title: Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies.
abstract: The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has led to the development of small-molecule compounds, known as 'BH3-mimetics', that bind to pro-survival BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and, specifically, its roles in cancer development and therapy.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia.
authors.forename: Alex R D
authors.initials: AR
authors.lastname: Delbridge
authors.affiliation: Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.affiliation: Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology; D016923:Cell Death; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins; D058990:Molecular Targeted Therapy / Q000379:methods*; D005810:Multigene Family; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D033681:Mitochondrial Membrane Transport Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; C581062:RTL10 protein, human; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein
references.citation: Cell. 1993 Nov 19;75(4):641-52
references.pmid: 8242740
references.citation: Cancer Cell. 2007 Aug;12 (2):171-85
references.pmid: 17692808
references.citation: Cell. 1995 Jan 27;80(2):285-91
references.pmid: 7834748
references.citation: N Engl J Med. 2016 Jan 28;374(4):311-22
references.pmid: 26639348
references.citation: Cell. 1993 Aug 27;74(4):597-608
references.pmid: 8358789
references.citation: Science. 1997 Feb 21;275(5303):1129-32
references.pmid: 9027314
references.citation: Nature. 2003 Dec 11;426(6967):671-6
references.pmid: 14668867
references.citation: Annu Rev Genet. 1984;18:553-612
references.pmid: 6397126
references.citation: Science. 1992 Dec 18;258(5090):1955-7
references.pmid: 1470921
references.citation: J Biol Chem. 1998 Dec 4;273(49):32479-86
references.pmid: 9829980
references.citation: Nat Med. 2013 Feb;19(2):202-8
references.pmid: 23291630
references.citation: Cell Growth Differ. 1994 Apr;5(4):411-7
references.pmid: 8043515
references.citation: Cell. 2012 Dec 7;151(6):1179-84
references.pmid: 23217705
references.citation: Cell. 1996 Jul 12;86(1):147-57
references.pmid: 8689682
references.citation: J Histochem Cytochem. 1992 Dec;40(12):1819-25
references.pmid: 1453000
references.citation: Nature. 1988 Nov 17;336(6196):259-61
references.pmid: 2848196
references.citation: Science. 1997 Feb 14;275(5302):967-9
references.pmid: 9020077
references.citation: Science. 1997 Jul 18;277(5324):370-2
references.pmid: 9219694
references.citation: Nature. 1995 Apr 20;374(6524):731-3
references.pmid: 7715729
references.citation: Nat Rev Drug Discov. 2008 Dec;7(12):989-1000
references.pmid: 19043450
references.citation: Science. 1993 Sep 17;261(5128):1584-8
references.pmid: 8372353
references.citation: Genes Dev. 2013 Jun 15;27(12):1351-64
references.pmid: 23788622
references.citation: Mol Cell. 2000 Dec;6(6):1389-99
references.pmid: 11163212
references.citation: Cell. 2012 Oct 12;151(2):344-55
references.pmid: 23063124
references.citation: Blood. 2010 Dec 9;116(24):5256-67
references.pmid: 20829369
references.citation: Blood. 2013 Aug 29;122(9):1587-98
references.pmid: 23881917
references.citation: Nat Med. 2012 Mar 18;18(4):521-8
references.pmid: 22426421
references.citation: Cell. 1985 Jul;41(3):677-83
references.pmid: 2988782
references.citation: J Biol Chem. 1990 Mar 25;265(9):4929-33
references.pmid: 2180952
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109 (8):2766-71
references.pmid: 21768359
references.citation: Cell. 1994 Oct 21;79(2):353-64
references.pmid: 7954801
references.citation: Science. 2000 May 12;288(5468):1053-8
references.pmid: 10807576
references.citation: PLoS Med. 2007 Oct;4(10 ):1681-89; discussion 1690
references.pmid: 17973573
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3668-72
references.pmid: 9108035
references.citation: Genes Dev. 2013 Jun 15;27(12):1365-77
references.pmid: 23788623
references.citation: Science. 1995 Oct 6;270(5233):96-9
references.pmid: 7569956
references.citation: Trends Cell Biol. 2008 Apr;18(4):157-64
references.pmid: 18314333
references.citation: J Cell Sci. 2009 Aug 15;122(Pt 16):2801-8
references.pmid: 19795525
references.citation: J Immunol. 1990 May 1;144(9):3602-10
references.pmid: 2184193
references.citation: Genes Dev. 2001 Jun 15;15(12 ):1481-6
references.pmid: 11410528
references.citation: Cell. 2000 Nov 10;103(4):645-54
references.pmid: 11106734
references.citation: Cell Death Dis. 2015 Jan 15;6:e1590
references.pmid: 25590800
references.citation: Nat Rev Mol Cell Biol. 2014 Jan;15(1):49-63
references.pmid: 24355989
references.citation: Mol Cell. 2001 Mar;7(3):683-94
references.pmid: 11463392
references.citation: Cancer Chemother Pharmacol. 2010 Oct;66(5):869-80
references.pmid: 20099064
references.citation: Endocrinology. 2006 Oct;147(10):4960-7
references.pmid: 16794010
references.citation: J Hepatol. 2010 May;52(5):698-704
references.pmid: 20347499
references.citation: FEBS J. 2015 Mar;282(6):1006-16
references.pmid: 25565426
references.citation: Science. 1999 Nov 26;286(5445):1735-8
references.pmid: 10576740
references.citation: Cell Death Dis. 2013 Nov 07;4:e909
references.pmid: 24201808
references.citation: Proc Natl Acad Sci U S A. 1989 Jun;86(12):4589-93
references.pmid: 2543982
references.citation: Nature. 2009 Aug 20;460(7258):1035-9
references.pmid: 19626005
references.citation: PLoS Med. 2007 Oct;4(10 ):1669-79; discussion 1680
references.pmid: 17973572
references.citation: J Immunol. 1993 Aug 15;151(4):1979-88
references.pmid: 8345191
references.citation: J Clin Invest. 2008 Nov;118(11):3651-9
references.pmid: 18949058
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3516-20
references.pmid: 7682708
references.citation: Nature. 1991 Jan 17;349(6306):254-6
references.pmid: 1987477
references.citation: Cancer Res. 2008 May 1;68(9):3421-8
references.pmid: 18451170
references.citation: Science. 2011 Nov 25;334(6059):1129-33
references.pmid: 22033517
references.citation: Br J Cancer. 1972 Aug;26(4):239-57
references.pmid: 4561027
references.citation: Science. 2004 Jul 30;305(5684):626-9
references.pmid: 15286356
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2599-604
references.pmid: 23349374
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Science. 2001 Apr 27;292(5517):727-30
references.pmid: 11326099
references.citation: Mol Cell. 2005 Feb 4;17 (3):393-403
references.pmid: 15694340
references.citation: Genes Dev. 2012 Jan 15;26(2):120-5
references.pmid: 22279045
references.citation: Blood. 1997 Aug 1;90(3):1168-74
references.pmid: 9242549
references.citation: Nat Rev Cancer. 2009 May;9(5):321-6
references.pmid: 19343035
references.citation: Nature. 1989 Nov 9;342(6246):195-8
references.pmid: 2478890
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9
references.pmid: 15079075
references.citation: Mol Cell Biol. 1989 Feb;9(2):701-10
references.pmid: 2651903
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8661-5
references.pmid: 1924327
references.citation: EMBO J. 1998 Mar 16;17(6):1675-87
references.pmid: 9501089
references.citation: Blood. 2015 May 21;125(21):3273-80
references.pmid: 25847014
references.citation: Clin Cancer Res. 2011 Sep 15;17(18):5973-81
references.pmid: 21821698
references.citation: Mol Cell Biol. 2004 Jul;24(14):6172-83
references.pmid: 15226421
references.citation: Science. 2010 Nov 19;330(6007):1095-9
references.pmid: 20929728
references.citation: Int J Cancer. 1978 Jul 15;22(1):14-21
references.pmid: 355152
references.citation: J Exp Med. 2006 Dec 25;203(13):2939-51
references.pmid: 17178918
references.citation: Genes Dev. 2000 Jan 1;14(1):23-7
references.pmid: 10640272
references.citation: Curr Top Microbiol Immunol. 1990;166:175-81
references.pmid: 2073796
references.citation: Am J Pathol. 2011 Nov;179(5):2162-8
references.pmid: 21893020
references.citation: Proc Natl Acad Sci U S A. 1985 Nov;82(21):7439-43
references.pmid: 2865728
references.citation: Cancer Res. 1996 Aug 1;56(15):3546-50
references.pmid: 8758925
references.citation: Cell. 1994 Oct 21;79(2):329-39
references.pmid: 7954799
references.citation: Nature. 1988 Sep 29;335(6189):440-2
references.pmid: 3262202
references.citation: Oncogene. 2013 Jun 20;32(25):3071-9
references.pmid: 22824797
references.citation: Nature. 1995 Apr 20;374(6524):736-9
references.pmid: 7715731
references.citation: FASEB J. 2006 Oct;20(12):2147-9
references.pmid: 16935937
references.citation: Science. 1997 Feb 21;275(5303):1132-6
references.pmid: 9027315
references.citation: Nature. 2002 Feb 21;415(6874):922-6
references.pmid: 11859372
references.citation: Cell Death Differ. 2007 May;14(5):943-51
references.pmid: 17205078
references.citation: Cancer Cell. 2003 Oct;4(4):321-8
references.pmid: 14585359
references.citation: Genes Dev. 2003 Sep 15;17(18):2233-8
references.pmid: 12952892
references.citation: Cell. 1998 Aug 21;94(4):491-501
references.pmid: 9727492
references.citation: J Clin Oncol. 2012 Sep 1;30(25):3127-35
references.pmid: 22649144
references.citation: Cell. 1989 Apr 7;57(1):79-88
references.pmid: 2649247
references.citation: Cancer Res. 1995 Jun 15;55(12):2576-82
references.pmid: 7780971
references.citation: Science. 2001 Sep 7;293(5536):1829-32
references.pmid: 11546872
references.citation: Dev Biol. 1977 Mar;56(1):110-56
references.pmid: 838129
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19500-5
references.pmid: 18048346
references.citation: Oncogene. 1996 Aug 15;13(4):665-75
references.pmid: 8761287
references.citation: Nature. 2010 Sep 30;467(7315):596-9
references.pmid: 20823850
references.citation: EMBO J. 1998 Jan 15;17 (2):384-95
references.pmid: 9430630
references.citation: Blood. 2013 Mar 21;121(12 ):2285-8
references.pmid: 23341542
references.citation: Nature. 1993 Jan 28;361(6410):365-9
references.pmid: 8381212
references.citation: Int J Cancer. 1996 Dec 11;68(6):727-30
references.pmid: 8980174
references.citation: Cell Death Differ. 2009 Jul;16(7):1030-9
references.pmid: 19390557
references.citation: Cell Death Differ. 2015 Jul;22(7):1071-80
references.pmid: 25952548
references.citation: Nat Chem Biol. 2013 Jun;9(6):390-7
references.pmid: 23603658
references.citation: Cancer Res. 2008 May 1;68(9):3413-20
references.pmid: 18451169
references.citation: Cell. 1991 Jul 26;66(2):233-43
references.pmid: 1713127
references.citation: J Clin Invest. 2010 Jun;120(6):2109-18
references.pmid: 20484815
references.citation: Blood. 2005 Dec 15;106(13):4131-8
references.pmid: 16118324
references.citation: EMBO J. 1995 Dec 15;14(24):6136-47
references.pmid: 8557033
references.citation: Cancer Cell. 2013 Jul 8;24(1):120-9
references.pmid: 23845444
references.citation: Cell Death Differ. 2012 Jun;19(6):915-25
references.pmid: 22281706
references.citation: Mol Cell. 2005 Feb 18;17 (4):525-35
references.pmid: 15721256
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3268-77
references.pmid: 18519752
references.citation: J Neurosci. 2008 Jun 11;28(24):6068-78
references.pmid: 18550749
references.citation: Cell. 2007 Mar 23;128(6):1173-86
references.pmid: 17382885
references.citation: Dev Cell. 2001 Nov;1(5):645-53
references.pmid: 11709185
references.citation: J Biol Chem. 1997 Dec 5;272(49):30866-72
references.pmid: 9388232
references.citation: Mol Cell Biol. 1987 May;7(5):1673-80
references.pmid: 3037331
references.citation: Acta Histochem. 2011 Dec;113(8):810-4
references.pmid: 21277008
references.citation: Nature. 1996 May 23;381(6580):335-41
references.pmid: 8692274
references.citation: Br J Haematol. 2015 Sep;170(5):669-78
references.pmid: 25942994
references.citation: Science. 2007 Feb 9;315 (5813):856-9
references.pmid: 17289999
references.citation: Nature. 1983 Aug 18-24;304(5927):596-602
references.pmid: 6308472
references.citation: Cancer Cell. 2006 Nov;10(5):389-99
references.pmid: 17097561
references.citation: J Clin Oncol. 2012 Feb 10;30(5):488-96
references.pmid: 22184378
references.citation: Cell. 2013 Jan 31;152(3):519-31
references.pmid: 23374347
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(14):5214-8
references.pmid: 3523487
references.citation: Oncogene. 1995 Oct 5;11(7):1389-94
references.pmid: 7478561
references.citation: Lancet Oncol. 2010 Dec;11(12):1149-59
references.pmid: 21094089
references.citation: Nature. 2008 Oct 23;455(7216):1076-81
references.pmid: 18948948
references.citation: Cold Spring Harb Perspect Biol. 2013 Apr 01;5(4):a008714
references.pmid: 23545417
references.citation: Cell. 1986 Mar 28;44(6):817-29
references.pmid: 3955651
references.citation: Immunity. 2003 Sep;19(3):341-52
references.pmid: 14499110
references.citation: EMBO J. 1997 Apr 1;16(7):1686-94
references.pmid: 9130713
references.citation: Science. 1995 Mar 10;267(5203):1506-10
references.pmid: 7878471
references.citation: Cell Death Differ. 2008 Jun;15(6):1019-29
references.pmid: 18259198
references.citation: Nat Immunol. 2002 Oct;3(10):932-9
references.pmid: 12244308
references.citation: Oncogene. 1989 Nov;4(11):1331-6
references.pmid: 2554236
references.citation: Cell. 2007 Jun 29;129(7):1337-49
references.pmid: 17604722
references.citation: Nature. 1992 Oct 8;359(6395):552-4
references.pmid: 1406975
references.citation: Cancer Res. 1990 Oct 15;50(20):6565-70
references.pmid: 2208117
references.citation: Nature. 1999 Aug 26;400(6747):886-91
references.pmid: 10476969
references.citation: Oncogene. 1993 Jan;8(1):1-9
references.pmid: 8423986
references.citation: Genes Dev. 1996 Nov 15;10(22):2859-69
references.pmid: 8918887
references.citation: PLoS Med. 2007 Oct 9;4(10):e294
references.pmid: 17927446
references.citation: Science. 1984 Nov 30;226(4678):1097-9
references.pmid: 6093263
references.citation: Oncogene. 1988 May;2(5):431-5
references.pmid: 3131717
references.citation: Cell. 1986 Oct 10;47(1):19-28
references.pmid: 2875799
references.citation: Mol Cancer Res. 2007 Apr;5(4):331-9
references.pmid: 17426248
references.citation: Cell. 1994 Feb 25;76(4):665-76
references.pmid: 7907274
references.citation: Oncogene. 1991 Oct;6(10):1915-22
references.pmid: 1923514
references.citation: Nature. 1990 Nov 22;348(6299):334-6
references.pmid: 2250705
references.citation: Cell Death Differ. 2013 Nov;20(11):1475-84
references.pmid: 23832116
references.citation: Autophagy. 2008 Jul;4(5):600-6
references.pmid: 18497563
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12401-6
references.pmid: 9356461
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14907-12
references.pmid: 16997913
references.citation: Nature. 2002 Oct 10;419(6907):634-7
references.pmid: 12374983
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9
references.pmid: 16166262
references.citation: Oncogene. 2005 Feb 17;24(8):1348-58
references.pmid: 15608680
references.citation: Int Immunol. 1992 Jul;4(7):821-4
references.pmid: 1498090
references.citation: Nat Immunol. 2013 Mar;14(3):290-7
references.pmid: 23377201
references.citation: Cell. 1993 Oct 22;75(2):229-40
references.pmid: 8402909
references.citation: Cell. 1998 Aug 21;94(4):481-90
references.pmid: 9727491
references.citation: Oncogene. 1995 Nov 2;11(9):1921-8
references.pmid: 7478623
references.citation: J Cell Biol. 2004 Jun 21;165(6):835-42
references.pmid: 15210730
references.citation: Blood. 1998 Apr 15;91(8):2991-7
references.pmid: 9531611
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Mol Cell Biol. 2008 Sep;28(17):5391-402
references.pmid: 18573879
references.citation: Mol Cancer Ther. 2003 Oct;2(10):1031-43
references.pmid: 14578468
references.citation: Apoptosis. 2007 May;12(5):897-911
references.pmid: 17453159
references.citation: Cell. 1985 Jul;41(3):899-906
references.pmid: 3924412
references.citation: Science. 2005 Feb 18;307(5712):1101-4
references.pmid: 15718471
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11318-23
references.pmid: 11572983
references.citation: N Engl J Med. 2009 Oct 15;361(16):1570-83
references.pmid: 19828534
references.citation: Blood. 2010 Oct 7;116(14 ):2531-42
references.pmid: 20570860
references.citation: Nature. 1992 Oct 8;359(6395):554-6
references.pmid: 1406976
references.citation: Trends Biochem Sci. 2014 Mar;39(3):101-11
references.pmid: 24503222
references.citation: Cell. 1991 Nov 29;67(5):879-88
references.pmid: 1835668
references.citation: Cell. 1991 Nov 29;67(5):889-99
references.pmid: 1959134
references.citation: Cell. 1993 Aug 27;74(4):609-19
references.pmid: 8358790
references.citation: Genes Dev. 2014 Jan 1;28(1):58-70
references.pmid: 24395247
references.citation: Science. 1997 Feb 14;275(5302):983-6
references.pmid: 9020082
references.citation: Nature. 1990 Nov 22;348(6299):331-3
references.pmid: 2250704
references.citation: Blood. 2014 Dec 18;124(26):3939-46
references.pmid: 25368374
references.citation: Int J Oncol. 2002 Sep;21(3):515-9
references.pmid: 12168094
references.citation: Science. 2003 Nov 7;302(5647):1036-8
references.pmid: 14500851