Many conventional anticancer drugs have an associated lack of safety by their toxicity. Relatively faster mutations in tumor cells pose a significant obstacle in treatment of cancer. Recently, “Mitocans” have emerged as a novel class of anticancer agents selectively targeting tumor cells and thus, are much less toxic than conventional anticancer chemotherapeutic agents. Mitocans are drugs that act directly on mitochondria within the cell, thus causing changes in energy metabolism of the cell. Amongst these mitocans, α-Tocopheryl succinate or vitamin E analogs are studied very well by researchers. This review discusses mitochondrial drug targeting strategies and a variety of novel mitochondrial drug targets of mitocans, such as electron transport chain, mitochondrial permeability transition, Bcl-2 family proteins and mitochondrial DNA. The purpose of this review is to focus on the various classes of mitocans, the mechanisms by which these drugs specifically act on tumor cells and their applications in cancer chemotherapeutics.
S. D. John, A. Hadfield, N. Hirst and A. T. McGown, “Tubulin and Microtubules as Targets for Anticancer Drugs,” Progress in Cell Cycle Research, Vol. 5, 2003, pp. 309-325.
M. C. S. Stig Linder, “Lysosomes and Endoplasmic Reticulum: Targets for Improved, Selective Anticancer Therapy,” Drug Resistance Updates, Vol. 8, 2005, pp. 199-204.
A. Szewczyk and L. Wojtczak, “Mitochondria as a Pharmacological Target,” Pharmacological Reviews, Vol. 54, 2002, pp. 101-127.
P. Costantini, E. Jacotot, D. Decaudin and G. Kroemer, “Mitochondrion as a Novel Target of Anticancer Chemotherapy,” Journal of National Cancer Institute, Vol. 92, 2000, pp. 1042-1053.
J. Neuzil, M. Tomasetti, Y. Zhao, L.-F. Dong, M. Birringer, X.-F. Wang, P. Low, K. Wu, B. A. Salvatore and S. J. Ralph, “Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent,” Molecular Pharmacology, Vol. 71, 2007, pp. 1185-1199.
P. P. G. Kroemer, N. Zamzami, J. L. Vayssiere and B. Mignotte, “The Biochemistry of Programmed Cell Death,” FASEB Journal, Vol. 9, 1995, pp. 1277-1287.
J. Neuzil, J. C. Dyason, R. Freeman, L.-F. Dong, L. Prochazka, X.-F. Wang, I. Scheffler and S. J. Ralph, “Mitocans as Anti-cancer Agents Targeting Mitochondria: Lessons from Studies with Vitamin E Analogues, Inhibitors of Complex II,” Journal of Bioenergetics and Biomembranes, Vol. 39, 2007, pp. 65-72.
D. R. Green and J. C. Reed, “Mitochondria and Apoptosis,” Science, Vol. 281, 1998, pp. 1309-1312.
S. Passarella and A. Atlante, “Teaching the Role of Mitochondrial Transport in Energy Metabolism,” Biochemistry and Molecular Biology Education, Vol. 35, 2007, pp. 125-132.
R. Shepherd, N. Checcarelli, A. Naini, D. De Vivo, S. DiMauro and C. Sue, “Measurement of ATP Production in Mitochondrial Disorders,” Journal of Inherited Metabolic Disease, Vol. 29, 2006, pp. 86-91.
H. P. Indo, M. Davidson, H.-C. Yen, S. Suenaga, K. Tomita, T. Nishii, M. Higuchi, Y. Koga, T. Ozawa and H. J. Majima, “Evidence of ROS Generation by Mitochondria in Cells with Impaired Electron Transport Chain and Mitochondrial DNA Damage,” Mitochondrion, Vol. 7, 2007, pp. 106-118.
Y. Chen, W. H. Yuen, J. Fu, G. Huang, A. J. Melendez, F. B. M. Ibrahim, H. Lu and X. Cao, “The Mitochondrial Respiratory Chain Controls Intracellular Calcium Signaling and NFAT Activity Essential for Heart Formation in Xenopus laevis,” Molecular and Cellular Biology, Vol. 27, 2007, pp. 6420- 6432.
N. Gattermann, “Mitochondrial DNA Mutations in the Hematopoietic System,” Leukemia, Vol. 18, 2003, pp. 18- 22.
A. M. Porcelli, A. Angelin, A. Ghelli, E. Mariani, A. Martinuzzi, V. Carelli, V. Petronilli, P. Bernardi and M. Rugolo, “Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels,” Journal of Biological Chemistry, Vol. 284, 2009, pp. 2045-2052.
H. Sayba?ili, M. Yüksel, G. Haklar and A. S. Yal?in, “Effect of Mitochondrial Electron Transport Chain Inhibitors on Superoxide Radical Generation in Rat Hippocampal and Striatal Slices,” Antioxidants and Redox Signaling, Vol. 3, 2001, pp. 1099-1104.
K. Staniek, L. Gille, A. V. Kozlov and H. Nohl, “Mitochondrial Superoxide Radical Formation is Controlled by Electron Bifurcation to the High and Low Potential Pathways,” Free Radical Research, Vol. 36, 2002, pp. 381-387.
H. Pelicano, L. Feng, Y. Zhou, J. S. Carew, E. O. Hileman, W. Plunkett, M. J. Keating and P. Huang, “Inhibition of Mitochondrial Respiration a Novel Strategy to Enhance Drug-Induced Apoptosis in Human Leukemia Cells by a Reactive Oxygen Species-Mediated Mechanism,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 37832- 37839.
M. J. F. G. A. Murrell and L. Bromley, “Modulation of fibroblast Proliferation by Oxygen Free Radicals,” Biochemical Journal, Vol. 265, 1990, pp. 659-665.
J. Emerit, J. M. Klein, A. Coutellier and F. Congy, “Free Radicals and Lipid Peroxidation in Cell Biology: Physiopathologic Prospects,” Pathologie-Biologie, Vol. 39, No. 316, 1991.
T. P. Szatrowskiand and C. F. Nathan, “Production of Large Amounts of Hydrogen Peroxide by Human Tumor Cells,” Cancer Research, Vol. 51, 1991, pp. 794-798.
S. Toyokunia, K. Okamoto, J. Yodoi and H. Hiai, “Persistent Oxidative Stress in Cancer,” FEBS Letters, Vol. 358, 1995, pp. 1-3.
S. Toyokuni, “Oxidative Stress and Cancer: The Role of Redox Regulation,” Biotherapy, Vol. 11, 1998, pp. 47- 154.
E. A. Hileman, G. Achanta and P. Huang, “Superoxide Dismutase: An Emerging Target for Cancer Therapeutics,” Expert Opinion on Therapeutic Targets, Vol. 5, 2001, pp. 697-710.
P. Huang, L. Feng, E. A. Oldham, M. J. Keating and W. Plunkett, “Superoxide Dismutase as a Target for the Selective Killing of Cancer Cells,” Nature, Vol. 407, 2000, pp. 390-395.
J. G. ?b, D. Nowis, M. Skrzycki, H. Czeczot, A. Barańczyk-Ku?ma, G. M. Wilczyński, M. Makowski, P. Mróz, K. Kozar, R. Kamiński, A. Jalili, M. Kope?, T. Grzela and M. Jakóbisiak, “Antitumor Effects of Photodynamic Therapy Are Potentiated by 2-Methoxyestradiol A Superoxide Dismutase Inhibitor,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 407-414.
S. J. Ralph, P. Low, L. Dong, A. Lawen and J. Neuzil, “Mitocans: Mitochondrial Targeted Anti-Cancer Drugs as improved Therapies and Related Patent Documents,” Recent Patents on Anti-Cancer Drug Discovery, Vol. 1, 2006, pp. 327-346.
R. J. Green, “Mitochondrial Targeting as a Novel Paradigm of Cancer Therapy: The Emergence of Mitocans,” Science, Vol. 281, 1998, pp. 1309-1312.
S. M. Cardoso, I. Santana, R. H. Swerdlow and C. R. Oliveira, “Mitochondria Dysfunction of Alzheimer’s Disease Cybrids Enhances Abeta Toxicity,” Journal of Neurochemistry, Vol. 89, 2004, pp. 1417-1426.
M.T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature, Vol. 443, 2006, pp. 787-795.
X. Chen, D. Stern and S. Du Yan, “Mitochondrial Dysfunction and Alzheimers Disease,” Current Alzheimer Research, Vol. 3, 2006, pp. 515-520.
R. Castellani, K. Hirai, G. Aliev, K. L. Drew, A. Nunomura, A. Takeda, A. D. Cash, M. E. Obrenovich, G. Perry and M. A. Smith, “Role of Mitochondrial Dysfunction in Alzheimer’s Disease,” Journal of Neuroscience Research, Vol. 70, pp. 357-360.
C. P. Ramsey and B. I. Giasson, “Role of Mitochondrial Dysfunction in Parkinson’s Disease: Implications for Treatment,” Drugs Aging, Vol. 24, 2007, pp. 95-105.
S. S. Ghosh, R. H. Swerdlow, S. W. Miller, B. Sheeman, W. D. Parker Jr. and R. E. Davis, “Use of Cytoplasmic Hybrid Cell Lines for Elucidating the Role of Mitochondrial Dysfunction in Alzheimer’s Disease and Parkinson’s Disease,” Annals of the New York Academy of Sciences, Vol. 893, 1999, pp. 176-191.
J. T. Greenamyre, G. MacKenzie, T. I. Peng and S. E. Stephans, “Mitochondrial Dysfunction in Parkinson’s Disease,” Biochemical Society Symposia, Vol. 66, 1999, pp. 85-97.
J. M. A. Oliveira, M. B. Jekabsons, S. Chen, A. Lin, A. C. Rego, J. Gon?alves, L. M. Ellerby and D. G. Nicholls, “Mitochondrial Dysfunction in Huntington’s Disease: The Bioenergetics of Isolated and in Situ Mitochondria from Transgenic Mice,” Journal of Neurochemistry, Vol. 101, 2007, pp. 241-249.
R. A. Quintanillaand and G. V. W. Johnson, “Role of Mitochondrial Dysfunction In the Pathogenesis of Huntington’s Disease,” Brain Research Bulletin, Vol. 80, 2009, pp. 242-247.
P. Shi, J. Gal, D. M. Kwinter, X. Liu and H. Zhu, “Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, Vol. 1802, 2010, pp. 45-51.
F. M. Menzies, M. R. Cookson, R. W. Taylor, D. M. Turnbull, Z. M. A. Chrzanowska-Lightowlers, L. Dong, D. A. Figlewicz and P.J. Shaw, “Mitochondrial Dysfunction in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis,” Brain, Vol. 125, 2002, pp. 1522-1533.
I. Hervias, M. F. Beal and G. Manfredi, “Mitochondrial Dysfunction and Amyotrophic Lateral Sclerosis,” Muscle & Nerve, Vol. 33, 2006, pp. 598-608.
E. Seppet, M. Gruno, A. Peetsalu, Z. Gizatullina, H.P. Nguyen, S. Vielhaber, M.H.P. Wussling, S. Trumbeckaite, O. Arandarcikaite, D. Jerzembeck, M. Sonnabend, K. Jegorov, S. Zierz, F. Striggow and F. N. Gellerich, “Mitochondria and Energetic Depression in Cell Pathophysiology,” International Journal of Molecular Sciences, Vol. 10, 2009, pp. 2252-2303.
H. J. Ahn, Y. S. Kim, J.-U. Kim, S. M. Han, J. W. Shin and H. O. Yang, “Mechanism of Taxol-Induced Apoptosis in Human SKOV3 Ovarian Carcinoma Cells,” Journal of Cellular Biochemistry, Vol. 91, 2004, pp. 1043-1052.
N. Andre, D. Braguer, G. Brasseur, A. Goncalves, D. Lemesle-Meunier, S. Guise, M. A. Jordan and C. Briand, “Paclitaxel Induces Release of Cytochrome c from Mitochondria Isolated from Human Neuroblastoma Cells,” Cancer Research, Vol. 60, 2000, pp. 5349-5353.
J. F. Kidd, M. F. Pilkington, M. J. Schell, K. E. Fogarty, J. N. Skepper, C. W. Taylor and P. Thorn, “Paclitaxel Affects Cytosolic Calcium Signals by Opening the Mitochondrial Permeability Transition Pore,” The Journal of Biological Chemistry, Vol. 277, 2002, pp. 6504-6510.
K. Ozgurand and L. Anthony, “Alteration of the Mitochondrial Apoptotic Pathway Is Key to Acquired Paclitaxel Resistance and Can be Reversed by ABT-737,” Cancer Res, Vol. 68, 2008, pp. 7985-7994.
M. Crompton and L. Andreeva, “On the Interactions of Ca2+ and Cyclosporin A With a Mitochondrial Inner Membrane Pore: A Study Using Cobaltammine Complex Inhibitors of the Ca2+ Uniporter,” Biochemical Journal, Vol. 302, 1994, pp. 181-185.
D. W. Jung, P. C. Bradshaw and D. R. Pfeiffer, “Properties of a Cyclosporin-Insensitive Permeability Transition Pore in Yeast Mitochondria,” The Journal of Biological Chemistry, Vol. 272, 1997, pp. 21104-21112.
K. M. Broekemeier and D. R. Pfeiffer, “Inhibition of the Mitochondrial Permeability Transition by Cyclosporin A during long Time Frame Experiments: Relationship between Pore Opening and the Activity of Mitochondrial Phospholipases,” Biochemistry, Vol. 34, 1995, pp. 16440- 16449.
R. Scatena, P. Bottoni, G. Botta, G. E. Martorana and B. Giardina, “The Role of Mitochondria in Pharmacotoxicology: A Reevaluation of an Old, Newly Emerging Topic,” Am J Physiol Cell Physiol, Vol. 293, 2007, pp. C12-21.
A. A. Johnson, A. S. Ray, J. Hanes, Z. Suo, J. M. Colacino, K. S. Anderson and K. A. Johnson, “Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase,” The Journal of Biological Chemistry, Vol. 276, 2001, pp. 40847-40857.
L. F. Pereira, M. B. M. Oliveira and E. G. S. Carnieri, “Mitochondrial Sensitivity to AZT,” Cell Biochemistry and Function, Vol. 16, 1998, pp. 173-181.
T. Sato, H. Nishida, M. Miyazaki and H. Nakaya, “Effects of Sulfonylureas on Mitochondrial ATP-Sensitive Channels in Cardiac Myocytes: Implications for Sulfonylurea Controversy,” Diabetes/Metabolism Research and Reviews, Vol. 22, 2006, 341-347.
A. Szewczyk, “Intracellular Targets for Antidiabetic Sulfonylureas and Potassium Channel Openers,” Biochemical Pharmacology, Vol. 54, 1997, pp. 961-965.
P. A. Smith, P. Proks and A. Moorhouse, “Direct Effects of Tolbutamide on Mitochondrial Function, Intracellular Ca2+ and Exocytosis in Pancreatic β-Cells,” Pflügers Archiv European Journal of Physiology, Vol. 437, 1999, pp. 577-588.
M. Zaugg, E. Lucchinetti, D. R. Spahn, T. Pasch, C. Garcia and M. C. Schaub, “Differential Effects of Anesthetics on Mitochondrial K(ATP) Channel Activity and Cardiomyocyte Protection,” Anesthesiology, Vol. 97, 2002, pp. 15-23.
Y. Zhang, Y. Dong, X. Wu, Y. Lu, Z. Xu, A. Knapp, Y. Yue, T. Xu and Z. Xie, “The Mitochondrial Pathway of Anesthetic Isoflurane-Induced Apoptosis,” The Journal of Biological Chemistry, Vol. 285, 2010, pp. 4025-4037.
M. G. D. Spierings, M. Saleh, C. Bender, J. Chipuk, U. Maurer and D. R. Green, “Connected to Death: The (Unexpurgated) Mitochondrial pathway of Apoptosis,” Science, Vol. 310, 2005, p. 2.
M. Zoratti and I. Szabò, “The Mitochondrial Permeability Transition,” Biochimica et Biophysica Acta, Vol. 1241, 1995, pp. 139-176.
T. Hirsch, P. Marchetti, S. A. Susin, B. Dallaporta, N. Zamzami, I. Marzo, M. Geuskens and G. Kroemer, “The Apoptosis-Necrosis Paradox. Apoptogenic Proteases Activated after Mitochondrial Permeability Transition Determine the Mode of Cell Death,” Oncogene, Vol. 15, 1997, pp. 1573-1581.
N. Zamzami, S. A. Susin, P. Marchetti, T. Hirsch, I. Gómez-Monterrey, M. Castedo and G. Kroemer, “Mitochondrial Control of Nuclear Apoptosis,” Journal of Experimental Medicine, Vol. 183, 1996, pp. 1533-1544.
D. Green and G. Kroemer, “The Central Executioners of Apoptosis: Caspases or Mitochondria?” Trends in Cell Biology, Vol. 8, 1998, pp. 267-271. doi:10.1016/S0962-8924(98)01273-2
J. G. Pastorino, S.-T. Chen, M. Tafani, J. W. Snyder and J. L. Farber, “The Overexpression of Bax Produces Cell Death upon Induction of the Mitochondrial Permeability Transition,” Journal of Biological Chemistry, Vol. 273, 1998, pp. 7770-7775. doi:10.1074/jbc.273.13.7770
N. J. McCarthy, M. K. B. Whyte, C. S. Gilbert and G. I. Evan, “Inhibition of Ced-3/ICE Related Proteases Does not Prevent Cell Death Induced by Oncogenes, DNA Damage, or the Bcl-2 Homologue Bak,” Journal of Cell Biology, Vol. 136, 1997, pp. 215-227. doi:10.1083/jcb.136.1.215
F. Quignon, F. D. Bels, M. Koken, J. Feunteun, J.-C. Ameisen and H. D. Thé, “PML Induces a Novel Caspase-Independent Death Process,” Nature Genetics, Vol. 20, 1998, pp. 259-265. doi:10.1038/3068
A. Kawahara, Y. Ohsawa, H. Matsumura, Y. Uchiyama and S. Nagata, “Caspase Independent Cell Killing by Fas-Associated Protein with Death Domain,” Journal of Cell Biology, Vol. 143, 1998, pp. 1353-1360. doi:10.1083/jcb.143.5.1353
D. Vercammen, R. Beyaert, G. Denecker, V. Goossens, G. V. Loo, W. Declercq, J. Grooten, W. Fiers and P. Vandenabeele, “Inhibition of Caspases Increases the Sensitivity of L929 Cells to Necrosis Mediated by Tumor Necrosis Factor,” Journal of Experimental Medicine, Vol. 187, 1998, pp. 1477-1485. doi:10.1084/jem.187.9.1477
H. K. Bojes, X. Feng, J. P. Kehrer and G. M. Cohen, “Apoptosis in Hematopoietic Cells (FL5.12) Caused by Interleukin-3 Withdrawal: Relationship to Caspase Activity and the Loss of Glutathione,” Cell Death and Differentiation, Vol. 6, 1999, pp. 61-70. doi:10.1038/sj.cdd.4400452
C. Berndt, B. Moepps, S. Angermueller, P. Gierschik and P.H. Krammer, “CXCR4 and CD4 Mediate a Rapid CD95-Independent Cell Death in CD4(+) T Cells,” Proceedings of The National Academy of Science USA, Vol. 95, 1998, pp. 12556-12561.
D. E. Wood and E. W. Newcomb, “Caspase-Dependent Activation of Calpain during Drug-Induced Apoptosis,” Journal of Biological Chemistry, Vol. 274, 1999, pp. 8309-8315. doi:10.1074/jbc.274.12.8309
K. M. Henkels and J. J. Turchi, “Cisplatin-Induced Apoptosis Proceeds by Caspase-3-Dependent and -Independent Pathways in Cisplatin-Resistant and -Sensitive Human Ovarian Cancer Cell Lines,” Cancer Research, Vol. 59, 1999, pp. 3077-3083.
S. A. Susin, H. K. Lorenzo, N. Zamzami, I. Marzo, B. E. Snow, G. M. Brothers, J. Mangion, E. Jacotot, P. Costantini, M. Loeffler, N. Larochette, D. R. Goodlett, R. Aebersold, D. P. Siderovski, J. M. Penninger and G. Kroemer, “Molecular Characterization of Mitochondrial Apoptosis-Inducing Factor,” Nature, Vol. 397, 1999, pp. 441- 446.
X. Liu, C. N. Kim, J. Yang, R. Jemmerson and X. Wang, “Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c,” Cell, Vol. 86, 1996, pp. 147-157.
S. A. Susin, H. K. Lorenzo, N. Zamzami, I. Marzo, C. Brenner, N. Larochette, M.-C. Prévost, P. M. Alzari and G. Kroemer, “Mitochondrial Release of Caspase-2 and -9 during the Apoptotic Process,” Journal of Experimental Medicine, Vol. 189, 1999, pp. 381-394. doi:10.1084/jem.189.2.381
Y. Chen, E. McMillan-Ward, J. Kong, S. J. Israels and S. B. Gibson, “Mitochondrial Electron-Transport-Chain Inhibitors of Complexes I and II Induce Autophagic Cell Death Mediated by Reactive Oxygen Species,” Journal of Cell Science, Vol. 120, 2007, pp. 4155-4166. doi:10.1242/jcs.011163
H.-S. Huang, Z.-M. Liu, L. Ding, W.-C. Chang, P.-Y. Hsu, S.-H. Wang, C.-C. Chi and C.-H. Chuang, “Opposite Effect of ERK1/2 and JNK on p53-Independent p21WAF1/CIP1 Activation Involved in the Arsenic Trioxide-Induced Human Epidermoid Carcinoma A431 Cellular Cytotoxicity,” Journal of Biomedical Science, Vol. 13, 2006, pp. 113-125. doi:10.1007/s11373-005-9040-z
P. Kumar, Q. Gao, Y. Ning, Z. Wang, P. H. Krebsbach and P. J. Polverini, “Arsenic Trioxide Enhances the Therapeutic Efficacy of Radiation Treatment of Oral Squamous Carcinoma While Protecting Bone,” Molecular Cancer Therapeutics, Vol. 7, 2008, pp. 2060-2069. doi:10.1158/1535-7163.MCT-08-0287
C. Yedjou, L. Thuisseu, C. Tchounwou, M. Gomes, C. Howard and P. Tchounwou, “Ascorbic Acid Potentiation of Arsenic Trioxide Anticancer Activity Against Acute Promyelocytic Leukemia,” Archives of Drug Information, Vol. 2, 2009, pp. 59-65.
K. G. Wolter, Y.-T. Hsu, C. L. Smith, A. Nechushtan, X.-G. Xi and R. J. Youle, “Movement of Bax from the Cytosol to Mitochondria during Apoptosis,” Journal of Cell Biology, Vol. 139, 1997, pp. 1281-1292. doi:10.1083/jcb.139.5.1281
M. Narita, S. Shimizu, T. Ito, T. Chittenden, R. J. Lutz, H. Matsuda and Y. Tsujimoto, “Bax Interacts with the Permeability Transition Pore to Induce Permeability Transition and Cytochrome c Release in Isolated Mitochondria,” Proceedings of The National Academy of Science USA, Vol. 95, 1998, pp. 14681-14686. doi:10.1073/pnas.95.25.14681
I. Marzo, C. Brenner, N. Zamzami, J. M. Jürgensmeier, S. A. Susin, H. L. A. Vieira, M.-C. Prévost, Z. Xie, S. Matsuyama, J. C. Reed and G. Kroemer, “Bax and Adenine Nucleotide Translocator Cooperate in the Mitochondrial Control of Apoptosis,” Science, Vol. 281, 1998, pp. 2027- 2031.
M. Crompton, S. Virji and J. M. Ward, “Cyclophilin-D Binds Strongly to Complexes of the Voltage-Dependent Anion Channel and the Adenine Nucleotide Translocase to form the Permeability Transition Pore,” European Journal of Biochemistry, Vol. 258, 1998, pp. 729-735. doi:10.1046/j.1432-1327.1998.2580729.x
N. Brustovetsky and M. Klingenberg, “Mitochondrial ADP/ATP Carrier Can be Reversibly Converted into a Large Channel by Ca2+,” Biochemistry, Vol. 35, 1996, pp. 8483-8488.
G. Beutner, A. Rück, B. Riede, W. Welte and D. Brdiczka, “Complexes between Kinases, Mitochondrial Porin and Adenylate Translocator in Rat Brain Resemble the Permeability Transition Pore,” FEBS Letters, Vol. 396, 1996, pp. 189-195. doi:10.1016/0014-5793(96)01092-7
S. Shimizu, M. Narita and Y. Tsujimoto, “Bcl-2 Family Proteins Regulate the Release of Apoptogenic Cytochrome c by the Mitochondrial Channel VDAC,” Nature, Vol. 399, 1999, pp. 483-487.
C. Brenner, H. Cadiou, H. L. Vieira, N. Zamzami, I. Marzo, Z. Xie, B. Leber, D. Andrews, H. Duclohier, J. C. Reed and G. Kroemer, “Bcl-2 and Bax Regulate the Channel Activity of the Mitochondrial Adenine Nucleotide Translocator,” Oncogene, Vol. 19, 2000, pp. 329- 336.
J. E. Belizário, J. Alves, J. M. Occhiucci, M. Garay-Mal- partida and A. Sesso, “A Mechanistic View of Mitochondrial Death Decision Pores,” Brazilian Journal of Medical and Biological Research, Vol. 40, 207, pp. 1011- 1024.
S. Desagher, A. Osen-Sand, A. Nichols, R. Eskes, S. Montessuit, S. Lauper, K. Maundrell, B. Antonsson and J.-C. Martinou, “Bid-Induced Conformational Change of Bax Is Responsible for Mitochondrial Cytochrome c Release during Apoptosis,” Journal of Cell Biology, Vol. 144, 1999, pp. 5891-5901. doi:10.1083/jcb.144.5.891
E. Bossy-Wetzel, D. D. Newmeyer and D. R. Green, “Mitochondrial Cytochrome c Release in Apoptosis Occurs Upstream of DEVD-Specific Caspase Activation and Independently of Mitochondrial Transmembrane Depolarization,” EMBO Journal, Vol. 17, 1998, pp. 37-49. doi:10.1093/emboj/17.1.37
J. C. Reed, “Bcl-2 family Proteins,” Oncogene, Vol. 17, 1998, pp. 3225-3236.
Z. Huang, “Bcl-2 Family Proteins as Targets for Anticancer Drug Design,” Oncogene, Vol. 19, 2000, pp. 6627-6631.
K. Polyak, Y. Xia, J. L. Zweier, K. W. Kinzler and B. Vogelstein, “A Model for p53-Induced Apoptosis,” Nature, Vol. 389, 1997, pp. 300-305.
Z. Wang and Y. Sun, “Targeting p53 for Novel Anticancer Therapy,” Translational Oncology, Vol. 3, 2010, pp. 1-12.
J. Neuzil, X.-F. Wang, L.-F. Dong, P. Low and S. J. Ralph, “Molecular Mechanism of ‘Mitocan’-Induced Apoptosis in Cancer Cells Epitomizes the Multiple Roles of Reactive Oxygen Species and Bcl-2 Family Proteins,” FEBS Letters, Vol. 580, 2006, pp. 5125-5129. doi:10.1016/j.febslet.2006.05.072
R. N. Kolesnick, “Regulation of Ceramide Production and Apoptosis,” Annual Review of Physiology, Vol. 60, 1998, pp. 643-665. doi:10.1146/annurev.physiol.60.1.643
R. D. Maria, L. Lenti, F. Malisan, F. D’Agostino, B. Tomassini, A. Zeuner, M. R. Rippo and R. Testi, “Requirement for GD3 Ganglioside in CD95- and Ceramide-Induced Apoptosis,” Science, Vol. 277, 1997, pp. 1652-1655.
H. Basma, H. El-Refaey, M. K. Sgagias, K. H. Cowan, X. Luo and P.-W. Cheng, “BCL-2 Antisense and Cisplatin Combination Treatment of MCF-7 Breast Cancer Cells with or without Functional P53,” Journal of Biomedical Science, Vol. 12, 2005, pp. 999-1011. doi:10.1007/s11373-005-9025-y
A. Quillet-Mary, J.-P. Jaffrézou, V. Mansat, C. Bordier, J. Naval and G. Laurent, “Implication of Mitochondrial Hydrogen Peroxide Generation in Ceramide-induced Apoptosis,” Journal of Biological Chemistry, Vol. 272, 1997, pp. 21388-21395. doi:10.1074/jbc.272.34.21388
J. L. Scarlett, M. A. Packer, C. M. Porteous and M. P. Murphy, “Alterations to Glutathione and Nicotinamide Nucleotides during the Mitochondrial Permeability Transition Induced by Peroxynitrite 1,” Biochemical Pharmacology, Vol. 52, 1996, pp. 1047-1055. doi:10.1016/0006-2952(96)99426-5
P. Costantini, B.V. Chernyak, V. Petronilli, and P. Bernardi, “Modulation of the Mitochondrial Permeability Transition Pore by Pyridine Nucleotides and Dithiol Oxidation at Two Separate Sites,” Journal of Biological Chemistry, Vol. 271, 1996, pp. 6746-6751. doi:10.1074/jbc.271.12.6746
P. Costantini, A.-S. Belzacq, H. L. Vieira, N. Larochette, M. A. D. Pablo, N. Zamzami, S. A. Susin, C. Brenner and G. Kroemer, “Oxidation of a Critical Thiol Residue of the Adenine Nucleotide Translocator Enforces Bcl-2-Independent Permeability Transition Pore Opening and Apoptosis,” Oncogene, Vol. 19, 2000, pp. 307-314.
M. Klingenberg, “The ADP-ATP Translocation in mitochondria, a membrane potential controlled transport,” Journal of Membrane Biology, Vol. 56, 1980, pp. 97-105. doi:10.1007/BF01875961
E. Chávez and A. Osornio, “Temperature Dependence of the Atractyloside-Induced Mitochondrial Ca2+ Release,” International journal of Biochemistry, Vol. 20, 1988, pp. 731-736. doi:10.1016/0020-711X(88)90169-3
G. Kroemer, L. Galluzzi and C. Brenner, “Mitochondrial Membrane Permeabilization in Cell Death,” Physiological Reviews, Vol. 87, 2007, pp. 99-163.
S. A. Susin, N. Zamzami, M. Castedo, E. Daugas, H.-G. Wang, S. Geley, F. Fassy, J. C. Reed and G. Kroemer, “The Central Executioner of Apoptosis: Multiple Connections between Protease Activation and Mitochondria in Fas/APO-1/CD95- and Ceramide-induced Apoptosis,” Journal of Experimental Medicine, Vol. 86, 1997, pp. 25- 37. doi:10.1084/jem.186.1.25
P. Bernardi and V. Petronilli, “The Permeability Transition Pore as a Mitochondrial Calcium Release Channel: A Critical Appraisal,” Journal of Bioenergetics and Biomembranes, Vol. 28, 1996, pp. 131-138. doi:10.1007/BF02110643
H. Puthalakath, D. C. S. Huang, L. A. O’Reilly, S. M. King and A. Strasser, “The Proapoptotic Activity of the Bcl-2 Family Member Bim Is Regulated by Interaction with the Dynein Motor Complex,” Molecular Cell, Vol. 3, 1999, pp. 287-296. doi:10.1016/S1097-2765(00)80456-6
F. Tsuruta, J. Sunayama, Y. Mori, S. Hattori, S. Shimizu, Y. Tsujimoto, K. Yoshioka, N. Masuyama and Y. Gotoh, “JNK Promotes Bax Translocation to Mitochondria through Phosphorylation of 14-3-3 Proteins,” EMBO J, Vol. 23, 2004, pp. 1889-1899. doi:10.1038/sj.emboj.7600194
H. Li, H. Zhu, C.-j. Xu and J. Yuan, “Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis,” Cell, Vol. 94, 1998, pp. 491-501.
J. Zha, H. Harada, E. Yang, J. Jockel and S. J. Korsmeyer, “Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL,” Cell, Vol. 87, 1996, pp. 619-628.
Y. V. Evtodienko, V. V. Teplova, S. S. Sidash, F. Ichas, and J.-P. Mazat, “Microtubule-Active Drugs Suppress the Closure of the Permeability Transition Pore in Tumour Mitochondria,” FEBS Letters, Vol. 393, 1996, pp. 86-88. doi:10.1016/0014-5793(96)00875-7
D. G. Kirsch, A. Doseff, B. N. Chau, D.-S. Lim, N. C. D. Souza-Pinto, R. Hansford, M. B. Kastan, Y. A. Lazebnik and J. M. Hardwick, “Caspase-3-Dependent Cleavage of Bcl-2 Promotes Release of Cytochrome c,” Journal of Biological Chemistry, Vol. 274, 1999, pp. 21155-21161. doi:10.1074/jbc.274.30.21155
J. Armstrong, “Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease,” British Journal of Pharmacology, Vol. 151, 2007, pp. 1154-1165.
A. Lena, M. Rechichi, A. Salvetti, B. Bartoli, D. Vecchio, V. Scarcelli, R. Amoroso, L. Benvenuti, R. Gagliardi, V. Gremigni and L. Rossi, “Drugs Targeting the Mitochondrial Pore Act as Citotoxic and Cytostatic Agents in Temozolomide-Resistant Glioma Cells,” Journal of Translational Medicine, Vol. 7, 2009, pp. 1-13.
V. Labi, M. Erlacher, S. Kiessling and A. Villunger, “BH3-only Proteins in Cell Death Initiation, Malignant Disease and Anticancer Therapy,” Cell Death and Differentiation, Vol. 13, 2006, pp. 1325-1338.
S. J. Ralph, “Arsenic-Based Antineoplastic Drugs and Their Mechanisms of Action,” Metal-Based Drugs, Vol. 1, 2008, pp. 13.
H. Pelicano, D. S. Martin, R.-H. Xu and P. Huang, “Glycolysis Inhibition for Anticancer Treatment,” Oncogene, Vol. 25, 2006, pp. 4633-4646.
Y. H. Ko, B. L. Smith, Y. Wang, M. G. Pomper, D. A. Rini, M. S. Torbenson, J. Hullihen and P. L. Pedersen, “Advanced cancers: eradication in all cases using 3 bromopyruvate therapy to deplete ATP,” Biochemical and Biophysical Research Communications, Vol. 324, 2004, pp. 269-275.
L. Arzoine, N. Zilberberg, R. Ben-Romano and V. Shoshan-Barmatz, “Voltage-dependent Anion Channel 1-based Peptides Interact with Hexokinase to Prevent Its Anti-apoptotic Activity,” Journal of Biological Chemistry, Vol. 284, 2009, pp. 3946-3955.
S. Abu-Hamad, H. Zaid, A. Israelson, E. Nahon and V. Shoshan-Barmatz, “Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1 Mapping the Site of Binding,” Journal of Biological Chemistry, Vol. 283, 2008, pp. 13482-13490.
F. Chiara, D. Castellaro, O. Marin, V. Petronilli, W.S. Brusilow, M. Juhaszova, S. J. Sollott, M. Forte, P. Bernardi and A. Rasola, “Hexokinase II Detachment from Mitochondria Triggers Apoptosis through the Permeability Transition Pore Independent of Voltage-Dependent Anion Channels,” PLoS ONE, Vol. 3, 2008, pp. 1852.
J. Neuzil, T. Marco, M. A. Sleiman, A. Renata, S. B. A. B. Marc and F. M. W, “Vitamin E Analogues: A New Class of Inducers of Apoptosis with Selective Anti-Cancer Effects,” Current Cancer Drug Targets, Vol. 4, 2004, pp. 355-372.
W. Kim, J.-H. Yoon, J.-M. Jeong, G.-J. Cheon, T.-S. Lee, J.-I. Yang, S.-C. Park and H.-S. Lee, “Apoptosis-Inducing Antitumor Efficacy of Hexokinase II Inhibitor in Hepatocellular Carcinoma,” Molecular Cancer Therapeutics, Vol. 6, 2007, pp. 2554-2562.
J. O’Neill, M. Manion, P. Schwartz and D. M. Hockenbery, “Promises and Challenges of Targeting Bcl-2 Anti-Apoptotic Proteins for Cancer Therapy,” Biochimica et Biophysica Acta, Vol. 1705, 2004, pp. 43-51.
W.-S. Yeow, A. Baras, A. Chua, D. M. Nguyen, S. S. Sehgal, D. S. Schrump and D. M. Nguyen, “Gossypol, a Phytochemical with BH3-Mimetic Property, Sensitizes Cultured Thoracic Cancer Cells to Apo2 Ligand/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand,” The Journal of Thoracic and Cardiovascular Surgery, Vol. 132, 2006, pp. 1356-1362.
A. Degterev, A. Lugovskoy, M. Cardone, B. Mulley, G. Wagner, T. Mitchison and J. Yuan, “Identification of Small-Molecule Inhibitors of Interaction between the BH3 Domain and Bcl-xL,” Nature Cell Biology, Vol. 3, 2001, pp. 173-182.
C.-W. Shiau, J.-W. Huang, D.-S. Wang, J.-R. Weng, C.-C. Yang, C.-H. Lin, C. Li and C.-S. Chen, “α-Tocopheryl Succinate Induces Apoptosis in Prostate Cancer Cells in Part through Inhibition of Bcl-xL/Bcl-2 Function,” Journal of Biological Chemistry, Vol. 281, 2006, pp. 11819- 11825.
K. N. Prasad, B. Kumar, X.-D. Yan, A. J. Hanson and W. C. Cole, “α-Tocopheryl Succinate, the Most Effective Form of Vitamin E for Adjuvant Cancer Treatment: A Review,” Journal of the American College of Nutrition, Vol. 22, 2003, pp. 108-117.
K. B. Kim, A. Y. Bedikian, L. H. Camacho, N. E. Papadopoulos and C. McCullough, “A Phase II Trial of Arsenic Trioxide in Patients with Metastatic Melanoma,” Cancer, Vol. 104, 2005, pp. 1687-1692.
S. Amadori, P. Fenaux, H. Ludwig, M. O’Dwyer and M. Sanz, “Use of Arsenic Trioxide in Haematological Malignancies: Insight into the Clinical Development of a Novel Agent,” Current Medical Research and Opinion, Vol. 21, 2005, pp. 403-411.
A.-S. Belzacq, C. E. Hamel, H. L. A. Vieira, I. Cohen, D. Haouzi, D. Métivier, P. Marchetti, C. Brenner and G. Kroemer, “Adenine Nucleotide Translocator Mediates the Mitochondrial Membrane Permeabilization Induced by Lonidamine, Arsenite and CD437,” Oncogene, Vol. 20, 2001, pp. 7579-7587.
L. Biasutto, L.-F. Dong, M. Zoratti and J. Neuzil, “Mitochondrially Targeted Anti-Cancer Agents,” Mitochondrion, 2010.
L. Ravagnan, I. Marzo, P. Costantini, S. A. Susin, N. Zamzami, P. X. Petit, F. Hirsch, M. Goulbern, M.-F. Poupon, L. Miccoli, Z. Xie, J. C. Reed and G. Kroemer, “Lonidamine Triggers Apoptosis via a Direct, Bcl-2-In- hibited Effect on the Mitochondrial Permeability Transition Pore,” Oncogene, Vol. 18, 1999, pp. 2537-2546.
S.-Y. Sun, P. Yue, G. S. Wu, W. S. El-Deiry, B. Shroot, W. K. Hong and R. Lotan, “Mechanisms of Apoptosis Induced by the Synthetic Retinoid CD437 in Human Non-Small Cell Lung Carcinoma Cells,” Oncogene, Vol. 18, 1999, pp. 2357-2365.
P. Marchetti, N. Zamzami, B. Joseph, S. Schraen- Maschke, C. Méreau-Richard, P. Costantini, D. Métivier, S. A. Susin, G. Kroemer and P. Formstecher, “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 Research, Vol. 59, 1999, pp. 6257-6266.
M. Pfahl and F. J. Piedrafita, “Retinoid Targets for Apoptosis Induction,” Oncogene, Vol. 22, 2003, pp. 9058- 9062.
D. Schadendorf, M. A. Kern, M. Artuc, H. L. Pahl, T. Rosenbach, I. Fichtner, W. Nürnberg, S. Stüting, E. V. Stebut, M. Worm, A. Makki, K. Jurgovsky, G. Kolde and B. M. Henz, “Treatment of Melanoma Cells with the Synthetic Retinoid CD437 Induces Apoptosis via Activation of AP-1 in vitro, and Causes Growth Inhibition in Xenografts in vivo,” Journal of Cell Biology, Vol. 135, 1996, pp. 1889-1898.
X. Zhao and R. A. Spanjaard, “The Apoptotic Action of the Retinoid CD437/AHPN: Diverse Effects, Common Basis,” Journal of Biomedical Science, Vol. 10, 2003, pp. 44-49.
J. S. Modica-Napolitano, K. Koya, E. Weisberg, B. T. Brunelli, Y. Li and L. B. Chen, “Selective Damage to Carcinoma Mitochondria by the Rhodacyanine MKT- 077,” Cancer Research, Vol. 56, 1996, pp. 544-550.
D. J. Propper, J. P. Braybrooke, D. J. Taylor, R. Lodi, P. Styles, J. A. Cramer, W. C. J. Collins, N. C. Levitt, D. C. Talbot, T. S. Ganesan and A. L. Harris, “Phase I Trial of the Selective Mitochondrial Toxin MKT 077 in Chemo- Resistant Solid Tumours,” Annals of Oncology, Vol. 10, 1999, pp. 923-927.
R. Wadhwa, T. Sugihara, A. Yoshida, H. Nomura, R. R. Reddel, R. Simpson, H. Maruta and S. C. Kaul, “Selective Toxicity of MKT-077 to Cancer Cells Is Mediated by Its Binding to the hsp70 Family Protein mot-2 and Reactivation of p53 Function,” Cancer Research, Vol. 60, 2000, pp. 6818-6821.
J. S. Modica-Napolitano, B. T. Brunelli, K. Koya and L.B. Chen, “Photoactivation Enhances the Mitochondrial Toxicity of the Cationic Rhodacyanine MKT-077,” Cancer Research, Vol. 58, 1998, pp. 71-75.
T. Minamikawa, A. Sriratana, D. A. Williams, D. N. Bowser, J. S. Hill and P. Nagley, “Chloromethyl-X- Rosamine (MitoTracker Red) Photosensitises Mitochondria and Induces Apoptosis in Intact Human Cells,” Journal of Cell Science, Vol. 112, 1999, pp. 2419-2430.
S. Fulda, C. Scaffidi, S. A. Susin, P. H. Krammer, G. Kroemer, M. E. Peter and K.-M. Debatin, “Activation of Mitochondria and Release of Mitochondrial Apoptogenic Factors by Betulinic Acid,” Journal of Biological Chemistry, Vol. 273, 1998, pp. 33942-33948.
S. Fulda and K.-M. Debatin, “Sensitization for Anticancer Drug-Induced Apoptosis by Betulinic Acid,” Neoplasia, Vol. 7, 2005, pp. 162-170.
S. Fulda and G. Kroemer, “Targeting Mitochondrial Apoptosis by Betulinic Acid in Human Cancers,” Drug Discovery Today, Vol. 14, 2009, pp. 885-890.
V. E. Kagan, A. Bayir, H. Bayir, D. Stoyanovsky, G. G. Borisenko, Y. Y. Tyurina, P. Wipf, J. Atkinson, J. S. Greenberger, R. S. Chapkin and N. A. Belikova, “Mitochondria-Targeted Disruptors and Inhibitors of Cytochrome C/Cardiolipin Peroxidase Complexes: A New Strategy in Anti-Apoptotic Drug Discovery,” Molecular Nutrition & Food Research, Vol. 53, 2009, pp. 104-114.
X. Gao, X. Wen, L. Esser, B. Quinn, L. Yu, C.-A. Yu and D. Xia, “Structural Basis for the Quinone Reduction in the bc1 Complex: A Comparative Analysis of Crystal Structures of Mitochondrial Cytochrome bc1 with Bound Substrate and Inhibitors at the Qi Site,” Biochemistry, Vol. 42, 2003, pp. 9067-9080.
L. F. Dong, V. J. A. Jameson, D. Tilly, J. Cerny, E. Mahdavian, A. Marín-Hernández, L. Hernández-Esquivel, S. Rodríguez-Enríquez, J. Stursa and P. K. Witting, “Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II,” Journal of Biological Chemistry, Vol. 286, pp. 3717.
D. R. Pfeiffer, T. I. Gudz, S. A. Novgorodov and W. L. Erdahl, “The Peptide Mastoparan Is a Potent Facilitator of the Mitochondrial Permeability Transition,” Journal of Biological Chemistry, Vol. 270, 1995, pp. 4923-4932.
H. M. Ellerby, W. Arap, L. M. Ellerby, R. Kain, R. Andrusiak, G. D. Rio, S. Krajewski, C. R. Lombardo, R. Rao, E. Ruoslahti, D. E. Bredesen and R. Pasqualini, “Anti-Cancer Activity of Targeted Pro-Apoptotic Peptides,” Nature Medicine, Vol. 5, 1999, pp. 1032-1038.
W. Schuler, K. Wecker, H. D. Rocquigny, Y. Baudat, J. Sire and B. P. Roques, “NMR Structure of the (52-96) C-Terminal Domain of the HIV-1 Regulatory Protein Vpr: Molecular Insights into Its Biological Functions,” Journal of Molecular Biology, Vol. 285, 1999, pp. 2105-2117.