Home LiteratureArticle Details
PMID: 19228717 Published · ppublish English Journal Article Review

Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy.

Clinical cancer research : an official journal of the American Association for Cancer Research ·Vol. 15 ·No. 4 ·2009-02-15 ·Pages 1126-32

Kang MH, Reynolds CP

Abstract

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.

MeSH Terms
Aniline Compounds/pharmacology Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects Biphenyl Compounds/pharmacology Gossypol/pharmacology Humans Indoles Mitochondria/drug effects Neoplasms/drug therapy,pathology Nitrophenols/pharmacology Piperazines/pharmacology Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors Pyrroles/pharmacology Sulfonamides/pharmacology Thionucleotides/therapeutic use
Chemicals
ABT-737 Aniline Compounds Antineoplastic Agents Biphenyl Compounds Indoles Nitrophenols Piperazines Proto-Oncogene Proteins c-bcl-2 Pyrroles Sulfonamides Thionucleotides oblimersen Gossypol obatoclax navitoclax
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kang Min H
Cancer Center and the Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
Reynolds C Patrick
References (83)
83 references, click to expand
  1. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.
    Nature. 1988 Sep 29;335(6189):440-2 PMID: 3262202
  2. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia.
    J Clin Oncol. 2005 Oct 20;23(30):7697-702 PMID: 16186597
  3. 2-Methoxy antimycin reveals a unique mechanism for Bcl-x(L) inhibition.
    Mol Cancer Ther. 2007 Jul;6(7):2073-80 PMID: 17620436
  4. Intracellular glutathione levels determine cell sensitivity to apoptosis induced by the antineoplasic agent N-(4-hydroxyphenyl) retinamide.
    Anticancer Res. 2005 May-Jun;25(3B):1945-51 PMID: 16158929
  5. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death.
    Semin Cancer Biol. 1993 Dec;4(6):327-32 PMID: 8142617
  6. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis.
    Science. 2005 Oct 7;310(5745):66-7 PMID: 16210526
  7. Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines.
    Apoptosis. 1997;2(6):540-8 PMID: 14646525
  8. Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines: Mcl-1 inactivation.
    J Natl Cancer Inst. 2008 Apr 16;100(8):580-95 PMID: 18398104
  9. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737.
    Cancer Res. 2007 Feb 1;67(3):1176-83 PMID: 17283153
  10. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells.
    Nat Med. 2001 Dec;7(12):1339-46 PMID: 11726975
  11. CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM.
    Blood. 1997 Apr 15;89(8):2833-41 PMID: 9108402
  12. An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
    Nature. 2005 Jun 2;435(7042):677-81 PMID: 15902208
  13. Apoptosis-based therapies for hematologic malignancies.
    Blood. 2005 Jul 15;106(2):408-18 PMID: 15797997
  14. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis.
    J Cell Biol. 2003 Jan 6;160(1):65-75 PMID: 12515825
  15. Fenretinide: the death of a tumor cell.
    J Natl Cancer Inst. 1999 Jul 7;91(13):1099-100 PMID: 10393709
  16. Oblimersen and alpha-interferon in metastatic renal cancer: a phase II study of the California Cancer Consortium.
    J Cancer Res Clin Oncol. 2007 Oct;133(10):705-11 PMID: 17508219
  17. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.
    Cancer Cell. 2002 Sep;2(3):183-92 PMID: 12242151
  18. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized.
    Cancer Cell. 2006 Nov;10(5):389-99 PMID: 17097561
  19. Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 family protein inhibitor.
    Apoptosis. 2005 Dec;10(6):1411-8 PMID: 16215673
  20. Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma.
    Am J Respir Cell Mol Biol. 2001 Nov;25(5):562-8 PMID: 11713097
  21. sHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell.
    Cancer Lett. 2008 Feb 8;259(2):198-208 PMID: 18037229
  22. Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy.
    Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6116-24 PMID: 17062688
  23. Preservation of mitochondrial structure and function after Bid- or Bax-mediated cytochrome c release.
    J Cell Biol. 2000 Sep 4;150(5):1027-36 PMID: 10973993
  24. A Phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse.
    Leuk Res. 2006 Jul;30(7):777-83 PMID: 16730060
  25. Bcl-2 inhibitors sensitize tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by uncoupling of mitochondrial respiration in human leukemic CEM cells.
    Cancer Res. 2004 May 15;64(10):3607-16 PMID: 15150119
  26. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation.
    Cell. 1989 Apr 7;57(1):79-88 PMID: 2649247
  27. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.
    Cancer Res. 2006 Sep 1;66(17):8731-9 PMID: 16951189
  28. A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma.
    Oncogene. 2007 Apr 5;26(16):2374-80 PMID: 17016430
  29. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7 PMID: 18040043
  30. Involvement of the bcl-2 gene in human follicular lymphoma.
    Science. 1985 Jun 21;228(4706):1440-3 PMID: 3874430
  31. Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants.
    J Biol Chem. 1990 Nov 15;265(32):19955-60 PMID: 2123195
  32. 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. 2007 Sep 15;110(6):2057-66 PMID: 17536015
  33. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak.
    Blood. 2007 May 15;109(10):4441-9 PMID: 17227835
  34. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1.
    EMBO J. 2007 May 16;26(10):2527-39 PMID: 17446862
  35. Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions.
    Mol Cancer Ther. 2007 Feb;6(2):692-702 PMID: 17308065
  36. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.
    J Clin Invest. 2007 Jan;117(1):112-21 PMID: 17200714
  37. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma.
    Blood. 2007 Jun 15;109(12):5430-8 PMID: 17332241
  38. Targeted therapy against Bcl-2-related proteins in breast cancer cells.
    Breast Cancer Res. 2005;7(6):R940-52 PMID: 16280040
  39. Bcl-2-family proteins and hematologic malignancies: history and future prospects.
    Blood. 2008 Apr 1;111(7):3322-30 PMID: 18362212
  40. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.
    Science. 2007 Feb 9;315(5813):856-9 PMID: 17289999
  41. The effect of antimycin A on mouse liver inner mitochondrial membrane channel activity.
    J Biol Chem. 1992 Apr 25;267(12):8123-7 PMID: 1569069
  42. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells.
    Clin Cancer Res. 2004 Dec 15;10(24):8284-92 PMID: 15623604
  43. Autophagy fights disease through cellular self-digestion.
    Nature. 2008 Feb 28;451(7182):1069-75 PMID: 18305538
  44. An ROS generator, antimycin A, inhibits the growth of HeLa cells via apoptosis.
    J Cell Biochem. 2007 Sep 1;102(1):98-109 PMID: 17372917
  45. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.
    Cancer Res. 2008 May 1;68(9):3421-8 PMID: 18451170
  46. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL.
    Nat Cell Biol. 2001 Feb;3(2):173-82 PMID: 11175750
  47. The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death.
    Cancer Res. 2006 Mar 1;66(5):2757-64 PMID: 16510597
  48. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane.
    Cell. 2002 Nov 1;111(3):331-42 PMID: 12419244
  49. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group.
    J Clin Oncol. 2006 Oct 10;24(29):4738-45 PMID: 16966688
  50. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.
    Cell. 2005 Sep 23;122(6):927-39 PMID: 16179260
  51. BID: a novel BH3 domain-only death agonist.
    Genes Dev. 1996 Nov 15;10(22):2859-69 PMID: 8918887
  52. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation.
    Mol Cell. 2002 Feb;9(2):423-32 PMID: 11864614
  53. Expression of bcl-xL can confer a multidrug resistance phenotype.
    Blood. 1995 Sep 1;86(5):1903-10 PMID: 7655019
  54. Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia.
    Immunology. 2005 Apr;114(4):441-9 PMID: 15804279
  55. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.
    Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7124-9 PMID: 10860979
  56. High bcl-2 expression in acute myeloid leukemia cells correlates with CD34 positivity and complete remission rate.
    Leukemia. 1997 Dec;11(12):2075-8 PMID: 9447823
  57. Clinical relevance of BCL-2 overexpression in childhood acute lymphoblastic leukemia.
    Blood. 1996 Feb 1;87(3):1140-6 PMID: 8562940
  58. Cell death: critical control points.
    Cell. 2004 Jan 23;116(2):205-19 PMID: 14744432
  59. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.
    Cancer Cell. 2006 Nov;10(5):375-88 PMID: 17097560
  60. 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. 2008 Feb 20;26(6):870-6 PMID: 18281659
  61. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients.
    J Clin Oncol. 2005 Jun 20;23(18):4089-99 PMID: 15867202
  62. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML).
    Blood. 2003 Mar 15;101(6):2125-31 PMID: 12424199
  63. Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.
    J Leukoc Biol. 2002 Jul;72(1):83-92 PMID: 12101266
  64. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML.
    Cell Cycle. 2006 Dec;5(23):2778-86 PMID: 17172851
  65. Prolonged survival of B-lineage acute lymphoblastic leukemia cells is accompanied by overexpression of bcl-2 protein.
    Blood. 1993 Feb 15;81(4):1025-31 PMID: 8427984
  66. 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. 2007 Mar 20;25(9):1114-20 PMID: 17296974
  67. Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy.
    Cancer Gene Ther. 2007 Jan;14(1):1-11 PMID: 17041564
  68. The Fas signaling pathway: more than a paradigm.
    Science. 2002 May 31;296(5573):1635-6 PMID: 12040174
  69. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis.
    Science. 2003 Apr 4;300(5616):135-9 PMID: 12624178
  70. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute.
    Cell Death Differ. 2008 Jun;15(6):1019-29 PMID: 18259198
  71. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death.
    Nature. 1996 May 23;381(6580):335-41 PMID: 8692274
  72. Mitochondria and apoptosis.
    Science. 1998 Aug 28;281(5381):1309-12 PMID: 9721092
  73. Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma.
    Br J Haematol. 2004 Apr;125(2):156-61 PMID: 15059137
  74. Expression of BCL-2 proto-oncogene in adult acute lymphoblastic leukemia.
    Leukemia. 1996 Mar;10(3):434-8 PMID: 8642858
  75. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis.
    Science. 2004 Feb 13;303(5660):1010-4 PMID: 14963330
  76. 'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737.
    Oncogene. 2007 Jun 7;26(27):3972-9 PMID: 17173063
  77. A phase I-II study of oblimersen sodium (G3139, Genasense) in combination with doxorubicin in advanced hepatocellular carcinoma (NCI # 5798).
    Invest New Drugs. 2008 Apr;26(2):193-4 PMID: 18060598
  78. Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2.
    Blood. 1995 Jan 15;85(2):359-67 PMID: 7811993
  79. An informatics approach identifying markers of chemosensitivity in human cancer cell lines.
    Cancer Res. 2000 Nov 1;60(21):6101-10 PMID: 11085534
  80. Live or let die: the cell's response to p53.
    Nat Rev Cancer. 2002 Aug;2(8):594-604 PMID: 12154352
  81. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer.
    Clin Cancer Res. 2005 May 15;11(10):3854-61 PMID: 15897586
  82. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2.
    Nature. 1990 Nov 22;348(6299):331-3 PMID: 2250704
  83. High expression of bcl-2 is the rule in acute lymphoblastic leukemia, except in Burkitt subtype at presentation, and is not correlated with the prognosis.
    Ann Hematol. 1994 Jul;69(1):17-24 PMID: 8061103
Article Info
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
Abbr.
Clin Cancer Res
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-08-0144
Published
2009-02-15
Pages
1126-32
Language
English
Region
United States
NLM ID
9502500
PMCID
PMC3182268
Subset
IM
Grants
NCI NIH HHS · R01 CA082830 · United States
External Links
PubMed source DOI: 10.1158/1078-0432.CCR-08-0144 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2