Skip to main content

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

  • Review Article
  • Published:

Targeting mitochondria for cancer therapy

Key Points

  • Mitochondria exert both vital and lethal functions in physiological and pathological conditions. Mitochondria are not only indispensable for energy production and the survival of eukaryotic cells, but are also crucial regulators of the intrinsic (mitochondrial) pathway of apoptosis.

  • Mitochondrial functions are frequently altered in cancers. Most classical anticancer agents engage signalling pathways that lie upstream of mitochondria and converge on these organelles to trigger cell death. Thus, drugs that directly target mitochondria constitute unique tools to bypass drug resistance.

  • Metabolic reprogramming is a central feature of cancer cells that is intricately linked to mitochondria and provides unique opportunities for the development of drugs that target the Achilles' heel of cancer.

  • The permeabilization of mitochondrial membranes constitutes a central event during mitochondrial apoptosis. Several classes of pharmacological compounds have been identified that impinge on mitochondrial membrane permeabilization, including modulators of the B-cell lymphoma protein 2 (BCL-2) protein family, metabolic inhibitors, voltage-dependent anion channel (VDAC)-targeting and adenine nucleotide translocase (ANT)-targeting agents, redox-active molecules, retinoids, heat-shock protein 90 (HSP90) inhibitors, as well as natural compounds with distinct mechanisms of action.

  • Several mitochondrially-targeted agents with anticancer activity are derived from natural compounds and have been identified by serendipity rather than by high-throughput screening methods. Thus, the systematic screening of large libraries of natural substances most likely represents a treasure trove for anticancer drug discovery.

  • Mitochondria are the most prominent source of intracellular reactive oxygen species (ROS) and low levels of ROS have been implicated in cancer cell stemness. Mitochondrially-targeted redox-active agents may therefore provide a novel strategy to selectively target cancer stem cells.

Abstract

Mitochondria are the cells' powerhouse, but also their suicidal weapon store. Dozens of lethal signal transduction pathways converge on mitochondria to cause the permeabilization of the mitochondrial outer membrane, leading to the cytosolic release of pro-apoptotic proteins and to the impairment of the bioenergetic functions of mitochondria. The mitochondrial metabolism of cancer cells is deregulated owing to the use of glycolytic intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions. Activation of the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mitochondrial permeability transition (MPT).
Figure 2: Chemical structures of selected mitochondrially-targeted anticancer agents.
Figure 3: Mitochondrial outer membrane permeabilization (MOMP).
Figure 4: The heat-shock protein, 90 kDa (HSP90) system in cancer cells.

Similar content being viewed by others

References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Google Scholar 

  2. Fulda, S. Tumor resistance to apoptosis. Int. J. Cancer 124, 511–515 (2009).

    CAS  PubMed  Google Scholar 

  3. Fulda, S. & Debatin, K. M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798–4811 (2006).

    CAS  PubMed  Google Scholar 

  4. Kroemer, G., Galluzzi, L. & Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163 (2007).

    CAS  PubMed  Google Scholar 

  5. Galluzzi, L. et al. No death without life: vital functions of apoptotic effectors. Cell Death Differ. 15, 1113–1123 (2008).

    CAS  PubMed  Google Scholar 

  6. Galluzzi, L. & Kroemer, G. Necroptosis: a specialized pathway of programmed necrosis. Cell 135, 1161–1163 (2008).

    CAS  PubMed  Google Scholar 

  7. Golstein, P. & Kroemer, G. Cell death by necrosis: towards a molecular definition. Trends Biochem. Sci. 32, 37–43 (2007).

    CAS  PubMed  Google Scholar 

  8. Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 18, 165–173 (2008).

    CAS  PubMed  Google Scholar 

  9. Bellance, N., Lestienne, P. & Rossignol, R. Mitochondria: from bioenergetics to the metabolic regulation of carcinogenesis. Front. Biosci. 14, 4015–4034 (2009).

    Google Scholar 

  10. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009). First demonstration that breast cancer stem cells maintain lower levels of ROS than their non-tumorigenic counterparts, providing a link between the management of ROS by cancer stem cells and tumour resistance to radiotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13, 472–482 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Modica-Napolitano, J. S. & Singh, K. K. Mitochondrial dysfunction in cancer. Mitochondrion 4, 755–762 (2004).

    CAS  PubMed  Google Scholar 

  13. Canter, J. A., Kallianpur, A. R., Parl, F. F. & Millikan, R. C. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res. 65, 8028–8033 (2005).

    CAS  PubMed  Google Scholar 

  14. Petros, J. A. et al. mtDNA mutations increase tumorigenicity in prostate cancer. Proc. Natl Acad. Sci. USA 102, 719–724 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Galluzzi, L. et al. Mitochondrial gateways to cancer. Mol. Aspects Med. 31, 1–20 (2010).

    CAS  PubMed  Google Scholar 

  16. Armstrong, J. S. Mitochondrial medicine: pharmacological targeting of mitochondria in disease. Br. J. Pharmacol. 151, 1154–1165 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Galluzzi, L., Larochette, N., Zamzami, N. & Kroemer, G. Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25, 4812–4830 (2006).

    CAS  PubMed  Google Scholar 

  18. Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria as targets for cancer chemotherapy. Semin. Cancer Biol. 19, 57–66 (2009).

    CAS  PubMed  Google Scholar 

  19. Bouchier-Hayes, L., Munoz-Pinedo, C., Connell, S. & Green, D. R. Measuring apoptosis at the single cell level. Methods 44, 222–228 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakagawa, T. et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652–658 (2005).

    CAS  PubMed  Google Scholar 

  21. Baines, C. P., Kaiser, R. A., Sheiko, T., Craigen, W. J. & Molkentin, J. D. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nature Cell Biol. 9, 550–555 (2007).

    CAS  PubMed  Google Scholar 

  22. Galluzzi, L. & Kroemer, G. Mitochondrial apoptosis without VDAC. Nature Cell Biol. 9, 487–489 (2007).

    CAS  PubMed  Google Scholar 

  23. Kokoszka, J. E. et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461–465 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Majewski, N. et al. Hexokinase–mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830 (2004).

    CAS  PubMed  Google Scholar 

  25. Zamora, M., Granell, M., Mampel, T. & Vinas, O. Adenine nucleotide translocase 3 (ANT3) overexpression induces apoptosis in cultured cells. FEBS Lett. 563, 155–160 (2004).

    CAS  PubMed  Google Scholar 

  26. Bauer, M. K., Schubert, A., Rocks, O. & Grimm, S. Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J. Cell Biol. 147, 1493–1502 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Le Bras., M. et al. Chemosensitization by knockdown of adenine nucleotide translocase-2. Cancer Res. 66, 9143–9152 (2006).

    CAS  PubMed  Google Scholar 

  28. Marzo, I. et al. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281, 2027–2031 (1998).

    CAS  PubMed  Google Scholar 

  29. Belzacq, A. S. et al. Bcl-2 and Bax modulate adenine nucleotide translocase activity. Cancer Res. 63, 541–546 (2003).

    CAS  PubMed  Google Scholar 

  30. Shen, Q. et al. Adenine nucleotide translocator cooperates with core cell death machinery to promote apoptosis in Caenorhabditis elegans. Mol. Cell Biol. 29, 3881–3893 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhivotovsky, B., Galluzzi, L., Kepp, O. & Kroemer, G. Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery. Cell Death Differ. 16, 1419–1425 (2009).

    CAS  PubMed  Google Scholar 

  32. Don, A. S. et al. A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 3, 497–509 (2003). Demonstrates that GSAO, a peptide trivalent arsenical that acts as an ANT cross-linker, inhibits tumour angiogenesis by selectively targeting mitochondria in proliferating endothelial cells.

    CAS  PubMed  Google Scholar 

  33. Belzacq, A. S. et al. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20, 7579–7587 (2001).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  35. Dogliotti, L. et al. Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J. Clin. Oncol. 14, 1165–1172 (1996).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Lehenkari, P. P. et al. Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol. Pharmacol. 61, 1255–1262 (2002).

    CAS  PubMed  Google Scholar 

  38. Diel, I. J. et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann. Oncol. 19, 2007–2011 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Green, J. R. Antitumor effects of bisphosphonates. Cancer 97, 840–847 (2003).

    PubMed  Google Scholar 

  40. Tang, X. et al. Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells. Int. J. Cancer 126, 90–103 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Slack, J. L. & Rusiniak, M. E. Current issues in the management of acute promyelocytic leukemia. Ann. Hematol. 79, 227–238 (2000).

    CAS  PubMed  Google Scholar 

  42. Marchetti, P. et al. The novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus. Cancer Res. 59, 6257–6266 (1999).

    CAS  PubMed  Google Scholar 

  43. Notario, B., Zamora, M., Vinas, O. & Mampel, T. All-trans-retinoic acid binds to and inhibits adenine nucleotide translocase and induces mitochondrial permeability transition. Mol. Pharmacol. 63, 224–231 (2003).

    CAS  PubMed  Google Scholar 

  44. Parrella, E. et al. Antitumor activity of the retinoid-related molecules (E)-3-(4′-hydroxy-3′-adamantylbiphenyl-4-yl)acrylic acid (ST1926) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma: role of retinoic acid receptor γ and retinoid-independent pathways. Mol. Pharmacol. 70, 909–924 (2006).

    CAS  PubMed  Google Scholar 

  45. Sala, F. et al. Development and validation of a liquid chromatography–tandem mass spectrometry method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in plasma of patients in a Phase I study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877, 3118–3126 (2009).

    CAS  PubMed  Google Scholar 

  46. Maaser, K. et al. Up-regulation of the peripheral benzodiazepine receptor during human colorectal carcinogenesis and tumor spread. Clin. Cancer Res. 11, 1751–1756 (2005).

    CAS  PubMed  Google Scholar 

  47. Galiegue, S., Casellas, P., Kramar, A., Tinel, N. & Simony-Lafontaine, J. Immunohistochemical assessment of the peripheral benzodiazepine receptor in breast cancer and its relationship with survival. Clin. Cancer Res. 10, 2058–2064 (2004).

    CAS  PubMed  Google Scholar 

  48. Okaro, A. C., Fennell, D. A., Corbo, M., Davidson, B. R. & Cotter, F. E. Pk11195, a mitochondrial benzodiazepine receptor antagonist, reduces apoptosis threshold in Bcl-XL and Mcl-1 expressing human cholangiocarcinoma cells. Gut 51, 556–561 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Decaudin, D. et al. Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo. Cancer Res. 62, 1388–1393 (2002).

    CAS  PubMed  Google Scholar 

  50. Gonzalez-Polo, R. A. et al. PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor. Oncogene 24, 7503–7513 (2005).

    CAS  PubMed  Google Scholar 

  51. Walter, R. B. et al. PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism. Blood 106, 3584–3593 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Palmeira, C. M. & Wallace, K. B. Benzoquinone inhibits the voltage-dependent induction of the mitochondrial permeability transition caused by redox-cycling naphthoquinones. Toxicol. Appl. Pharmacol. 143, 338–347 (1997).

    CAS  PubMed  Google Scholar 

  53. Petronilli, V. et al. The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents. J. Biol. Chem. 269, 16638–16642 (1994).

    CAS  PubMed  Google Scholar 

  54. Costantini, P. et al. 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 (2000).

    CAS  PubMed  Google Scholar 

  55. Lim, D. et al. Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy. Invest. New Drugs 23, 235–239 (2005).

    PubMed  Google Scholar 

  56. Sarin, S. K. et al. High dose vitamin K3 infusion in advanced hepatocellular carcinoma. J. Gastroenterol. Hepatol. 21, 1478–1482 (2006).

    CAS  PubMed  Google Scholar 

  57. Magda, D. & Miller, R. A. Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin. Cancer Biol. 16, 466–476 (2006).

    CAS  PubMed  Google Scholar 

  58. Mehta, M. P. et al. Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. Int. J. Radiat. Oncol. Biol. Phys. 73, 1069–1076 (2009).

    CAS  PubMed  Google Scholar 

  59. Bradley, K. A. et al. Motexafin gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a Children's Oncology Group phase I study. Neuro Oncol. 10, 752–758 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Bey, E. A. et al. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by β-lapachone. Proc. Natl Acad. Sci. USA 104, 11832–11837 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Maeda, H. et al. Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine. Cell Death Differ. 11, 737–746 (2004).

    CAS  PubMed  Google Scholar 

  62. Dragovich, T. et al. Phase I trial of imexon in patients with advanced malignancy. J. Clin. Oncol. 25, 1779–1784 (2007).

    CAS  PubMed  Google Scholar 

  63. Moulder, S. et al. A phase I trial of imexon, a pro-oxidant, in combination with docetaxel for the treatment of patients with advanced breast, non-small cell lung and prostate cancer. Invest. New Drugs 6 Jun 2009 (doi:10.1007/s10637-009-9273-1).

    PubMed  Google Scholar 

  64. Trachootham, D. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006). Demonstrates that abnormal ROS generation in tumour cells can be exploited for selectively killing cancer versus normal cells by means of the natural compound PEITC.

    CAS  PubMed  Google Scholar 

  65. Xiao, D. et al. 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 (2006).

    CAS  PubMed  Google Scholar 

  66. Alexandre, J. et al. Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J. Natl Cancer Inst. 98, 236–244 (2006).

    CAS  PubMed  Google Scholar 

  67. Huang, P., Feng, L., Oldham, E. A., Keating, M. J. & Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407, 390–395 (2000).

    CAS  PubMed  Google Scholar 

  68. Wood, L. et al. Inhibition of superoxide dismutase by 2-methoxyoestradiol analogues and oestrogen derivatives: structure–activity relationships. Anticancer Drug Des. 16, 209–215 (2001).

    CAS  PubMed  Google Scholar 

  69. Juarez, J. C. et al. Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc. Natl Acad. Sci. USA 105, 7147–7152 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lu, J., Chew, E. H. & Holmgren, A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc. Natl Acad. Sci. USA 104, 12288–12293 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Tuma, R. S. Reactive oxygen species may have antitumor activity in metastatic melanoma. J. Natl Cancer Inst. 100, 11–12 (2008).

    PubMed  Google Scholar 

  72. Matei, D. et al. Activity of 2 methoxyestradiol (Panzem NCD) in advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis: a Hoosier Oncology Group trial. Gynecol. Oncol. 115, 90–96 (2009).

    CAS  PubMed  Google Scholar 

  73. Tevaarwerk, A. J. et al. Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies. Clin. Cancer Res. 15, 1460–1465 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rajkumar, S. V. et al. Novel therapy with 2-methoxyestradiol for the treatment of relapsed and plateau phase multiple myeloma. Clin. Cancer Res. 13, 6162–6167 (2007).

    CAS  PubMed  Google Scholar 

  75. Sweeney, C. et al. A phase II multicenter, randomized, double-blind, safety trial assessing the pharmacokinetics, pharmacodynamics, and efficacy of oral 2-methoxyestradiol capsules in hormone-refractory prostate cancer. Clin. Cancer Res. 11, 6625–6633 (2005).

    CAS  PubMed  Google Scholar 

  76. O'Day, S. et al. Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J. Clin. Oncol. 27, 5452–5458 (2009).

    CAS  PubMed  Google Scholar 

  77. Berkenblit, A. et al. Phase I clinical trial of STA-4783 in combination with paclitaxel in patients with refractory solid tumors. Clin. Cancer Res. 13, 584–590 (2007).

    CAS  PubMed  Google Scholar 

  78. Chipuk, J. E., Bouchier-Hayes, L. & Green, D. R. Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ. 13, 1396–1402 (2006).

    CAS  PubMed  Google Scholar 

  79. Willis, S. N. & Adams, J. M. Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 17, 617–625 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lovell, J. F. et al. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135, 1074–1084 (2008).

    CAS  PubMed  Google Scholar 

  81. Leu, J. I., Dumont, P., Hafey, M., Murphy, M. E. & George, D. L. Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex. Nature Cell Biol. 6, 443–450 (2004).

    CAS  PubMed  Google Scholar 

  82. Chipuk, J. E. et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010–1014 (2004).

    CAS  PubMed  Google Scholar 

  83. Gavathiotis, E. et al. BAX activation is initiated at a novel interaction site. Nature 455, 1076–1081 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bellot, G. et al. TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax. Cell Death Differ. 14, 785–794 (2007).

    CAS  PubMed  Google Scholar 

  85. Ross, K., Rudel, T. & Kozjak-Pavlovic, V. TOM-independent complex formation of Bax and Bak in mammalian mitochondria during TNFα-induced apoptosis. Cell Death Differ. 16, 697–707 (2009).

    CAS  PubMed  Google Scholar 

  86. Rostovtseva, T. K. et al. Bax activates endophilin B1 oligomerization and lipid membrane vesiculation. J. Biol. Chem. 284, 34390–34399 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kuwana, T. et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111, 331–342 (2002).

    CAS  PubMed  Google Scholar 

  88. Lucken-Ardjomande, S., Montessuit, S. & Martinou, J. C. Contributions to Bax insertion and oligomerization of lipids of the mitochondrial outer membrane. Cell Death Differ. 15, 929–937 (2008).

    CAS  PubMed  Google Scholar 

  89. Cipolat, S. et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126, 163–175 (2006).

    CAS  PubMed  Google Scholar 

  90. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).

    CAS  PubMed  Google Scholar 

  91. Lessene, G., Czabotar, P. E. & Colman, P. M. BCL-2 family antagonists for cancer therapy. Nature Rev. Drug Discov. 7, 989–1000 (2008).

    CAS  Google Scholar 

  92. Vogler, M., Dinsdale, D., Dyer, M. J. & Cohen, G. M. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ. 16, 360–367 (2009).

    CAS  PubMed  Google Scholar 

  93. Vogler, M. et al. Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ. 16, 1030–1039 (2009).

    CAS  PubMed  Google Scholar 

  94. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005). Describes the discovery of ABT-737, an inhibitor of BCL-2, BCL-X L and BCL-W, by nuclear magnetic resonance-based screening, parallel synthesis and structure-based design.

    CAS  PubMed  Google Scholar 

  95. Chen, S., Dai, Y., Harada, H., Dent, P. & Grant, S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 67, 782–791 (2007).

    CAS  PubMed  Google Scholar 

  96. Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006).

    CAS  PubMed  Google Scholar 

  97. Mason, K. D. et al. In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas. Proc. Natl Acad. Sci. USA 105, 17961–17966 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. van Delft, M. F. et al. 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 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Kang, M. H. et al. Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood 110, 2057–2066 (2007).

    CAS  PubMed  Google Scholar 

  100. Kutuk, O. & Letai, A. Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737. Cancer Res. 68, 7985–7994 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Hann, C. L. et al. Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. Cancer Res. 68, 2321–2328 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Tagscherer, K. E. et al. Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene 27, 6646–6656 (2008).

    CAS  PubMed  Google Scholar 

  103. Kuroda, J. et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc. Natl Acad. Sci. USA 103, 14907–14912 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kuroda, J. et al. Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr–Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr–Abl-positive leukemia. Cell Death Differ. 14, 1667–1677 (2007).

    CAS  PubMed  Google Scholar 

  105. Kohl, T. M. et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia 21, 1763–1772 (2007).

    CAS  PubMed  Google Scholar 

  106. Cragg, M. S., Kuroda, J., Puthalakath, H., Huang, D. C. & Strasser, A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med. 4, e316 (2007).

    PubMed Central  Google Scholar 

  107. Gong, Y. et al. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med. 4, e294 (2007).

    PubMed  PubMed Central  Google Scholar 

  108. Cragg, M. S. et al. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J. Clin. Invest. 118, 3651–3659 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Paoluzzi, L. et al. The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 112, 2906–2916 (2008).

    CAS  PubMed  Google Scholar 

  110. Miller, L. A. et al. BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis. J. Invest. Dermatol. 129, 964–971 (2009).

    CAS  PubMed  Google Scholar 

  111. Whitecross, K. F. et al. Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. Blood 113, 1982–1991 (2009).

    CAS  PubMed  Google Scholar 

  112. Huang, S. & Sinicrope, F. A. BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res. 68, 2944–2951 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Song, J. H., Kandasamy, K. & Kraft, A. S. ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis. J. Biol. Chem. 283, 25003–25013 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Mason, K. D. et al. The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 23, 2034–2041 (2009).

    CAS  PubMed  Google Scholar 

  115. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    CAS  PubMed  Google Scholar 

  116. Lock, R. et al. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr. Blood Cancer 50, 1181–1189 (2008).

    PubMed  Google Scholar 

  117. Shoemaker, A. R. et al. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res. 66, 8731–8739 (2006).

    CAS  PubMed  Google Scholar 

  118. Lynn, A. & Jones, L. Gossypol and some other terpenoids, flavonoids, and phenols that affect quality of cottonseed protein. Am. Oil Chemists Soc. 56, 727–730 (1979).

    Google Scholar 

  119. Azmi, A. S. & Mohammad, R. M. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J. Cell Physiol. 218, 13–21 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Liu, G. et al. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin. Cancer Res. 15, 3172–3176 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kitada, S. et al. Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048). Blood 111, 3211–3219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Nguyen, M. et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc. Natl Acad. Sci. USA 104, 19512–19517 (2007). First demonstration that obatoclax triggers apoptosis by neutralizing MCL1.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Trudel, S. et al. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood 109, 5430–5438 (2007).

    CAS  PubMed  Google Scholar 

  124. Perez-Galan, P., Roue, G., Villamor, N., Campo, E. & Colomer, D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 109, 4441–4449 (2007).

    CAS  PubMed  Google Scholar 

  125. Konopleva, M. et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 68, 3413–3420 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. O'Brien, S. M. et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 113, 299–305 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Schimmer, A. D. et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 8295–8301 (2008).

    CAS  PubMed  Google Scholar 

  128. Wang, J. L. et al. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc. Natl Acad. Sci. USA 97, 7124–7129 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Manero, F. et al. The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Cancer Res. 66, 2757–2764 (2006).

    CAS  PubMed  Google Scholar 

  130. Moulder, S. L. et al. Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer. Clin. Cancer Res. 14, 7909–7916 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. O'Brien, S. et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J. Clin. Oncol. 25, 1114–1120 (2007).

    CAS  PubMed  Google Scholar 

  132. Rheingold, S. R. et al. Phase I Trial of G3139, a bcl-2 antisense oligonucleotide, combined with doxorubicin and cyclophosphamide in children with relapsed solid tumors: a Children's Oncology Group Study. J. Clin. Oncol. 25, 1512–1518 (2007).

    CAS  PubMed  Google Scholar 

  133. Rudin, C. M. et al. Randomized phase II Study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J. Clin. Oncol. 26, 870–876 (2008).

    CAS  PubMed  Google Scholar 

  134. Chanan-Khan, A. A. et al. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk. Lymphoma 50, 559–565 (2009).

    CAS  PubMed  Google Scholar 

  135. Simons, A. L., Ahmad, I. M., Mattson, D. M., Dornfeld, K. J. & Spitz, D. R. 2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res. 67, 3364–3370 (2007).

    CAS  PubMed  Google Scholar 

  136. Pastorino, J. G., Hoek, J. B. & Shulga, N. Activation of glycogen synthase kinase 3β disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res. 65, 10545–10554 (2005).

    CAS  PubMed  Google Scholar 

  137. Chiara, F. et al. Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PLoS One 3, e1852 (2008).

    PubMed  PubMed Central  Google Scholar 

  138. Galluzzi, L., Kepp, O., Tajeddine, N. & Kroemer, G. Disruption of the hexokinase-VDAC complex for tumor therapy. Oncogene 27, 4633–4635 (2008).

    CAS  PubMed  Google Scholar 

  139. Goldin, N. et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27, 4636–4643 (2008).

    CAS  PubMed  Google Scholar 

  140. Kim, W. et al. Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma. Mol. Cancer Ther. 6, 2554–2562 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  142. Chen, Z., Zhang, H., Lu, W. & Huang, P. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim. Biophys. Acta 1787, 553–560 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Bonnet, S. et al. A mitochondria–K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007). Proof-of-concept study that the PDK inhibitor dichloroacetate induces apoptosis by shifting metabolism from glycolysis to glucose oxidation (resulting in mitochondrial depolarization), and by upregulating the K+ channel Kv1.5.

    CAS  PubMed  Google Scholar 

  144. Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

    CAS  PubMed  Google Scholar 

  145. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    CAS  PubMed  Google Scholar 

  146. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009). Identification of a novel molecular link between cellular metabolism and gene regulation through histone acetylation.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Beckers, A. et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 67, 8180–8187 (2007).

    CAS  PubMed  Google Scholar 

  148. Carvalho, M. A. et al. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int. J. Cancer 123, 2557–2565 (2008).

    CAS  PubMed  Google Scholar 

  149. Mootha, V. K. et al. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115, 629–640 (2003).

    CAS  PubMed  Google Scholar 

  150. Kang, B. H. et al. Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131, 257–270 (2007).

    CAS  PubMed  Google Scholar 

  151. Wright, G. L. et al. VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase. FASEB J. 22, 3264–3275 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Plescia, J. et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7, 457–468 (2005). Development of the first cell-permeable peptidomimetic that disrupts the interaction between the chaperone HSP90 and the anti-apoptotic and mitotic regulator survivin.

    CAS  PubMed  Google Scholar 

  153. Gyurkocza, B. et al. Antileukemic activity of shepherdin and molecular diversity of hsp90 inhibitors. J. Natl Cancer Inst. 98, 1068–1077 (2006).

    CAS  PubMed  Google Scholar 

  154. Kang, B. H. et al. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J. Clin. Invest. 119, 454–464 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Rodina, A. et al. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nature Chem. Biol. 3, 498–507 (2007).

    CAS  Google Scholar 

  156. Caldas-Lopes, E. et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc. Natl Acad. Sci. USA 106, 8368–8373 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Paduch, R., Kandefer-Szerszen, M., Trytek, M. & Fiedurek, J. Terpenes: substances useful in human healthcare. Arch. Immunol. Ther. Exp. (Warsz) 55, 315–327 (2007).

    CAS  Google Scholar 

  158. Liby, K. T., Yore, M. M. & Sporn, M. B. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nature Rev. Cancer 7, 357–369 (2007).

    CAS  Google Scholar 

  159. Cichewicz, R. H. & Kouzi, S. A. Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Med. Res. Rev. 24, 90–114 (2004).

    CAS  PubMed  Google Scholar 

  160. Fulda, S. et al. Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res. 57, 4956–4964 (1997).

    CAS  PubMed  Google Scholar 

  161. Fulda, S. et al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem. 273, 33942–33948 (1998).

    CAS  PubMed  Google Scholar 

  162. Fulda, S., Susin, S. A., Kroemer, G. & Debatin, K. M. Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res. 58, 4453–4460 (1998).

    CAS  PubMed  Google Scholar 

  163. Andre, N. et al. Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells. FEBS Lett. 532, 256–260 (2002).

    CAS  PubMed  Google Scholar 

  164. Wick, W., Grimmel, C., Wagenknecht, B., Dichgans, J. & Weller, M. Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing. J. Pharmacol. Exp. Ther. 289, 1306–1312 (1999).

    CAS  Google Scholar 

  165. Tan, Y., Yu, R. & Pezzuto, J. M. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin. Cancer Res. 9, 2866–2875 (2003).

    CAS  PubMed  Google Scholar 

  166. Selzer, E. et al. Effects of betulinic acid alone and in combination with irradiation in human melanoma cells. J. Invest. Dermatol. 114, 935–940 (2000).

    CAS  PubMed  Google Scholar 

  167. Selzer, E. et al. Betulinic acid-induced Mcl-1 expression in human melanoma — mode of action and functional significance. Mol. Med. 8, 877–884 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Thurnher, D. et al. Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck 25, 732–740 (2003).

    PubMed  Google Scholar 

  169. Fulda, S. & Debatin, K. M. Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors. Med. Pediatr. Oncol. 35, 616–618 (2000).

    CAS  PubMed  Google Scholar 

  170. Meng, R. D. & El-Deiry, W. S. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. Exp. Cell Res. 262, 154–169 (2001).

    CAS  PubMed  Google Scholar 

  171. Salti, G. I. et al. Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent. Melanoma Res. 11, 99–104 (2001).

    CAS  PubMed  Google Scholar 

  172. Zuco, V. et al. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett. 175, 17–25 (2002).

    CAS  PubMed  Google Scholar 

  173. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    CAS  PubMed  Google Scholar 

  174. Gledhill, J. R., Montgomery, M. G., Leslie, A. G. & Walker, J. E. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl Acad. Sci. USA 104, 13632–13637 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Tinhofer, I. et al. Resveratrol, a tumor-suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl-2. FASEB J. 15, 1613–1615 (2001).

    CAS  PubMed  Google Scholar 

  176. Chen, C. et al. Mitochondrial ATP synthasome: three-dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for Pi and ADP/ATP. J. Biol. Chem. 279, 31761–31768 (2004).

    CAS  PubMed  Google Scholar 

  177. Biasutto, L. et al. Development of mitochondria-targeted derivatives of resveratrol. Bioorg Med. Chem. Lett. 18, 5594–5597 (2008).

    CAS  PubMed  Google Scholar 

  178. Jeong, S. H. et al. A novel resveratrol derivative, HS1793, overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Biochem. Pharmacol. 77, 1337–1347 (2009).

    CAS  PubMed  Google Scholar 

  179. Morrison, D. K. The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol. 19, 16–23 (2009).

    CAS  PubMed  Google Scholar 

  180. Korsmeyer, S. J. BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 59, 1693s–1700s (1999).

    CAS  PubMed  Google Scholar 

  181. Boocock, D. J. et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol. Biomarkers Prev. 16, 1246–1252 (2007).

    CAS  PubMed  Google Scholar 

  182. Constantinou, C., Papas, A. & Constantinou, A. I. Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogs. Int. J. Cancer 123, 739–752 (2008).

    CAS  PubMed  Google Scholar 

  183. Zhao, Y., Neuzil, J. & Wu, K. Vitamin E analogues as mitochondria-targeting compounds: from the bench to the bedside? Mol. Nutr. Food Res. 53, 129–139 (2009).

    CAS  PubMed  Google Scholar 

  184. Jia, L., Yu, W., Wang, P., Sanders, B. G. & Kline, K. In vivo and in vitro studies of anticancer actions of α-TEA for human prostate cancer cells. Prostate 68, 849–860 (2008).

    CAS  PubMed  Google Scholar 

  185. Hahn, T. et al. Dietary administration of the proapoptotic vitamin E analogue α-tocopheryloxyacetic acid inhibits metastatic murine breast cancer. Cancer Res. 66, 9374–9378 (2006).

    CAS  PubMed  Google Scholar 

  186. Lawson, K. A. et al. Comparison of vitamin E derivatives α-TEA and VES in reduction of mouse mammary tumor burden and metastasis. Exp. Biol. Med. (Maywood) 229, 954–963 (2004).

    CAS  Google Scholar 

  187. Dong, L. F. et al. Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 27, 4324–4335 (2008). Identification of the interaction with the proximal and distal ubiquinone-binding sites of the respiratory complex II as the molecular basis for the mitochondrial targeting of α-TOS.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Dong, L. F. et al. Suppression of tumor growth in vivo by the mitocan α-tocopheryl succinate requires respiratory complex II. Clin. Cancer Res. 15, 1593–1600 (2009).

    CAS  PubMed  Google Scholar 

  189. Dong, L. F. et al. Vitamin E analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: the role of oxidative stress. Cancer Res. 67, 11906–11913 (2007).

    CAS  PubMed  Google Scholar 

  190. Neuzil, J. et al. Induction of cancer cell apoptosis by α-tocopheryl succinate: molecular pathways and structural requirements. FASEB J. 15, 403–415 (2001).

    CAS  PubMed  Google Scholar 

  191. Fariss, M. W., Nicholls-Grzemski, F. A., Tirmenstein, M. A. & Zhang, J. G. Enhanced antioxidant and cytoprotective abilities of vitamin E succinate is associated with a rapid uptake advantage in rat hepatocytes and mitochondria. Free Radic. Biol. Med. 31, 530–541 (2001).

    CAS  PubMed  Google Scholar 

  192. Wright, M. E. et al. Effects of α-tocopherol and β-carotene supplementation on upper aerodigestive tract cancers in a large, randomized controlled trial. Cancer 109, 891–898 (2007).

    CAS  PubMed  Google Scholar 

  193. Kim, J. H. et al. Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. Cancer Res. 65, 6312–6320 (2005).

    CAS  PubMed  Google Scholar 

  194. Steele, A. J. et al. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 20, 1073–1079 (2006).

    CAS  PubMed  Google Scholar 

  195. Zhang, S., Ong, C. N. & Shen, H. M. Involvement of proapoptotic Bcl-2 family members in parthenolide-induced mitochondrial dysfunction and apoptosis. Cancer Lett. 211, 175–188 (2004).

    CAS  PubMed  Google Scholar 

  196. Guzman, M. L. et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110, 4427–4435 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Guzman, M. L. et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105, 4163–4169 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Pajak, B., Gajkowska, B. & Orzechowski, A. Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells. Folia Histochem. Cytobiol. 46, 129–135 (2008).

    CAS  PubMed  Google Scholar 

  199. Rosen, J. M. & Jordan, C. T. The increasing complexity of the cancer stem cell paradigm. Science 324, 1670–1673 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Smith, J., Ladi, E., Mayer-Proschel, M. & Noble, M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc. Natl Acad. Sci. USA 97, 10032–10037 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Tsatmali, M., Walcott, E. C. & Crossin, K. L. Newborn neurons acquire high levels of reactive oxygen species and increased mitochondrial proteins upon differentiation from progenitors. Brain Res. 1040, 137–150 (2005).

    CAS  PubMed  Google Scholar 

  202. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    CAS  PubMed  Google Scholar 

  203. Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature Med. 12, 446–451 (2006).

    CAS  PubMed  Google Scholar 

  204. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

    CAS  PubMed  Google Scholar 

  205. Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007).

    CAS  PubMed  Google Scholar 

  206. Simon, M. C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nature Rev. Mol. Cell Biol. 9, 285–296 (2008).

    CAS  Google Scholar 

  207. Brahimi-Horn, M. C., Chiche, J. & Pouyssegur, J. Hypoxia signalling controls metabolic demand. Curr. Opin. Cell Biol. 19, 223–229 (2007).

    CAS  PubMed  Google Scholar 

  208. Warburg, O., Posener, K. & Negelein, E. Über den Stoffwechsel der Tumoren. Biochemische Zeitschrift 152, 319–344 (1924) (in German).

    Google Scholar 

  209. Miyamoto, S., Murphy, A. N. & Brown, J. H. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 15, 521–529 (2008).

    CAS  PubMed  Google Scholar 

  210. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Wang, H. Q. et al. Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene 24, 3574–3582 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  213. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006).

    CAS  PubMed  Google Scholar 

  214. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006). This is the first demonstration that the absence of a single p53 target gene, synthesis of SCO2, recapitulates the metabolic switch towards glycolysis that is exhibited by p53-deficient cells, thereby providing a possible explanation for the Warburg effect.

    CAS  PubMed  Google Scholar 

  215. Semenza, G. L. Life with oxygen. Science 318, 62–64 (2007).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  217. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell. Metab. 3, 187–197 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  219. Murphy, M. P. Selective targeting of bioactive compounds to mitochondria. Trends Biotechnol. 15, 326–330 (1997).

    CAS  PubMed  Google Scholar 

  220. Galluzzi, L. et al. Methods for the assessment of mitochondrial membrane permeabilization in apoptosis. Apoptosis 12, 803–813 (2007).

    CAS  PubMed  Google Scholar 

  221. Yousif, L. F., Stewart, K. M. & Kelley, S. O. Targeting mitochondria with organelle-specific compounds: strategies and applications. Chembiochem 10, 1939–1950 (2009).

    CAS  PubMed  Google Scholar 

  222. Ross, M. F., Filipovska, A., Smith, R. A., Gait, M. J. & Murphy, M. P. Cell-penetrating peptides do not cross mitochondrial membranes even when conjugated to a lipophilic cation: evidence against direct passage through phospholipid bilayers. Biochem. J. 383, 457–468 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Kelso, G. F. et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem. 276, 4588–4596 (2001).

    CAS  PubMed  Google Scholar 

  224. Yousif, L. F., Stewart, K. M., Horton, K. L. & Kelley, S. O. Mitochondria-penetrating peptides: sequence effects and model cargo transport. Chembiochem 10, 2081–2088 (2009).

    CAS  PubMed  Google Scholar 

  225. Neupert, W. & Herrmann, J. M. Translocation of proteins into mitochondria. Annu. Rev. Biochem. 76, 723–749 (2007).

    CAS  PubMed  Google Scholar 

  226. Mukhopadhyay, A., Ni, L., Yang, C. S. & Weiner, H. Bacterial signal peptide recognizes HeLa cell mitochondrial import receptors and functions as a mitochondrial leader sequence. Cell. Mol. Life Sci. 62, 1890–1899 (2005).

    CAS  PubMed  Google Scholar 

  227. Vestweber, D. & Schatz, G. DNA–protein conjugates can enter mitochondria via the protein import pathway. Nature 338, 170–172 (1989).

    CAS  PubMed  Google Scholar 

  228. Srivastava, S. & Moraes, C. T. Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum. Mol. Genet. 10, 3093–3099 (2001).

    CAS  PubMed  Google Scholar 

  229. Horton, K. L., Stewart, K. M., Fonseca, S. B., Guo, Q. & Kelley, S. O. Mitochondria-penetrating peptides. Chem. Biol. 15, 375–382 (2008).

    CAS  PubMed  Google Scholar 

  230. Maiti, K. K. et al. Guanidine-containing molecular transporters: sorbitol-based transporters show high intracellular selectivity toward mitochondria. Angew. Chem. Int. Ed. Engl. 46, 5880–5884 (2007).

    CAS  PubMed  Google Scholar 

  231. Yamada, Y. et al. MITO-Porter: A liposome-based carrier system for delivery of macromolecules into mitochondria via membrane fusion. Biochim. Biophys. Acta 1778, 423–432 (2008).

    CAS  PubMed  Google Scholar 

  232. Weissig, V. et al. DQAsomes: a novel potential drug and gene delivery system made from dequalinium. Pharm. Res. 15, 334–337 (1998).

    CAS  PubMed  Google Scholar 

  233. Galluzzi, L. et al. Methods to dissect mitochondrial membrane permeabilization in the course of apoptosis. Methods Enzymol. 442, 355–374 (2008).

    PubMed  Google Scholar 

  234. Deniaud, A. et al. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27, 285–299 (2008).

    CAS  PubMed  Google Scholar 

  235. Yamada, Y., Akita, H., Kogure, K., Kamiya, H. & Harashima, H. Mitochondrial drug delivery and mitochondrial disease therapy — an approach to liposome-based delivery targeted to mitochondria. Mitochondrion 7, 63–71 (2007).

    CAS  PubMed  Google Scholar 

  236. Sergeeva, A., Kolonin, M. G., Molldrem, J. J., Pasqualini, R. & Arap, W. Display technologies: application for the discovery of drug and gene delivery agents. Adv. Drug Deliv. Rev. 58, 1622–1654 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Pathania, D., Millard, M. & Neamati, N. Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv. Drug Deliv. Rev. 61, 1250–1275 (2009).

    CAS  PubMed  Google Scholar 

  238. Kitada, S. et al. Discovery, characterization, and structure–activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J. Med. Chem. 46, 4259–4264 (2003).

    CAS  PubMed  Google Scholar 

  239. Kirshner, J. R. et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol. Cancer Ther. 7, 2319–2327 (2008).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to all colleagues whose articles we were unable to cite due to space limitations. We are indebted to O. Kepp for help in figure preparation. S.F. is supported by the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Bildung und Forschung, Wilhelm-Sander-Stiftung, Else-Kröner-Fresenius Stiftung, the Novartis Stiftung für therapeutische Forschung, the European Union (ApopTrain, APO-SYS), and IAP6/18. G.K. is supported by the Ligue Nationale contre le cancer (équipe labellisée), Agence National de Recherche (ANR), Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation pour la Recherche Médicale (FRM), and the European Union (Active p53, ApopTrain, APO-SYS, ChemoRes, TransDeath, RIGHT).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Simone Fulda or Guido Kroemer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Overview of the development status of mitochondrially-targeted drugs (PDF 817 kb)

Glossary

Intrinsic pathway of apoptosis

Also known as mitochondrial apoptosis, it is triggered by intracellular stimuli such as Ca2+ overload and overproduction of reactive oxygen species. By contrast, extrinsic apoptosis is initiated at the plasma membrane by specific transmembrane receptors.

Mitochondrial membrane permeabilization

The rupture of mitochondrial membranes leads to their functional impairment as well as to the release of toxic mitochondrial intermembrane space proteins into the cytosol.

Mitochondrial permeability transition

(MPT). Long-lasting openings of the permeability transition pore complex lead to an abrupt increase in the inner mitochondrial membrane permeability to ions and low molecular mass solutes, in turn provoking osmotic swelling of the mitochondrial matrix and mitochondrial membrane permeabilization.

Mitochondrial outer membrane permeabilization

(MOMP). The pore-forming activity of pro-apoptotic BCL-2 family members like BAX and BAK results in the loss of the outer mitochondrial membrane impermeability to proteins.

BH3-only proteins

A subset of proteins from the BCL-2 family that share significant homology only within the BCL-2 homology 3 (BH3) domain and act as intracellular stress sensors.

Mitochondrial fusion

In physiological conditions, the mitochondrial network is constantly remodelled by fusion and fission events, which allow mitochondria to adapt to the metabolic needs of the cell.

Heat-shock proteins

(HSPs). A family of evolutionarily conserved proteins that contribute to the proper folding of native polypeptides and prevent the aggregation of denatured proteins. The expression of HSPs is increased in response to elevated temperatures and other types of stress.

Apoptosome

A supramolecular complex comprising cytochrome c, apoptotic peptidase activating factor 1 and deoxyATP that is required for the autocatalytic activation of procaspase 9.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fulda, S., Galluzzi, L. & Kroemer, G. Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9, 447–464 (2010). https://doi.org/10.1038/nrd3137

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3137

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research