Targeting mitochondria for cancer therapy.
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.
Fulda
Simone
S
University Children's Hospital, Ulm University, Eythstrasse 24, D-89075 Ulm, Germany. simone.fulda@uniklinik-ulm.de
Galluzzi
Lorenzo
L
Kroemer
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D011758:Pyrroles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011758:Pyrroles; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000077185:Resveratrol; C520962:obatoclax
Curr Opin Cell Biol. 2005 Dec;17(6):617-25
16243507
Cell. 2006 Jul 14;126(1):177-89
16839885
Semin Cancer Biol. 2009 Feb;19(1):57-66
19101636
J Clin Oncol. 2007 May 1;25(13):1779-84
17470869
Nature. 2005 Jun 2;435(7042):677-81
15902208
J Natl Cancer Inst. 2006 Aug 2;98(15):1068-77
16882944
Oncogene. 2008 Aug 7;27(34):4636-43
18408762
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5594-7
18823777
Nature. 2005 Mar 31;434(7033):652-8
15800626
Cancer Res. 2007 Jan 15;67(2):782-91
17234790
Mol Pharmacol. 2002 May;61(5):1255-62
11961144
J Neurooncol. 2003 May;63(1):81-6
12814259
Br J Pharmacol. 2007 Aug;151(8):1154-65
17519949
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7147-52
18480265
J Clin Invest. 2008 Nov;118(11):3651-9
18949058
Cancer Cell. 2005 Oct;8(4):311-21
16226706
J Biol Chem. 1998 Dec 18;273(51):33942-8
9852046
Blood. 2007 Dec 15;110(13):4427-35
17804695
Cell Death Differ. 2008 May;15(5):929-37
18259190
Physiol Rev. 2007 Jan;87(1):99-163
17237344
Pediatr Blood Cancer. 2008 Jun;50(6):1181-9
18085673
Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14907-12
16997913
Clin Cancer Res. 2005 Sep 15;11(18):6625-33
16166441
J Cell Biol. 1999 Dec 27;147(7):1493-502
10613907
Clin Cancer Res. 2008 Dec 15;14(24):8295-301
19088047
FASEB J. 2008 Sep;22(9):3264-75
18524868
Cell. 2007 Oct 19;131(2):257-70
17956728
Methods Enzymol. 2008;442:355-74
18662579
Cancer Cell. 2006 Nov;10(5):389-99
17097561
Cell. 2006 Dec 15;127(6):1109-22
17112576
Clin Cancer Res. 2007 Oct 15;13(20):6162-7
17947482
Apoptosis. 2007 May;12(5):803-13
17294081
J Clin Invest. 2009 Mar;119(3):454-64
19229106
Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11832-7
17609380
Cancer Res. 2005 Jul 15;65(14):6312-20
16024633
Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10032-7
10944195
Cell. 2008 Dec 26;135(7):1161-3
19109884
Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):584-90
17255281
Cell. 2008 Dec 12;135(6):1074-84
19062087
Leukemia. 2006 Jun;20(6):1073-9
16628188
Oncogene. 2008 Nov 6;27(52):6646-56
18663354
Nat Cell Biol. 2007 May;9(5):487-9
17473857
Cancer Cell. 2007 Jan;11(1):37-51
17222789
Cell Death Differ. 2007 Apr;14(4):785-94
17096026
Int J Cancer. 2008 Aug 15;123(4):739-52
18512238
Clin Cancer Res. 2008 Dec 1;14(23):7909-16
19047121
Mol Med. 2002 Dec;8(12):877-84
12606824
Exp Cell Res. 2001 Jan 15;262(2):154-69
11139340
Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13632-7
17698806
Adv Drug Deliv Rev. 2009 Nov 30;61(14):1250-75
19716393
Nature. 2008 Mar 13;452(7184):181-6
18337815
J Invest Dermatol. 2009 Apr;129(4):964-71
18987671
Oncogene. 2006 Aug 7;25(34):4812-30
16892093
Cancer Res. 2006 Sep 1;66(17):8731-9
16951189
J Natl Cancer Inst. 2006 Feb 15;98(4):236-44
16478742
Cancer Res. 2008 Apr 15;68(8):2944-51
18413764
Invest New Drugs. 2010 Oct;28(5):634-40
19499186
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7
18040043
Chembiochem. 2009 Aug 17;10(12):1939-50
19637148
Clin Cancer Res. 2005 Mar 1;11(5):1751-6
15755996
Arch Immunol Ther Exp (Warsz). 2007 Sep-Oct;55(5):315-27
18219762
Cell. 2007 Jan 26;128(2):325-39
17254970
Cancer Res. 2006 Sep 15;66(18):9143-52
16982757
Mol Aspects Med. 2010 Feb;31(1):1-20
19698742
Cell Death Differ. 2004 Jul;11(7):737-46
15002036
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Oct 1;877(27):3118-26
19695967
Nat Rev Mol Cell Biol. 2008 Apr;9(4):285-96
18285802
Mitochondrion. 2007 Feb-Apr;7(1-2):63-71
17296332
Clin Cancer Res. 2009 Feb 15;15(4):1460-5
19228747
Blood. 2007 May 15;109(10):4441-9
17227835
Clin Cancer Res. 2009 Mar 1;15(5):1593-600
19223492
FASEB J. 2001 Feb;15(2):403-15
11156956
Oncogene. 2006 Aug 7;25(34):4798-811
16892092
Blood. 2007 Sep 15;110(6):2057-66
17536015
Cancer Res. 2008 Oct 1;68(19):7985-94
18829556
Nat Rev Cancer. 2005 Nov;5(11):857-66
16327764
Nature. 2008 Oct 23;455(7216):1076-81
18948948
Oncogene. 2005 Nov 17;24(51):7503-13
16091749
Methods. 2008 Mar;44(3):222-8
18314052
Leuk Lymphoma. 2009 Apr;50(4):559-65
19373653
J Biol Chem. 2009 Dec 4;284(49):34390-9
19805544
Blood. 2008 Mar 15;111(6):3211-9
18202226
FASEB J. 2001 Jul;15(9):1613-5
11427503
J Cell Physiol. 2009 Jan;218(1):13-21
18767026
Science. 2009 Jun 26;324(5935):1670-3
19556499
Oncogene. 2005 May 19;24(22):3574-82
15806173
Neuro Oncol. 2008 Oct;10(5):752-8
18715950
Ann Hematol. 2000 May;79(5):227-38
10870476
Blood. 2007 Jun 15;109(12):5430-8
17332241
Trends Cell Biol. 2009 Jan;19(1):16-23
19027299
Biochim Biophys Acta. 2008 Feb;1778(2):423-32
18054323
Nature. 2000 Sep 21;407(6802):390-5
11014196
J Biol Chem. 2004 Jul 23;279(30):31761-8
15166242
Trends Cell Biol. 2008 Apr;18(4):165-73
18296052
Trends Biotechnol. 1997 Aug;15(8):326-30
9263481
J Clin Oncol. 2003 Sep 15;21(18):3462-8
12972521
Cell. 2006 Jul 14;126(1):163-75
16839884
Adv Drug Deliv Rev. 2006 Dec 30;58(15):1622-54
17123658
Ann Oncol. 2008 Dec;19(12):2007-11
18664560
Cancer. 2007 Mar 1;109(5):891-8
17265529
Leukemia. 2007 Aug;21(8):1763-72
17554384
Cancer Res. 2008 May 1;68(9):3421-8
18451170
Nature. 2004 Oct 21;431(7011):997-1002
15496926
Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1069-76
18977094
Cell Death Differ. 2008 Jul;15(7):1113-23
18309324
FEBS Lett. 2002 Dec 4;532(1-2):256-60
12459501
Clin Cancer Res. 2004 Mar 15;10(6):2058-64
15041726
Mol Nutr Food Res. 2009 Jan;53(1):129-39
19072740
J Pharmacol Exp Ther. 1999 Jun;289(3):1306-12
10336521
Cancer Res. 2005 Nov 15;65(22):10545-54
16288047
Brain Res. 2005 Apr 8;1040(1-2):137-50
15804435
Mol Cell Biol. 2009 Jul;29(14):3881-93
19414600
Gut. 2002 Oct;51(4):556-61
12235080
PLoS One. 2008 Mar 19;3(3):e1852
18350175
Cell Death Differ. 2009 Mar;16(3):360-7
18806758
Biochem J. 2004 Nov 1;383(Pt. 3):457-68
15270716
Blood. 2005 Jun 1;105(11):4163-9
15687234
Int J Cancer. 2010 Jan 1;126(1):90-103
19569175
Clin Cancer Res. 2009 May 1;15(9):3172-6
19366825
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17961-6
19004807
Med Pediatr Oncol. 2000 Dec;35(6):616-8
11107130
Int J Cancer. 2008 Dec 1;123(11):2557-65
18770866
J Invest Dermatol. 2000 May;114(5):935-40
10771474
Cancer Res. 2006 Mar 1;66(5):2757-64
16510597
Cell. 2002 Nov 1;111(3):331-42
12419244
Cancer Res. 2007 Dec 15;67(24):11906-13
18089821
Cell Metab. 2006 Mar;3(3):187-97
16517406
Cancer Res. 2002 Mar 1;62(5):1388-93
11888910
Semin Cancer Biol. 2006 Dec;16(6):466-76
17112739
Cell Stem Cell. 2007 Jun 7;1(1):101-12
18371339
Nat Med. 2006 Apr;12(4):446-51
16565722
Cell. 2003 Nov 26;115(5):629-40
14651853
Cancer Lett. 2002 Jan 10;175(1):17-25
11734332
Cancer Cell. 2003 May;3(5):497-509
12781367
Cancer Res. 2008 May 1;68(9):3413-20
18451169
Oncogene. 2008 Jan 10;27(3):285-99
17700538
Cancer Res. 2003 Jan 15;63(2):541-6
12543814
Head Neck. 2003 Sep;25(9):732-40
12953308
Oncogene. 2001 Nov 15;20(52):7579-87
11753636
Mol Pharmacol. 2006 Sep;70(3):909-24
16788091
J Natl Cancer Inst. 2008 Jan 2;100(1):11-2
18159075
Science. 2009 May 22;324(5930):1076-80
19461003
Gynecol Oncol. 2009 Oct;115(1):90-96
19577796
Cell Death Differ. 2009 Jul;16(7):1030-9
19390557
Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73
19416831
Exp Biol Med (Maywood). 2004 Oct;229(9):954-63
15388892
J Clin Oncol. 2009 Nov 10;27(32):5452-8
19826135
Blood. 2005 Nov 15;106(10):3584-93
16051742
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7124-9
10860979
J Biol Chem. 2008 Sep 5;283(36):25003-13
18599488
Cell Death Differ. 2009 Nov;16(11):1419-25
19696789
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):719-24
15647368
Cell Death Differ. 2007 Sep;14(9):1667-77
17510658
Biochim Biophys Acta. 2009 May;1787(5):553-60
19285479
Hum Mol Genet. 2001 Dec 15;10(26):3093-9
11751691
Anticancer Drug Des. 2001 Aug-Oct;16(4-5):209-15
12049479
Chembiochem. 2009 Aug 17;10(12):2081-8
19670199
Nature. 2009 Apr 9;458(7239):780-3
19194462
Free Radic Biol Med. 2001 Aug 15;31(4):530-41
11498286
Blood. 2009 Feb 26;113(9):1982-91
19060243
Cell Death Differ. 2009 May;16(5):697-707
19165229
Cancer Res. 2007 Sep 1;67(17):8180-7
17804731
Cancer Cell. 2006 Nov;10(5):375-88
17097560
J Clin Oncol. 2008 Feb 20;26(6):870-6
18281659
Mol Pharmacol. 2003 Jan;63(1):224-31
12488555
Cell. 2007 Jun 29;129(7):1261-74
17604717
Cell Mol Life Sci. 2005 Aug;62(16):1890-9
16041565
Mitochondrion. 2004 Sep;4(5-6):755-62
16120430
J Clin Oncol. 2007 Mar 20;25(9):1114-20
17296974
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52
17548692
Front Biosci (Landmark Ed). 2009 Jan 01;14:4015-34
19273331
Biochem Pharmacol. 2009 Apr 15;77(8):1337-47
19426672
Cell. 2000 Jan 7;100(1):57-70
10647931
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93
17640917
Pharm Res. 1998 Feb;15(2):334-7
9523323
Nat Cell Biol. 2007 May;9(5):550-5
17417626
Angew Chem Int Ed Engl. 2007;46(31):5880-4
17607670
Cancer Res. 1997 Nov 1;57(21):4956-64
9354463
Trends Biochem Sci. 2007 Jan;32(1):37-43
17141506
Folia Histochem Cytobiol. 2008;46(2):129-35
18519227
Nature. 2004 Jan 29;427(6973):461-5
14749836
Cancer Res. 1998 Oct 1;58(19):4453-60
9766678
Cancer Res. 1999 Apr 1;59(7 Suppl):1693s-1700s
10197582
Cancer. 2003 Feb 1;97(3 Suppl):840-7
12548584
Cancer Res. 2007 Apr 1;67(7):3364-70
17409446
Cancer Res. 2005 Sep 1;65(17):8028-33
16140977
Cancer Cell. 2006 Sep;10(3):241-52
16959615
Cell Death Differ. 2008 Mar;15(3):521-9
18064042
Cancer Res. 2008 Apr 1;68(7):2321-8
18381439
Curr Opin Cell Biol. 2007 Apr;19(2):223-9
17303407
Clin Cancer Res. 2008 Mar 15;14(6):1831-9
18347186
Blood. 2009 Jan 8;113(2):299-305
18931344
Cancer Cell. 2005 May;7(5):457-68
15894266
Mol Cancer Ther. 2007 Sep;6(9):2554-62
17876052
Cancer Cell. 2008 Jun;13(6):472-82
18538731
Cell Metab. 2006 Mar;3(3):177-85
16517405
J Biol Chem. 1994 Jun 17;269(24):16638-42
7515881
Oncogene. 2008 Jul 17;27(31):4324-35
18372923
Science. 1998 Sep 25;281(5385):2027-31
9748162
Carcinogenesis. 2006 Nov;27(11):2223-34
16774948
Cancer Res. 1999 Dec 15;59(24):6257-66
10626821
Science. 2004 Feb 13;303(5660):1010-4
14963330
Nature. 1989 Mar 9;338(6211):170-2
2918937
Cell Death Differ. 2006 Aug;13(8):1396-402
16710362
Blood. 2008 Oct 1;112(7):2906-16
18591385
Clin Cancer Res. 2003 Jul;9(7):2866-75
12855667
Leukemia. 2009 Nov;23(11):2034-41
19641525
Invest New Drugs. 2005 Jun;23(3):235-9
15868379
Nat Chem Biol. 2007 Aug;3(8):498-507
17603540
J Biol Chem. 2001 Feb 16;276(7):4588-96
11092892
Melanoma Res. 2001 Apr;11(2):99-104
11333133
PLoS Med. 2007 Oct;4(10):1681-89; discussion 1690
17973573
J Clin Oncol. 1996 Apr;14(4):1165-72
8648371
Annu Rev Biochem. 2007;76:723-49
17263664
Cell. 2006 Jul 14;126(1):107-20
16839880
J Med Chem. 2003 Sep 25;46(20):4259-64
13678404
Cancer Lett. 2004 Aug 10;211(2):175-88
15219941
FEBS Lett. 2004 Apr 9;563(1-3):155-60
15063741
Cancer Res. 2006 Oct 1;66(19):9374-8
17018590
J Clin Oncol. 2007 Apr 20;25(12):1512-8
17442993
Prostate. 2008 Jun 1;68(8):849-60
18324647
Chem Biol. 2008 Apr;15(4):375-82
18420144
Med Res Rev. 2004 Jan;24(1):90-114
14595673
Nat Rev Drug Discov. 2008 Dec;7(12):989-1000
19043450
Mol Cancer Ther. 2008 Aug;7(8):2319-27
18723479
J Gastroenterol Hepatol. 2006 Sep;21(9):1478-82
16911696
Oncogene. 2000 Jan 13;19(2):307-14
10645010
Toxicol Appl Pharmacol. 1997 Apr;143(2):338-47
9144450
Nat Rev Cancer. 2007 May;7(5):357-69
17446857
Nat Cell Biol. 2004 May;6(5):443-50
15077116
PLoS Med. 2007 Oct 9;4(10):e294
17927446
Oncogene. 2008 Aug 7;27(34):4633-5
18469866
Int J Cancer. 2009 Feb 1;124(3):511-5
19003982
Mol Cell. 2004 Dec 3;16(5):819-30
15574336
Cancer Cell. 2006 Jun;9(6):425-34
16766262
Science. 2007 Oct 5;318(5847):62-4
17916722