause unusual accumulation and retention of rhodamine 123 by human breast adenocarcinoma-derived MCF-7 cells. J Biol Chem 260:13844–13850.PubMedGoogle Scholar
  55. Degli-Esposti, M. and Dive, C. 2003. Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun 304:455–461.PubMedGoogle Scholar
  56. Deitrich, R.A., Petersen, D. and Vasiliou, V. 2007. Removal of acetaldehyde from the body. Novartis Found Symp 285:23–40.PubMedGoogle Scholar
  57. Dilda, P.J., Decollogne, S., Rossiter-Thornton, M. and Hogg, P.J. 2005. Para to ortho repositioning of the arsenical moiety of the angiogenesis inhibitor 4-(N.-(S-glutathionylacetyl)amino) phenylarsenoxide results in a markedly increased cellular accumulation and antiproliferative activity Cancer Res 65:11729–11734.PubMedGoogle Scholar
  58. Don, A.S., Kisker, O., Dilda, P., Donoghue, N., Zhao, X., Decollogne, S., Creighton, B., Flynn, E., Folkman, J. and Hogg, P.J. 2003. A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 3:497–509.PubMedGoogle Scholar
  59. Dong, L.F., Low, P., Dyason, J., Wang, X.F., Prochazka, L., Witting, P.K., Freeman, R., Swettenham, E., Valis, K., Liu, J., Zobalova, R., Turanek, J., Spitz , D.R., Domann, F.E., Scheffler, I.E., Ralph, S.J.and Neuzil, J. 2007a. α-Tocopheryl succinate induces apoptosis by targeting biquinone-binding sites in mitochondrial respiratory complex II.J Biol Chem.Google Scholar
  60. Dong, L.F., Swettenham, E., Eliasson, J., Wang, X.F., Gold, M., Medunic, Y., Stantic, M., Low, P., Prochazka, L., Witting, P.K., Turanek, J., Akporiaye, E.T., Ralph, S.J. and Neuzil, J. 2007b. Vitamin E analogs inhibit angiogenesis by selective apoptosis induction in proliferating endothelial cells: The role of oxidative stress. Cancer Res 67:11906–11913.Google Scholar
  61. Dyall, S.D., Agius, S.C., De Marcos Lousa, C., Trezeguet, V. and Tokatlidis, K. 2003. The dynamic dimerization of the yeast ADP/ATP carrier in the inner mitochondrial membrane is affected by conserved cysteine residues. J Biol Chem 278:26757–26764.PubMedGoogle Scholar
  62. Ellerby, H.M., Arap, W., Ellerby, L.M., Kain, R., Andrusiak, R., Rio, G.D., Krajewski, S., Lombardo, C.R., Rao, R., Ruoslahti, E., Bredesen, D.E. and Pasqualini, R. 1999. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5:1032–1038.PubMedGoogle Scholar
  63. Fantin, V.R., Berardi, M.J., Scorrano, L., Korsmeyer, S.J. and Leder, P. 2002. A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. Cancer Cell 2:29–42.PubMedGoogle Scholar
  64. Fantin, V.R., Berardi, M.J., Babbe, H., Michelman, M.V., Manning, C.M. and Leder, P. 2005. A bifunctional targeted peptide that blocks HER-2 tyrosine kinase and disables mitochondrial function in HER-2-positive carcinoma cells. Cancer Res 65:6891–6900.PubMedGoogle Scholar
  65. Firth, J.D., Ebert, B.L. and Ratcliffe, P.J. 1995. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 270:21021–21027.PubMedGoogle Scholar
  66. Fomenko, D.E. and Gladyshev, V.N. 2003. Identity and functions of CxxC-derived motifs. Biochemistry 42:11214–11225.PubMedGoogle Scholar
  67. Fomenko, D.E., Xing, W., Adair, B.M., Thomas, D.J. and Gladyshev, V.N. 2007. High-throughput identification of catalytic redox-active cysteine residues. Science 315:387–389.PubMedGoogle Scholar
  68. Fukuda, R., Zhang, H., Kim, J.W., Shimoda, L., Dang, C.V. and Semenza, G.L. 2007. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129:111–122.PubMedGoogle Scholar
  69. Gamboa-Vujicic, G., Emma, D.A., Liao, S.Y., Fuchtner, C. and Manetta, A. 1993. Toxicity of the mitochondrial poison dequalinium chloride in a murine model system. J Pharm Sci 82:231–235.PubMedGoogle Scholar
  70. Garattini, E., Gianni, M. and Terao, M. 2004. Retinoid related molecules an emerging class of apoptotic agents with promising therapeutic potential in oncology: pharmacological activity and mechanisms of action. Curr Pharm Des 10:433–448.PubMedGoogle Scholar
  71. Gerweck, L.E. 2000. The pH difference between tumor and normal tissue offers a tumor specific target for the treatment of cancer. Drug Resist Updat 3:49–50.PubMedGoogle Scholar
  72. Gerweck, L.E., Vijayappa, S. and Kozin, S. 2006. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther 5:1275–1279.PubMedGoogle Scholar
  73. Gincel, D., Zaid, H. and Shoshan-Barmatz, V. 2001. Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. Biochem J 358:147–155.PubMedGoogle Scholar
  74. Gledhill, J.R. and Walker, J.E. 2005. Inhibition sites in F1-ATPase from bovine heart mitochondria. Biochem J 386:591–598.PubMedGoogle Scholar
  75. Gosslau, A., Chen, M., Ho, C.T. and Chen, K.Y. 2005. A methoxy derivative of resveratrol analogue selectively induced activation of the mitochondrial apoptotic pathway in transformed fibroblasts. Br J Cancer 92:513–521.PubMedGoogle Scholar
  76. Gottlieb, E. and Tomlinson, I.P. 2005. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5:857–866.PubMedGoogle Scholar
  77. Guzman, M.L., Rossi, R.M., Karnischky, L., Li, X., Peterson, D.R., Howard, D.S. and Jordan, C.T. 2005. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105:4163–4169.PubMedGoogle Scholar
  78. Hail, N., Jr Kim, H.J. and Lotan, R. 2006. Mechanisms of fenretinide-induced apoptosis. Apoptosis 11:1677–1694.PubMedGoogle Scholar
  79. Han, D., Williams, E. and Cadenas, E. 2001. Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem J 353 :(Pt 2)411–416.PubMedGoogle Scholar
  80. Han, D., Antunes, F., Daneri, F. and Cadenas, E. 2002. Mitochondrial superoxide anion production and release into intermembrane space. Methods Enzymol 349:271–280.PubMedGoogle Scholar
  81. Han, D., Antunes, F., Canali, R., Rettori, D. and Cadenas, E. 2003. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278:5557–5563.PubMedGoogle Scholar
  82. Hansen, J.M., Zhang, H. and Jones, D.P. 2006. Differential oxidation of thioredoxin-1, thioredoxin-2, and glutathione by metal ions. Free Radic Biol Med 40:138–145.PubMedGoogle Scholar
  83. Harguindey, S., Orive, G., Luis Pedraz, J., Paradiso, A. and Reshkin, S.J. 2005. The role of pH dynamics and the Na+./H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin - one single nature Biochim Biophys Acta 1756:1–24.PubMedGoogle Scholar
  84. Hirano, S., Kobayashi, Y., Hayakawa, T., Cui, X., Yamamoto, M., Kanno, S. and Shraim, A. 2005. Accumulation and toxicity of monophenyl arsenicals in rat endothelial cells. Arch Toxicol 79:54–61.PubMedGoogle Scholar
  85. Hsieh, A.C. and Moasser, M.M. 2007. Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 97:453–457.PubMedGoogle Scholar
  86. Inarrea, P., Moini, H., Han, D., Rettori, D., Aguilo, I., Alava, M.A., Iturralde, M. and Cadenas, E. 2007. Mitochondrial respiratory chain and thioredoxin reductase regulate intermembrane Cu,Zn-superoxide dismutase activity: implications for mitochondrial energy metabolism and apoptosis. Biochem J 405:173–179.PubMedGoogle Scholar
  87. Izumi, H., Torigoe, T., Ishiguchi, H., Uramoto, H., Yoshida, Y., Tanabe, M., Ise, T., Murakami, T., Yoshida, T., Nomoto, M. and Kohno, K. 2003. Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549.PubMedGoogle Scholar
  88. Inarrea, P., Moini, H., Rettori, D., Han, D., Martinez, J., Garcia, I., Fernandez-Vizarra, E., Iturralde, M. and Cadenas, E. 2005. Redox activation of mitochondrial intermembrane space Cu,Zn-superoxide dismutase. Biochem J 387:203–209.PubMedGoogle Scholar
  89. James, M.L., Selleri, S. and Kassiou, M. 2006. Development of ligands for the peripheral benzodiazepine receptor. Curr Med Chem 13:1991–2001.PubMedGoogle Scholar
  90. Jones, L.W., Narayan, K.S., Shapiro, C.E. and Sweatman, T.W. 2005. Rhodamine-123: therapy for hormone refractory prostate cancer, a phase I clinical trial. J Chemother 17:435–440.PubMedGoogle Scholar
  91. Joshi, S. and Hughes, J.B. 1981. Inhibition of coupling factor B activity by cadmium ion, arsenite-2,3-dimercaptopropanol, and phenylarsine oxide, and preferential reactivation by dithiols. J Biol Chem 256:11112–11116.PubMedGoogle Scholar
  92. Kagan, V.E., Tyurin, V.A., Jiang, J., Tyurina, Y.Y., Ritov, V.B., Amoscato, A.A., Osipov, A.N., Belikova, N.A., Kapralov, A.A., Kini, V., Vlasova, I.I., Zhao, Q., Zou, M., Di, P., Svistunenko, D.A., Kurnikov, I.V. and Borisenko, G.G. 2005. Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 1:223–232.PubMedGoogle Scholar
  93. Kallio, A., Zheng, A., Dahllund, J., Heiskanen, K.M. and Harkonen, P. 2005. Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. Apoptosis 10:1395–1410.PubMedGoogle Scholar
  94. Kessler, J.H., Mullauer, F.B., de Roo, G.M. and Medema, J.P. 2007. Broad in vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types. Cancer Lett 251:132–145.PubMedGoogle Scholar
  95. Kim, J.H., Liu, L., Lee, S.O., Kim, Y.T., You, K.R. and Kim, D.G. 2005. Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. Cancer Res 65:6312–6320.PubMedGoogle Scholar
  96. Kim, J.-W., Gao, P. and Dang, C.V. 2007. Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev 27:291–298.Google Scholar
  97. King, A., Selak, M.A. and Gottlieb, E. 2006. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25:4675–4682.PubMedGoogle Scholar
  98. Knowles, H.J. and Harris, A.L. 2001. Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis. Breast Cancer Res 3:318–322.PubMedGoogle Scholar
  99. Ko, Y.H., Smith, B.L., Wang, Y., Pomper, M.G., Rini, D.A., Torbenson, M.S., Hullihen, J. and Pedersen, P.L. 2004. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 324:269–275.PubMedGoogle Scholar
  100. Koivunen, P., Tiainen, P., Hyvarinen, J., Williams, K.E., Sormunen, R., Klaus, S.J., Kivirikko, K.I. and Myllyharju, J. 2007. An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on HIF-. α. J Biol Chem282:30544–30552.PubMedGoogle Scholar
  101. Koobs, D.H. 1972. Phosphate mediation of the Crabtree and Pasteur effects. Does the change in energy metabolism enhance the potential for malignancy? Science 178:127–133.PubMedGoogle Scholar
  102. Koukourakis, M.I., Giatromanolaki, A., Simopoulos, C., Polychronidis, A. and Sivridis, E. 2005. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis 22:25–30.PubMedGoogle Scholar
  103. Kozin, S.V., Shkarin, P. and Gerweck, L.E. (2001) The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer Res 61:4740–4743.PubMedGoogle Scholar
  104. Kwon, J., Lee, S.R., Yang, K.S., Ahn, Y., Kim, Y.J., Stadtman, E.R. and Rhee, S.G. 2004. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci USA 101:16419–16424.PubMedGoogle Scholar
  105. Lampidis, T.J., Bernal, S.D., Summerhayes, I.C. and Chen, L.B. 1983. Selective toxicity of rhodamine 123 in carcinoma cells in vitro. Cancer Res 43:716–720.PubMedGoogle Scholar
  106. Lampidis, T.J., Hasin, Y., Weiss, M.J. and Chen, L.B. 1985. Selective killing of carcinoma cells “in vitro” by lipophilic-cationic compounds: a cellular basis. Biomed Pharmacother 39:220–226.PubMedGoogle Scholar
  107. Larochette, N., Decaudin, D., Jacotot, E., Brenner, C., Marzo, I., Susin, S.A., Zamzami, N., Xie, Z., Reed, J. and Kroemer, G. 1999. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res 249:413–421.PubMedGoogle Scholar
  108. Larsson, A. 1973. Thioredoxin reductase from rat liver. Eur J Biochem 35:346–349.PubMedGoogle Scholar
  109. Lee, A.H. and Tannock, I.F. 1998. Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells. Cancer Res 58:1901–1908.PubMedGoogle Scholar
  110. Lee, S.R., Yang, K.S., Kwon, J., Lee, C., Jeong, W. and Rhee, S.G. 2002. Reversible inactivation of the tumor suppressor PTEN by H2.O2 J Biol Chem 277:20336–20342.PubMedGoogle Scholar
  111. Lenaz, G. 2001. The mitochondrial production of reactive oxygen species: Mechanisms and implications in human pathology. IUBMB Life 52:159–164.PubMedGoogle Scholar
  112. Liu, W.K., Ho, J.C., Cheung, F.W., Liu, B.P., Ye, W.C. and Che, C.T. 2004. Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line. Eur J Pharmacol 498:71–78.PubMedGoogle Scholar
  113. Liu, J., Rone, M.B. and Papadopoulos, V. 2006. Protein–protein interactions mediate mitochondrial cholesterol transport and steroid biosynthesis. J Biol Chem 281:38879–38893.PubMedGoogle Scholar
  114. Lu, H., Dalgard, C.L., Mohyeldin, A., McFate, T., Tait, A.S. and Verma, A. 2005. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280:41928–41939.PubMedGoogle Scholar
  115. Lu, X., Qin, W., Li, J., Tan, N., Pan, D., Zhang, H., Xie, L., Yao, G., Shu, H., Yao, M., Wan, D., Gu, J. and Yang, S. (2005) The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Res 65:6843–6849.PubMedGoogle Scholar
  116. Maaser, K., Sutter, A.P. and Scherubl, H. 2005. Mechanisms of mitochondrial apoptosis induced by peripheral benzodiazepine receptor ligands in human colorectal cancer cells. Biochem Biophys Res Commun 332:646–652.PubMedGoogle Scholar
  117. Machida, K., Ohta, Y. and Osada, H. 2006. Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells. J Biol Chem 281:14314–14320.PubMedGoogle Scholar
  118. MacKenzie, E.D., Selak, M.A., Tennant, D.A., Payne, L.J., Crosby, S., Frederiksen, C.M., Watson, D.G. and Gottlieb, E. 2007. Cell-permeating . α-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells Mol Cell Biol27:3282–3289.PubMedGoogle Scholar
  119. Madesh, M. and Hajnoczky, G. 2001. VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release. J Cell Biol 155:1003–1015.PubMedGoogle Scholar
  120. Makin, G.W., Corfe, B.M., Griffiths, G.J., Thistlethwaite, A., Hickman, J.A. and Dive, C. 2001. Damage-induced Bax N-terminal change, translocation to mitochondria and formation of Bax dimers/complexes occur regardless of cell fate. EMBO J 20:6306–6315.PubMedGoogle Scholar
  121. Manning, B.D. and Cantley, L.C. 2007. AKT/PKB signaling: navigating downstream. Cell 129:1261–1274.PubMedGoogle Scholar
  122. Mathupala, S.P., Ko, Y.H. and Pedersen, P.L. 2006. Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777–4786.PubMedGoogle Scholar
  123. McLennan, H.R. and Degli Esposti, M. 2000. The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species. J Bioenerg Biomembr 32:153–162.PubMedGoogle Scholar
  124. McStay, G.P., Clarke, S.J. and Halestrap, A.P. 2002. Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J 367:541–548.PubMedGoogle Scholar
  125. Mikhailov, V., Mikhailova, M., Pulkrabek, D.J., Dong, Z., Venkatachalam, M.A. and Saikumar, P. 2001. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J Biol Chem 276:18361–18374.PubMedGoogle Scholar
  126. Modica-Napolitano, J.S. and Aprille, J.R. 1987. Basis for the selective cytotoxicity of rhodamine 123. Cancer Res 47:4361–4365.PubMedGoogle Scholar
  127. Modica-Napolitano, J.S. and Aprille, J.R. 2001. Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells. Adv Drug Deliv Rev 49:63–70.PubMedGoogle Scholar
  128. Modica-Napolitano, J.S. and Singh, K. 2002. Mitochondria as targets for detection and treatment of cancer. Expert Rev Mol Med 2002:1–19.Google Scholar
  129. Monkkonen, H., Auriola, S., Lehenkari, P., Kellinsalmi, M., Hassinen, I.E., Vepsalainen, J. and Monkkonen, J. 2006. A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147:437–445.PubMedGoogle Scholar
  130. Nakagawa, Y., Iinuma, M., Matsuura, N., Yi, K., Naoi, M., Nakayama, T., Nozawa, Y. and Akao, Y. 2005. A potent apoptosis-inducing activity of a sesquiterpene lactone, arucanolide, in HL60 cells: a crucial role of apoptosis-inducing factor. J Pharmacol Sci 97:242–252.PubMedGoogle Scholar
  131. Nechushtan, A., Smith, C.L., Hsu, Y.T. and Youle, R.J. 1999. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 18:2330–2341.PubMedGoogle Scholar
  132. Neuzil, J., Zhao, M., Ostermann, G., Sticha, M., Gellert, N., Weber, C., Eaton, J.W. and Brunk, U.T. 2002. α-Tocopheryl succinate, an agent with in vivo anti-tumour activity, induces apoptosis by causing lysosomal instability. Biochem J362:709–715.PubMedGoogle Scholar
  133. Neuzil, J., Wang, X.F., Dong, L.F., Low, P. and Ralph, S.J. 2006. Molecular mechanism of ‘mitocan’-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett 580:5125–5129.PubMedGoogle Scholar
  134. Neuzil, J., Dyason, J.C., Freeman, R., Dong, L.F., Prochazka, L., Wang, X.F., Scheffler, I., Ralph, S.J. 2007. Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II. J Bioenerg Biomembr 39:65–72.PubMedGoogle Scholar
  135. Nonn, L., Berggren, M. and Powis, G. 2003. Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis. Mol Cancer Res 1:682–689.PubMedGoogle Scholar
  136. Nury, H., Dahout-Gonzalez, C., Trezeguet, V., Lauquin, G.J., Brandolin, G. and Pebay-Peyroula, E. 2006. Relations between structure and function of the mitochondrial ADP/ATP carrier. Annu Rev Biochem 75:713–741.Google Scholar
  137. O’Hare, T., Corbin, A.S. and Druker, B.J. 2006. Targeted CML therapy: controlling drug resistance, seeking cure. Curr Opin Genet Dev 16:92–99.PubMedGoogle Scholar
  138. Ohnishi, T. and Salerno, J.C. 2005. Conformation-driven and semiquinone-gated proton-pump mechanism in the NADH-ubiquinone oxidoreductase (complex I). FEBS Lett 579:4555–4561.PubMedGoogle Scholar
  139. O’Neill, J., Manion, M., Schwartz, P. and Hockenbery, D.M. 2004. Promises and challenges of targeting Bcl-2 anti-apoptotic proteins for cancer therapy. Biochim Biophys Acta 1705:43–51.PubMedGoogle Scholar
  140. Ott, M., Robertson, J.D., Gogvadze, V., Zhivotovsky, B. and Orrenius, S. 2002. Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci USA 99:1259–1263.PubMedGoogle Scholar
  141. Ott, M., Gogvadze, V., Orrenius, S. and Zhivotovsky, B. 2007. Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922.PubMedGoogle Scholar
  142. Paddenberg, R., Ishaq, B., Goldenberg, A., Faulhammer, P., Rose, F., Weissmann, N., Braun-Dullaeus, R.C. and Kummer, W. 2003. Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. Am J Physiol 284:L710–L719.Google Scholar
  143. Pagliari, L.J., Kuwana, T., Bonzon, C., Newmeyer, D.D., Tu, S., Beere, H.M. and Green, D.R. 2005. The multidomain proapoptotic molecules Bax and Bak are directly activated by heat. Proc Natl Acad Sci USA 102:17975–17980.PubMedGoogle Scholar
  144. Papadopoulos, V., Baraldi, M., Guilarte, T.R., Knudsen, T.B., Lacapere, J.J., Lindemann, P., Norenberg, M.D., Nutt, D., Weizman, A., Zhang, M.R. and Gavish, M. 2006. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27:402–409.PubMedGoogle Scholar
  145. Papandreou, I., Cairns, R.A., Fontana, L., Lim, A.L. and Denko, N.C. 2006. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197.PubMedGoogle Scholar
  146. Parolin, M.L., Chesley, A., Matsos, M.P., Spriet, L.L., Jones, N.L. and Heigenhauser, G.J.F. 1999. Regulation of skeletal muscle glycogen phosphorylase and PDH during maximal intermittent exercise. Am J Physiol 277:E890–E900.PubMedGoogle Scholar
  147. Pastorino, J.G., Shulga, N. and Hoek, J.B. 2002. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 277:7610–7618.PubMedGoogle Scholar
  148. Pedersen, P.L. and Morris, H.P. 1974. Uncoupler stimulated adenosine triphosphatase activity. Deficiency in intact mitochondria from Morris hepatomas and ascites tumor cells. J Biol Chem 249:3327–3334.PubMedGoogle Scholar
  149. Pelicano, H., Feng, L., Zhou, Y., Carew, J.S., Hileman, E.O., Plunkett, W., Keating, M.J. and Huang, P. 2003. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 278:37832–37839.PubMedGoogle Scholar
  150. Pelicano, H., Xu, R.H., Du, M., Feng, L., Sasaki, R., Carew, J.S., Hu, Y., Ramdas, L., Hu, L., Keating, M.J., Zhang, W., Plunkett, W. and Huang, P. 2006. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J Cell Biol 175:913–923.PubMedGoogle Scholar
  151. Perier, C., Tieu, K., Guegan, C., Caspersen, C., Jackson-Lewis, V., Carelli, V., Martinuzzi, A., Hirano, M., Przedborski, S. and Vila, M. 2005. Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proc Natl Acad Sci USA 102:19126–19131.PubMedGoogle Scholar
  152. Petrosillo, G., Ruggiero, F.M., Pistolese, M. and Paradies, G. 2001. Reactive oxygen species generated from the mitochondrial electron transport chain induce cytochrome c dissociation from beef-heart submitochondrial particles via cardiolipin peroxidation. Possible role in the apoptosis. FEBS Lett 509:435–438.PubMedGoogle Scholar
  153. Pollard, P.J., Briere, J.J., Alam, N.A. et al. 2005. Accumulation of Krebs cycle intermediates and over-expression of HIF1 α in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239.PubMedGoogle Scholar
  154. Pretner, E., Amri, H., Li, W., Brown, R., Lin, C.S., Makariou, E., Defeudis, F.V., Drieu, K. and Papadopoulos, V. 2006. Cancer-related overexpression of the peripheral-type benzodiazepine receptor and cytostatic anticancer effects of Ginkgo biloba extract (EGb 761). Anticancer Res 26:9–22.PubMedGoogle Scholar
  155. 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 Patents Anti-cancer Drug Discovery 1:327–346.Google Scholar
  156. Ralph, S.J., Dyason, J.C., Freeman, R., Dong, L.F., Prochazka, L., Wang, X.F., Scheffler, I.E. and Neuzil, J. 2007. Mitocans as anti-cancer agents targeting mitochondria: Lessons from studies with vitamin E analogues, inhibitors of complex II. J Bioenerg Biomembr 39:65–72.PubMedGoogle Scholar
  157. Robey, R.B. and Hay, N. 2006. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25:4683–4696.PubMedGoogle Scholar
  158. Roche, T.E. and Hiromasa, Y. 2007. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 64:830–849.PubMedGoogle Scholar
  159. Rzeski, W., Stepulak, A., Szymanski, M., Sifringer, M., Kaczor, J., Wejksza, K., Zdzisinska, B. and Kandefer-Szerszen, M. 2006. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch Pharmacol 374:11–20.PubMedGoogle Scholar
  160. Sahara, N., Takeshita, A., Kobayashi, M., Shigeno, K., Nakamura, S., Shinjo, K., Naito, K., Maekawa, M., Horii, T., Ohnishi, K., Kitamura, K., Naoe, T., Hayash, H. and Ohno, R. 2004. Phenylarsine oxide (PAO) more intensely induces apoptosis in acute promyelocytic leukemia and As2.O3-resistant APL cell lines than As2O3 by activating the mitochondrial pathway Leuk Lymphoma 45:987–995.PubMedGoogle Scholar
  161. Sanborn, B.M., Felberg, N.T. and Hollocher, T.C. 1971. The inactivation of succinate dehydrogenase by bromopyruvate. Biochim Biophys Acta 227:219–231.PubMedGoogle Scholar
  162. Sareen, D., van Ginkel, P.R., Takach, J.C., Mohiuddin, A., Darjatmoko, S.R., Albert, D.M. and Polans, A.S. 2006. Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells. Invest Ophthalmol Vis Sci 47:3708–3716.PubMedGoogle Scholar
  163. Selak,M.A., Armour, S.M., MacKenzie, E.D., Boulahbel, H., Watson, D.G., Mansfield, K.D., Pan, Y., Simon, M.C., Thompson, C.B. and Gottlieb, E. 2005. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-. α prolyl hydroxylase Cancer Cell7:77–85.PubMedGoogle Scholar
  164. Semenza, G.L. 2007. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J 405:1–9.PubMedGoogle Scholar
  165. Sennoune, S.R., Luo, D. and Martinez-Zaguilan, R. 2004. Plasmalemmal vacuolar-type H + -ATPase in cancer biology. Cell Biochem Biophys 40:185–206.PubMedGoogle Scholar
  166. Shafir, I., Feng, W. and Shoshan-Barmataz, V. 1998. Voltage-dependent anion channel proteins in synaptosomes of the torpedo electric organ: immunolocalization, purification, and characterization. J Bioenerg Biomembr 30:499–510.PubMedGoogle Scholar
  167. Shiau, C.W., Huang, J.W., Wang, D.S., Weng, J.R., Yang, C.C., Lin, C.H., Li, C. and Chen, C.S. 2006. Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL./Bcl-2 function J Biol Chem 281:11819–11825.PubMedGoogle Scholar
  168. Shoshan-Barmatz, V., Israelson, A., Brdiczka, D. and Sheu, S.S. 2006. The voltage-dependent anion channel (VDAC): function in intracellular signalling, cell life and cell death. Curr Pharm Des 12:2249–2270.PubMedGoogle Scholar
  169. Skarsgard, L.D., Chaplin, D.J., Wilson, D.J., Skwarchuk, M.W., Vinczan, A. and Kristl, J. 1992. The effect of hypoxia and low pH on the cytotoxicity of chlorambucil. Int J Radiat Oncol Biol Phys 22:737–741.PubMedGoogle Scholar
  170. Slepkov, E.R., Rainey, J.K., Sykes, B.D. and Fliegel, L. 2007. Structural and functional analysis of the Na+./H+ exchanger Biochem J 401:623–633.PubMedGoogle Scholar
  171. Slot, J.W., Geuze, H.J., Freeman, B.A. and Crapo, J.D. 1986. Intracellular localization of the copper-zinc and manganese superoxide dismutases in rat liver parenchymal cells. Lab Invest 55:363–371.PubMedGoogle Scholar
  172. Smaili, S.S., Hsu, Y.T., Sanders, K.M., Russell, J.T. and Youle, R.J. 2001. Bax translocation to mitochondria subsequent to a rapid loss of mitochondrial membrane potential. Cell Death Differ 8:909–920.PubMedGoogle Scholar
  173. Smith, R.A., Porteous, C.M., Gane, A.M. and Murphy, M.P. 2003. Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci USA 100:5407–5412.PubMedGoogle Scholar
  174. Stankiewicz, A.R., Lachapelle, G., Foo, C.P., Radicioni, S.M. and Mosser, D.D. 2005. Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280:38729–38739.PubMedGoogle Scholar
  175. Steele, A.J., Jones, D.T., Ganeshaguru, K., Duke, V.M., Yogashangary, B.C., North, J.M., Lowdell, M.W., Kottaridis, P.D., Mehta, A.B., Prentice, A.G., Hoffbrand, A.V. and Wickremasinghe, R.G. 2006. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 20:1073–1079.PubMedGoogle Scholar
  176. Summerhayes, I.C., Lampidis, T.J., Bernal, S.D., Nadakavukaren, J.J. Nadakavukaren, K.K. Shepherd, E.L. Chen, L.B.1982Unusual retention of rhodamine 123 by mitochondria in muscle and carcinoma cells. Proc Natl Acad Sci USA 79:5292–5296.PubMedGoogle Scholar
  177. Suzuki, M., Youle, R.J. and Tjandra, N. 2000. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103:645–654.PubMedGoogle Scholar
  178. Tan, C., Dlugosz, P.J., Peng, J., Zhang, Z., Lapolla, S.M., Plafker, S.M., Andrews, D.W. and Lin, J. 2006. Auto-activation of the apoptosis protein BAX increases mitochondrial membrane permeability and is inhibited by BCL-2. J Biol Chem 281:14764–14775.PubMedGoogle Scholar
  179. Tinhofer, I., Bernhard, D., Senfter, M., Anether, G., Loeffler, M., Kroemer, G., Kofler, R., Csordas, A. and Greil, R. 2001. Resveratrol, a tumor-suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl-2. FASEB J 15:1613–1615.PubMedGoogle Scholar
  180. Trachootham, D., Zhou, Y., Zhang, H., Demizu, Y., Chen, Z., Pelicano, H., Chiao, P.J., Achanta, G., Arlinghaus, R.B., Liu, J. and Huang, P. 2006. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by . β-phenylethyl isothiocyanate Cancer Cell10:241–252.PubMedGoogle Scholar
  181. Trapp, S. and Horobin, R.W. 2005. A predictive model for the selective accumulation of chemicals in tumor cells. Eur Biophys J 34:959–966.PubMedGoogle Scholar
  182. Turrens, J.F. 1997. Superoxide production by the mitochondrial respiratory chain. Biosci Rep 17:3–8.PubMedGoogle Scholar
  183. Turrens, J.F., Alexandrem, A. and Lehninger, A.L. 1985. Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237:408–414.PubMedGoogle Scholar
  184. 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., Cory, S., Adams, J.M., Roberts, A.W. and Huang, D.C. 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.PubMedGoogle Scholar
  185. Vaupel, P. and Mayer, A. 2007. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239.PubMedGoogle Scholar
  186. Verrier, F., Deniaud, A., Lebras, M., Metivier, D., Kroemer, G., Mignotte, B., Jan, G. and Brenner, C. 2004. Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis. Oncogene 23:8049–8064.PubMedGoogle Scholar
  187. Vivanco, I. and Sawyers, C.L. 2002. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501.PubMedGoogle Scholar
  188. Vyssokikh, M., Zorova, L., Zorov, D., Heimlich, G., Jurgensmeier, J., Schreiner, D. and Brdiczka, D. 2004. The intra-mitochondrial cytochrome c distribution varies correlated to the formation of a complex between VDAC and the adenine nucleotide translocase: this affects Bax-dependent cytochrome c release. Biochim Biophys Acta 1644:27–36.PubMedGoogle Scholar
  189. Walenta, S. and Mueller-Klieser, W.F. 2004. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol 14:267–274.PubMedGoogle Scholar
  190. Wallace, D.C. 2005. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407.PubMedGoogle Scholar
  191. Wang, K., Gross, A., Waksman, G. and Korsmeyer, S.J. 1998. Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing. Mol Cell Biol 18:6083–6089.PubMedGoogle Scholar
  192. Warburg, O. 1956. On the origin of cancer cells. Science 123:309–314.PubMedGoogle Scholar
  193. Warburg, O., Wind, F. and Neglers, E. 1930. On the metabolism of tumors in the body. In Warburg (ed.). pp O. Metabolism of Tumors, Arnold Constable and Co. Press.London: 254–270.Google Scholar
  194. Wen, J., You, K.R., Lee, S.Y., Song, C.H. and Kim, D.G. 2002. Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem 277:38954–38964.PubMedGoogle Scholar
  195. Wolter, K.G., Hsu, Y.T., Smith, C.L., Nechushtan, A., Xi, X.G. and Youle, R.J. 1997. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139:1281–1292.PubMedGoogle Scholar
  196. Wu, X., Senechal, K., Neshat, M.S., Whang, Y.E. and Sawyers, C.L. 1998. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA 95:15587–15591.PubMedGoogle Scholar
  197. Xu, Y., Salerno, J.C., Wei, Y.H. and King, T.E. 1987. Stabilized ubisemiquinone in reconstituted succinate ubiquinone reductase. Biochem Biophys Res Commun 144:315–322.PubMedGoogle Scholar
  198. Xiao, D., Lew, K.L., Zeng, Y., Xiao, H., Marynowski, S.W., Dhir, R. and Singh, S.V. 2006. Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential. Carcinogenesis 27:2223–2234.PubMedGoogle Scholar
  199. Yethon, J.A., Epand, R.F., Leber, B., Epand, R.M. and Andrews, D.W. 2003. Interaction with a membrane surface triggers a reversible conformational change in Bax normally associated with induction of apoptosis. J Biol Chem 278:48935–48941.PubMedGoogle Scholar
  200. Yu, C.A., Nagoaka, S., Yu, L. and King, T.E. 1980. Evidence of ubisemiquinone radicals in electron transfer at the cytochromes b and c1 region of the cardiac respiratory chain. Arch Biochem Biophys 204:59–70.PubMedGoogle Scholar
  201. Zalk, R., Israelson, A., Garty, E.S., Azoulay-Zohar, H. and Shoshan-Barmatz, V. 2005. Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria. Biochem J 386:73–83.PubMedGoogle Scholar
  202. Zha, A., Aime-Sempe, C., Sato, T. and Reed, J.C. 1996. Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 271:7440–7444.PubMedGoogle Scholar
  203. Zhang, R., Al-Lamki, R., Bai, L., Streb, J.W., Miano, J.M., Bradley, J. and Min, W. 2004. Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ Res 94:1483–1491.PubMedGoogle Scholar
  204. Zhang, Z.Y., Davis, J.P. and Van Etten, R.L. 1992. Covalent modification and active site-directed inactivation of a low molecular weight phosphotyrosyl protein phosphatase. Biochemistry 31:1701–1711.PubMedGoogle Scholar
  205. Zhang, Z., Lapolla, S.M., Annis, M.G., Truscott, M., Roberts, G.J., Miao, Y., Shao, Y., Tan, C., Peng, J., Johnson, A.E., Zhang, X.C., Andrews, D.W. and Lin, J. 2004. Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax. J Biol Chem 279:43920–43928.PubMedGoogle Scholar
  206. Zhao, K., Zhao, G.M., Wu, D., Soong, Y., Birk, A.V., Schiller, P.W. and Szeto, H.H. 2004. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 279:34682–34690.PubMedGoogle Scholar
  207. Zheng, Y., Shi, Y., Tian, C., Jiang, C., Jin, H., Chen, J., Almasan, A., Tang, H. and Chen, Q. 2004. Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene 23:1239–1247.PubMedGoogle Scholar
  208. Zhivotovsky, B., Orrenius, S., Brustugun, O.T. and Doskeland, S.O. 1998. Injected cytochrome c induces apoptosis. Nature 391:449–450.PubMedGoogle Scholar
  209. Zhou, L., Jing, Y., Styblo, M., Chen, Z. and Waxman, S. 2005. Glutathione-S.-transferase pi inhibits As2O3-induced apoptosis in lymphoma cells: involvement of hydrogen peroxide catabolism Blood 105:1198–1203.PubMedGoogle Scholar
  210. Zini, R., Morin, C., Bertelli, A., Bertelli, A.A. and Tillement, J.P. 1999. Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res 25:87–97.PubMedGoogle Scholar
  211. Zuckerbraun, B.S., Chin, B.Y., Bilban, M., de Costa d’Avila, J., Rao, J., Billiar, T.R. and Otterbein, L.E. 2007. Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J 21:1099–1106.PubMedGoogle Scholar
  212. Zunino, S.J. and Storms, D.H. 2006. Resveratrol-induced apoptosis is enhanced in acute lymphoblastic leukemia cells by modulation of the mitochondrial permeability transition pore. Cancer Lett 240:123–134.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2009

Authors and Affiliations

  1. 1.Griffith University School of Medical SciencesAustralia

Personalised recommendations