Mitochondria: a target for cancer therapy

Mitochondria, the cells powerhouses, are essential for maintaining cell life, and they also play a major role in regulating cell death, which occurs upon permeabilization of their membranes. Once mitochondrial membrane permeabilization (MMP) occurs, cells die either by apoptosis or necrosis. Key factors regulating MMP include calcium, the cellular redox status (including levels of reactive oxygen species) and the mobilization and targeting to mitochondria of Bcl‐2 family members. Contemporary approaches to targeting mitochondria in cancer therapy use strategies that either modulate the action of Bcl‐2 family members at the mitochondrial outer membrane or use specific agents that target the mitochondrial inner membrane and the mitochondrial permeability transition (PT) pore. The aim of this review is to describe the major mechanisms regulating MMP and to discuss, with examples, mitochondrial targeting strategies for potential use in cancer therapy.

[1]  G. Kroemer,et al.  Mitochondrion as a novel target of anticancer chemotherapy. , 2000, Journal of the National Cancer Institute.

[2]  Ruedi Aebersold,et al.  Molecular characterization of mitochondrial apoptosis-inducing factor , 1999, Nature.

[3]  J. Lemasters,et al.  Cyclophilin D as a drug target. , 2003, Current medicinal chemistry.

[4]  Tetsuya Watanabe,et al.  Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death , 2005, Nature.

[5]  Dean P. Jones,et al.  Cysteine starvation activates the redox-dependent mitochondrial permeability transition in retinal pigment epithelial cells. , 2004, Investigative ophthalmology & visual science.

[6]  C. F. Bennett,et al.  The Role of Antiapoptotic Bcl-2 Family Members in Endothelial Apoptosis Elucidated with Antisense Oligonucleotides* , 1999, The Journal of Biological Chemistry.

[7]  A. Colell,et al.  Oxidative stress: Role of mitochondria and protection by glutathione , 1998, BioFactors.

[8]  S. Korsmeyer,et al.  Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix , 2004, Science.

[9]  A. Meister,et al.  Origin and turnover of mitochondrial glutathione. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[10]  A. Halestrap,et al.  The permeability transition pore complex: another view. , 2002, Biochimie.

[11]  B. Chait,et al.  CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals. , 2003, Genes & development.

[12]  R Marsault,et al.  Transfected Aequorin in the Measurement of Cytosolic Ca2+ Concentration ([Ca2+]c) , 1995, The Journal of Biological Chemistry.

[13]  J C Reed,et al.  Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. , 1998, Science.

[14]  J. Roth,et al.  Adenovirus-mediated Bax overexpression for the induction of therapeutic apoptosis in prostate cancer. , 2001, Cancer research.

[15]  C. Belka,et al.  Guardians of cell death: the Bcl-2 family proteins. , 2003, Essays in biochemistry.

[16]  A. Halestrap,et al.  Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. , 1998, The Biochemical journal.

[17]  S. Korsmeyer,et al.  VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis , 2003, Science.

[18]  S. Snyder,et al.  Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. B. Chen,et al.  Mitochondrial membrane potential in living cells. , 1988, Annual review of cell biology.

[20]  G. Kroemer,et al.  Bcl-2 inhibits the mitochondrial release of an apoptogenic protease , 1996, The Journal of experimental medicine.

[21]  Y. Hsu,et al.  Conformation of the Bax C‐terminus regulates subcellular location and cell death , 1999, The EMBO journal.

[22]  G. Cohen,et al.  The Apaf-1 apoptosome: a large caspase-activating complex. , 2002, Biochimie.

[23]  L Ji,et al.  A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax , 2000, Gene Therapy.

[24]  A. F. Schinder,et al.  Mitochondrial Dysfunction Is a Primary Event in Glutamate Neurotoxicity , 1996, The Journal of Neuroscience.

[25]  John Calvin Reed,et al.  Humanin peptide suppresses apoptosis by interfering with Bax activation , 2003, Nature.

[26]  C. Borner,et al.  Conformational control of Bax localization and apoptotic activity by Pro168 , 2004, The Journal of cell biology.

[27]  B. Roques,et al.  NMR structure of the (52-96) C-terminal domain of the HIV-1 regulatory protein Vpr: molecular insights into its biological functions. , 1999, Journal of molecular biology.

[28]  John Calvin Reed,et al.  bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. , 1992, Cancer research.

[29]  P. Vandenabeele,et al.  The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet , 2002, Cell Death and Differentiation.

[30]  H. Wajant,et al.  The Fas Signaling Pathway: More Than a Paradigm , 2002, Science.

[31]  B. Joseph,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. , 1999, Cancer research.

[32]  P. Waring,et al.  Cyclosporin A rescues thymocytes from apoptosis induced by very low concentrations of thapsigargin: effects on mitochondrial function. , 1996, Experimental cell research.

[33]  Sebastian Brandner,et al.  Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice , 2004, Molecular and Cellular Biology.

[34]  P Louisot,et al.  Mitochondrial contact sites. Lipid composition and dynamics. , 1990, The Journal of biological chemistry.

[35]  G. Kroemer,et al.  The HIV-1 Viral Protein R Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore , 2000, The Journal of experimental medicine.

[36]  S. Srinivasula,et al.  Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice , 2003, Nature.

[37]  David A. Boothman,et al.  Ku70 suppresses the apoptotic translocation of Bax to mitochondria , 2003, Nature Cell Biology.

[38]  D. Green,et al.  The Pathophysiology of Mitochondrial Cell Death , 2004, Science.

[39]  S. Smaili,et al.  Mitochondria in Ca2+ Signaling and Apoptosis , 2000, Journal of bioenergetics and biomembranes.

[40]  Jeffrey Robbins,et al.  Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death , 2005, Nature.

[41]  M. V. Heiden,et al.  Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria , 1997, Cell.

[42]  D. Hughes,et al.  The Apoptotic Protein tBid Promotes Leakage by Altering Membrane Curvature* , 2002, The Journal of Biological Chemistry.

[43]  L. Gerweck,et al.  Lonidamine-induced, pH dependent inhibition of cellular oxygen utilization. , 1988, Radiation research.

[44]  C. Dive,et al.  Mitochondrial membrane permeabilisation by Bax/Bak. , 2003, Biochemical and biophysical research communications.

[45]  E. Lander,et al.  Allelotype analysis of mouse lung carcinomas reveals frequent allelic losses on chromosome 4 and an association between allelic imbalances on chromosome 6 and K-ras activation. , 1994, Cancer research.

[46]  C. Klee,et al.  Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[47]  C. Bloomfield,et al.  Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  S. Campello,et al.  Bax Does Not Directly Participate in the Ca2+-induced Permeability Transition of Isolated Mitochondria* , 2004, Journal of Biological Chemistry.

[49]  D. Andrews,et al.  Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator , 2000, Oncogene.

[50]  D. Bredesen,et al.  Apoptosis: overview and signal transduction pathways. , 2000, Journal of neurotrauma.

[51]  J. Modica-Napolitano,et al.  Selective damage to carcinoma mitochondria by the rhodacyanine MKT-077. , 1996, Cancer research.

[52]  Dean P. Jones,et al.  Glutathione depletion enforces the mitochondrial permeability transition and causes cell death in HL60 cells that overexpress Bcl‐2 , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  A E Vercesi,et al.  Mitochondrial permeability transition and oxidative stress , 2001, FEBS letters.

[54]  Geng Wu,et al.  Structural basis of IAP recognition by Smac/DIABLO , 2000, Nature.

[55]  A. Vercesi,et al.  Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants. , 1990, The Journal of biological chemistry.

[56]  G. Kroemer,et al.  Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis , 2000, Oncogene.

[57]  M Crompton,et al.  The mitochondrial permeability transition pore and its role in cell death. , 1999, The Biochemical journal.

[58]  G. Kroemer,et al.  Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. , 1999, Experimental cell research.

[59]  J. Hayashi,et al.  Ditercalinium chloride, a pro-anticancer drug, intimately associates with mammalian mitochondrial DNA and inhibits its replication , 2003, Current Genetics.

[60]  R. Gottlieb Mitochondria: execution central , 2000, FEBS letters.

[61]  I. Scheffler,et al.  Mitochondria make a come back. , 2001, Advanced drug delivery reviews.

[62]  Y. Pu,et al.  Temporal relationship between cytochrome c release and mitochondrial swelling during UV-induced apoptosis in living HeLa cells. , 2001, Journal of cell science.

[63]  M. Lieber,et al.  Generation and Characterization of Endonuclease G Null Mice , 2005, Molecular and Cellular Biology.

[64]  R. Haworth,et al.  The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. , 1979, Archives of biochemistry and biophysics.

[65]  A. Vercesi,et al.  Ca2+-independent permeabilization of the inner mitochondrial membrane by peroxynitrite is mediated by membrane protein thiol cross-linking and lipid peroxidation. , 1997, Archives of Biochemistry and Biophysics.

[66]  W. Harrington,et al.  Apoptosis: programmed cell death at a molecular level. , 2003, Seminars in arthritis and rheumatism.

[67]  Xiaodong Wang,et al.  Structural and biochemical basis of apoptotic activation by Smac/DIABLO , 2000, Nature.

[68]  B. Chernyak,et al.  Modulation of the Mitochondrial Permeability Transition Pore by Pyridine Nucleotides and Dithiol Oxidation at Two Separate Sites (*) , 1996, The Journal of Biological Chemistry.

[69]  W. Garrard,et al.  Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G , 2005, Journal of cellular biochemistry.

[70]  T. Kuwana,et al.  Bcl-2-family proteins and the role of mitochondria in apoptosis. , 2003, Current opinion in cell biology.

[71]  G. Kroemer,et al.  The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition , 1998, Oncogene.

[72]  S. Korsmeyer,et al.  Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c , 2000, Cell Death and Differentiation.

[73]  Yigong Shi,et al.  Mechanisms of caspase activation and inhibition during apoptosis. , 2002, Molecular cell.

[74]  H. Nakayama,et al.  A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. , 2001, Molecular cell.

[75]  S. Javadov,et al.  Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. , 2004, Cardiovascular research.

[76]  P. Bénit,et al.  AIF deficiency compromises oxidative phosphorylation , 2004, The EMBO journal.

[77]  D. Vaux,et al.  The mitochondrial death squad: hardened killers or innocent bystanders? , 2005, Current opinion in cell biology.

[78]  D. Brenner,et al.  The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. , 1998, Biochimica et biophysica acta.

[79]  Z. Oltvai,et al.  Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[80]  H. Steinman The Bcl-2 oncoprotein functions as a pro-oxidant. , 1995, Journal of Biological Chemistry.

[81]  Xiaodong Wang,et al.  A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. , 2004, Science.

[82]  R. Haworth,et al.  The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. , 1979, Archives of biochemistry and biophysics.

[83]  J. Irish,et al.  Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line , 2002, Cell Death and Differentiation.

[84]  R. Aqeilan,et al.  Interleukin 2‐Bax: a novel prototype of human chimeric proteins for targeted therapy , 1999, FEBS letters.

[85]  D. Curiel,et al.  Pro‐apoptotic treatment with an adenovirus encoding Bax enhances the effect of chemotherapy in ovarian cancer , 2000, Journal of Gene Medicine.

[86]  L. Scorrano,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. , 1994, The Journal of biological chemistry.

[87]  J. Lemasters,et al.  Role of the mitochondrial permeability transition in apoptotic and necrotic death after ischemia/reperfusion injury to hepatocytes. , 2003, Current molecular medicine.

[88]  M. Crompton Mitochondrial intermembrane junctional complexes and their role in cell death , 2000, The Journal of physiology.

[89]  Z. Oltvai,et al.  BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax , 1994, Nature.

[90]  Christian Renken,et al.  Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release , 2000, The Journal of cell biology.

[91]  Brian J. Smith,et al.  Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. , 2005, Molecular cell.

[92]  J. Lai,et al.  High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[93]  M. Crompton,et al.  Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. , 1998, European journal of biochemistry.

[94]  H. Saito,et al.  Bax interacts with the voltage-dependent anion channel and mediates ethanol-induced apoptosis in rat hepatocytes. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[95]  K. Anderson The molecular basis of inhibition and toxicity of modified cytosine analogues targetting HIV-1 reverse transcriptase. , 2001, Antiviral chemistry & chemotherapy.

[96]  Ahmed Haouz,et al.  The crystal structure of the mouse apoptosis-inducing factor AIF , 2002, Nature Structural Biology.

[97]  Z. Oltvai,et al.  Bcl-2 functions in an antioxidant pathway to prevent apoptosis , 1993, Cell.

[98]  Xiaodong Wang,et al.  A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death , 2004, Science.

[99]  G. Kroemer Introduction: mitochondrial control of apoptosis. , 2002, Biochimie.

[100]  Y Li,et al.  [Mitochondria and apoptosis]. , 2000, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[101]  B. Chernyak,et al.  The mitochondrial permeability transition pore is modulated by oxidative agents through both pyridine nucleotides and glutathione at two separate sites. , 1996, European journal of biochemistry.

[102]  G. Paradies,et al.  Role of Reactive Oxygen Species and Cardiolipin in the Release of Cytochrome C from Mitochondria , 2022 .

[103]  M. Klingenberg,et al.  Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. , 1996, Biochemistry.

[104]  G. Kroemer,et al.  NADH Oxidase Activity of Mitochondrial Apoptosis-inducing Factor* , 2001, The Journal of Biological Chemistry.

[105]  W. May,et al.  Bcl-2 Phosphorylation Required for Anti-apoptosis Function* , 1997, The Journal of Biological Chemistry.

[106]  W. Neupert,et al.  Mechanisms of mitochondrial protein import , 2000, Protoplasma.

[107]  Masashi Narita,et al.  14-3-3 Interacts Directly with and Negatively Regulates Pro-apoptotic Bax* , 2003, The Journal of Biological Chemistry.

[108]  D. Xue,et al.  Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. , 2004, Current opinion in cell biology.

[109]  S. Novgorodov,et al.  The Peptide Mastoparan Is a Potent Facilitator of the Mitochondrial Permeability Transition (*) , 1995, The Journal of Biological Chemistry.

[110]  J. Martinou,et al.  Bid Induces the Oligomerization and Insertion of Bax into the Outer Mitochondrial Membrane , 2000, Molecular and Cellular Biology.

[111]  G. Kroemer,et al.  Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore , 1999, Oncogene.

[112]  G. Kroemer,et al.  PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection. , 1998, Experimental cell research.

[113]  V. Weissig,et al.  Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells. , 1996, Molecular pharmacology.

[114]  L. Scorrano,et al.  The mitochondrial permeability transition , 2022, BioFactors.

[115]  J. Martinou,et al.  The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event , 1999, The Journal of cell biology.

[116]  M. Murphy,et al.  Selective targeting of bioactive compounds to mitochondria. , 1997, Trends in biotechnology.

[117]  Yong-kui,et al.  Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. , 1999, Journal of the National Cancer Institute.