Exploiting BH3 Mimetics for Cancer Therapy

Chapter
First Online:

Abstract

In apoptotic cells, the transcriptional induction or posttranslational activation of Bcl-2-homolgy domain-3 (BH3)-only proteins triggers the activation of the pro-apoptotic pore-forming proteins Bax and Bak. All members of this subgroup of the Bcl-2 family share a nine amino acid BH3-domain which binds to a hydrophobic groove of anti-apoptotic Bcl-2 family members that comprises residues of their BH1, BH2 and BH3 domains. These observations led to the development of BH3 mimetics, a class of small-molecule inhibitors targeting the BH3-binding domain of the pro-survival Bcl-2 family members, thereby facilitating/activating Bax/Bak-dependent apoptosis. In addition, BH3 mimetics can displace the pro-autophagic BH3only protein Beclin-1 from a complex with pro-survival Bcl-2 family members to induce autophagy. BH3 mimetics hold great promise for the treatment of cancer and currently, a large variety of natural and synthetic BH3 mimetics are characterized in preclinical studies and developed in clinical studies in an aim to exploit their therapeutic potential for the treatment of cancer.

Keywords

Bcl-2 family BH3-only proteins Programmed cell death Apoptosis Autophagy Cell death resistance Cancer Mitochondrial membrane permeabilization Intrinsic apoptosis pathway Caspases Stress signaling Target specificity 
This is a preview of subscription content, log in to check access.

References

  1. Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337PubMedCentralPubMedCrossRefGoogle Scholar
  2. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87:171PubMedCrossRefGoogle Scholar
  3. Arnold AA, Aboukameel A, Chen J, Yang D, Wang S, Al-Katib A, Mohammad RM (2008) Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model. Mol Cancer 7:20PubMedCentralPubMedCrossRefGoogle Scholar
  4. Balakrishnan K, Wierda WG, Keating MJ, Gandhi V (2008) Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood 112:1971–1980PubMedCentralPubMedCrossRefGoogle Scholar
  5. Bodur C, Basaga H (2012) Bcl-2 inhibitors: emerging drugs in cancer therapy. Curr Med Chem 19:1804–1820PubMedCrossRefGoogle Scholar
  6. Bonapace L, Bornhauser BC, Schmitz M, Cario G, Ziegler U, Niggli FK, Schafer BW, Schrappe M, Stanulla M, Bourquin JP (2010) Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest 120:1310–1323PubMedCentralPubMedCrossRefGoogle Scholar
  7. Bouillet P, Strasser A (2002) BH3-only proteins – evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 115:1567–1574PubMedGoogle Scholar
  8. Cao X, Rodarte C, Zhang L, Morgan CD, Littlejohn J, Smythe WR (2007) Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma. Cancer Biol Ther 6:246–252PubMedCrossRefGoogle Scholar
  9. Chen J, Jin S, Abraham V, Huang X, Liu B, Mitten MJ, Nimmer P, Lin X, Smith M, Shen Y, Shoemaker AR, Tahir SK, Zhang H, Ackler SL, Rosenberg SH, Maecker H, Sampath D, Leverson JD, Tse C, Elmore SW (2012) The Bcl-2/Bcl-X(L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo. Mol Cancer Ther 10:2340–2349CrossRefGoogle Scholar
  10. Chonghaile TN, Letai A (2008) Mimicking the BH3 domain to kill cancer cells. Oncogene 27(Suppl 1):S149–S157PubMedCentralCrossRefGoogle Scholar
  11. Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12(Suppl 2):1509–1518PubMedCrossRefGoogle Scholar
  12. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656PubMedCrossRefGoogle Scholar
  13. Danial NN (2007) BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res 13:7254–7263PubMedCrossRefGoogle Scholar
  14. Dash R, Azab B, Quinn BA, Shen X, Wang XY, Das SK, Rahmani M, Wei J, Hedvat M, Dent P, Dmitriev IP, Curiel DT, Grant S, Wu B, Stebbins JL, Pellecchia M, Reed JC, Sarkar D, Fisher PB (2011) Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci U S A 108:8785–8790PubMedCentralPubMedCrossRefGoogle Scholar
  15. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10:51–64PubMedCentralPubMedCrossRefGoogle Scholar
  16. Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3:173–182PubMedCrossRefGoogle Scholar
  17. Degterev A, Boyce M, Yuan J (2003) A decade of caspases. Oncogene 22:8543–8567PubMedCrossRefGoogle Scholar
  18. Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16:663–669PubMedCrossRefGoogle Scholar
  19. Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411:342–348PubMedCrossRefGoogle Scholar
  20. Fischer U, Janicke RU, Schulze-Osthoff K (2003) Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ 10:76–100PubMedCrossRefGoogle Scholar
  21. Fulda S, Debatin KM (2004) Targeting apoptosis pathways in cancer therapy. Curr Cancer Drug Targets 4:569–576PubMedCrossRefGoogle Scholar
  22. Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811PubMedCrossRefGoogle Scholar
  23. Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G (2006) Mechanisms of cytochrome c release from mitochondria. Cell Death Differ 13:1423–1433PubMedCrossRefGoogle Scholar
  24. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906PubMedCrossRefGoogle Scholar
  25. Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78:217–245PubMedCrossRefGoogle Scholar
  26. Green DR (2006) At the gates of death. Cancer Cell 9:328–330PubMedCrossRefGoogle Scholar
  27. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  28. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93PubMedCentralPubMedCrossRefGoogle Scholar
  29. Heist RS, Fain J, Chinnasami B, Khan W, Molina JR, Sequist LV, Temel JS, Fidias P, Brainerd V, Leopold L, Lynch TJ (2010) Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol 5:1637–1643PubMedCrossRefGoogle Scholar
  30. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776PubMedCrossRefGoogle Scholar
  31. Hermanson D, Addo SN, Bajer AA, Marchant JS, Das SG, Srinivasan B, Al-Mousa F, Michelangeli F, Thomas DD, Lebien TW, Xing C (2009) Dual mechanisms of sHA 14–1 in inducing cell death through endoplasmic reticulum and mitochondria. Mol Pharmacol 76:667–678PubMedCentralPubMedCrossRefGoogle Scholar
  32. Hetschko H, Voss V, Senft C, Seifert V, Prehn JH, Kögel D (2008) BH3 mimetics reactivate autophagic cell death in anoxia-resistant malignant glioma cells. Neoplasia 10:873–885PubMedCentralPubMedGoogle Scholar
  33. Huang DC, Strasser A (2000) BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103:839–842PubMedCrossRefGoogle Scholar
  34. Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2:277–288PubMedCrossRefGoogle Scholar
  35. Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132PubMedCentralPubMedCrossRefGoogle Scholar
  36. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3:452–460PubMedGoogle Scholar
  37. Ko CH, Shen SC, Yang LY, Lin CW, Chen YC (2007) Gossypol reduction of tumor growth through ROS-dependent mitochondria pathway in human colorectal carcinoma cells. Int J Cancer 121:1670–1679PubMedCrossRefGoogle Scholar
  38. Kögel D, Fulda S, Mittelbronn M (2010) Therapeutic exploitation of apoptosis and autophagy for glioblastoma. Anticancer Agents Med Chem 10:438–449PubMedCrossRefGoogle Scholar
  39. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388PubMedCrossRefGoogle Scholar
  40. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163PubMedCrossRefGoogle Scholar
  41. Lei X, Chen Y, Du G, Yu W, Wang X, Qu H, Xia B, He H, Mao J, Zong W, Liao X, Mehrpour M, Hao X, Chen Q (2006) Gossypol induces Bax/Bak-independent activation of apoptosis and cytochrome c release via a conformational change in Bcl-2. FASEB J 20:2147–2149PubMedCrossRefGoogle Scholar
  42. Lessene G, Czabotar PE, Colman PM (2008) BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 7:989–1000PubMedCrossRefGoogle Scholar
  43. Lian J, Wu X, He F, Karnak D, Tang W, Meng Y, Xiang D, Ji M, Lawrence TS, Xu L (2010) A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ 18:60–71PubMedCentralPubMedCrossRefGoogle Scholar
  44. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B (2009) An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 15:3172–3176PubMedCentralPubMedCrossRefGoogle Scholar
  45. Lowe SW, Lin AW (2000) Apoptosis in cancer. Carcinogenesis 21:485–495PubMedCrossRefGoogle Scholar
  46. Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, Tasdemir E, Pierron G, Troulinaki K, Tavernarakis N, Hickman JA, Geneste O, Kroemer G (2007) Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26:2527–2539PubMedCentralPubMedCrossRefGoogle Scholar
  47. Malik SA, Orhon I, Morselli E, Criollo A, Shen S, Marino G, BenYounes A, Benit P, Rustin P, Maiuri MC, Kroemer G (2011) BH3 mimetics activate multiple pro-autophagic pathways. Oncogene 30:3918–3929PubMedCrossRefGoogle Scholar
  48. Manero F, Gautier F, Gallenne T, Cauquil N, Gree D, Cartron PF, Geneste O, Gree R, Vallette FM, Juin P (2006) The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Cancer Res 66:2757–2764PubMedCrossRefGoogle Scholar
  49. Martinou JC, Green DR (2001) Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2:63–67PubMedCrossRefGoogle Scholar
  50. Meng Y, Tang W, Dai Y, Wu X, Liu M, Ji Q, Ji M, Pienta K, Lawrence T, Xu L (2008) Natural BH3 mimetic (−)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther 7:2192–2202PubMedCentralPubMedCrossRefGoogle Scholar
  51. Milanesi E, Costantini P, Gambalunga A, Colonna R, Petronilli V, Cabrelle A, Semenzato G, Cesura AM, Pinard E, Bernardi P (2006) The mitochondrial effects of small organic ligands of BCL-2: sensitization of BCL-2-overexpressing cells to apoptosis by a pyrimidine-2,4,6-trione derivative. J Biol Chem 281:10066–10072PubMedCrossRefGoogle Scholar
  52. Mohammad RM, Goustin AS, Aboukameel A, Chen B, Banerjee S, Wang G, Nikolovska-Coleska Z, Wang S, Al-Katib A (2007) Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin Cancer Res 13:2226–2235PubMedCrossRefGoogle Scholar
  53. Nicholson DW (1999) Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 6:1028–1042PubMedCrossRefGoogle Scholar
  54. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681PubMedCrossRefGoogle Scholar
  55. Paoluzzi L, Gonen M, Gardner JR, Mastrella J, Yang D, Holmlund J, Sorensen M, Leopold L, Manova K, Marcucci G, Heaney ML, O’Connor OA (2008) Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood 111:5350–5358PubMedCrossRefGoogle Scholar
  56. Pattingre S, Levine B (2006) Bcl-2 inhibition of autophagy: a new route to cancer? Cancer Res 66:2885–2888PubMedCrossRefGoogle Scholar
  57. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939PubMedCrossRefGoogle Scholar
  58. Puthalakath H, Strasser A (2002) Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 9:505–512PubMedCrossRefGoogle Scholar
  59. Ranger AM, Malynn BA, Korsmeyer SJ (2001) Mouse models of cell death. Nat Genet 28:113–118PubMedCrossRefGoogle Scholar
  60. Ready N, Karaseva NA, Orlov SV, Luft AV, Popovych O, Holmlund JT, Wood BA, Leopold L (2011) Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer. J Thorac Oncol 6:781–785PubMedCrossRefGoogle Scholar
  61. Real PJ, Cao Y, Wang R, Nikolovska-Coleska Z, Sanz-Ortiz J, Wang S, Fernandez-Luna JL (2004) Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2. Cancer Res 64:7947–7953PubMedCrossRefGoogle Scholar
  62. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30:488–496PubMedCrossRefGoogle Scholar
  63. Shoemaker AR, Oleksijew A, Bauch J, Belli BA, Borre T, Bruncko M, Deckwirth T, Frost DJ, Jarvis K, Joseph MK, Marsh K, McClellan W, Nellans H, Ng S, Nimmer P, O’Connor JM, Oltersdorf T, Qing W, Shen W, Stavropoulos J, Tahir SK, Wang B, Warner R, Zhang H, Fesik SW, Rosenberg SH, Elmore SW (2006) A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res 66:8731–8739PubMedCrossRefGoogle Scholar
  64. Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, Oleksijew A, O'Connor JM, Wang B, Frost DJ, Bauch J, Marsh K, Tahir SK, Yang X, Tse C, Fesik SW, Rosenberg SH, Elmore SW (2008) Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res 14:3268–3277PubMedCrossRefGoogle Scholar
  65. Shore GC, Viallet J (2005) Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. Hematol Am Soc Hematol Educ Program 2005:226–230CrossRefGoogle Scholar
  66. Sinicrope FA, Penington RC, Tang XM (2004) 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 10:8284–8292PubMedCrossRefGoogle Scholar
  67. Smoot RL, Blechacz BR, Werneburg NW, Bronk SF, Sinicrope FA, Sirica AE, Gores GJ (2010) A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells. Cancer Res 70:1960–1969PubMedCentralPubMedCrossRefGoogle Scholar
  68. Strappazzon F, Vietri-Rudan M, Campello S, Nazio F, Florenzano F, Fimia GM, Piacentini M, Levine B, Cecconi F (2011) Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. EMBO J 30:1195–1208PubMedCentralPubMedCrossRefGoogle Scholar
  69. Tang G, Nikolovska-Coleska Z, Qiu S, Yang CY, Guo J, Wang S (2008) Acylpyrogallols as inhibitors of antiapoptotic Bcl-2 proteins. J Med Chem 51:717–720PubMedCrossRefGoogle Scholar
  70. Tian D, Das SG, Doshi JM, Peng J, Lin J, Xing C (2008) 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 259:198–208PubMedCentralPubMedCrossRefGoogle Scholar
  71. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68:3421–3428PubMedCrossRefGoogle Scholar
  72. Tzung SP, Kim KM, Basanez G, Giedt CD, Simon J, Zimmerberg J, Zhang KY, Hockenbery DM (2001) Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 3:183–191PubMedCrossRefGoogle Scholar
  73. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399PubMedCentralPubMedCrossRefGoogle Scholar
  74. Vogler M (2012) BCL2A1: the underdog in the BCL2 family. Cell Death Differ 19:67–74PubMedCentralPubMedCrossRefGoogle Scholar
  75. Vogler M, Dinsdale D, Dyer MJ, Cohen GM (2009a) Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 16:360–367PubMedCrossRefGoogle Scholar
  76. Vogler M, Weber K, Dinsdale D, Schmitz I, Schulze-Osthoff K, Dyer MJ, Cohen GM (2009b) Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ 16:1030–1039PubMedCrossRefGoogle Scholar
  77. Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V, Kögel D (2010) The pan-bcl-2 inhibitor (−)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 8:1002–1016PubMedCrossRefGoogle Scholar
  78. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, Croce CM, Alnemri ES, Huang Z (2000) 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 97:7124–7129PubMedCentralPubMedCrossRefGoogle Scholar
  79. Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S (2006) Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem 49:6139–6142PubMedCrossRefGoogle Scholar
  80. Wang Z, Song W, Aboukameel A, Mohammad M, Wang G, Banerjee S, Kong D, Wang S, Sarkar FH, Mohammad RM (2008) TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer. Int J Cancer 123:958–966PubMedCentralPubMedCrossRefGoogle Scholar
  81. Wei J, Stebbins JL, Kitada S, Dash R, Placzek W, Rega MF, Wu B, Cellitti J, Zhai D, Yang L, Dahl R, Fisher PB, Reed JC, Pellecchia M (2010) BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem 53:4166–4176PubMedCentralPubMedCrossRefGoogle Scholar
  82. Wendt MD, Shen W, Kunzer A, McClellan WJ, Bruncko M, Oost TK, Ding H, Joseph MK, Zhang H, Nimmer PM, Ng SC, Shoemaker AR, Petros AM, Oleksijew A, Marsh K, Bauch J, Oltersdorf T, Belli BA, Martineau D, Fesik SW, Rosenberg SH, Elmore SW (2006) Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo. J Med Chem 49:1165–1181PubMedCrossRefGoogle Scholar
  83. Weyland M, Manero F, Paillard A, Gree D, Viault G, Jarnet D, Menei P, Juin P, Chourpa I, Benoit JP, Grée R, Garcion E (2011) Mitochondrial targeting by use of lipid nanocapsules loaded with SV30, an analogue of the small-molecule Bcl-2 inhibitor HA14-1. J Control Release 151:74–82PubMedCrossRefGoogle Scholar
  84. Wolter KG, Wang SJ, Henson BS, Wang S, Griffith KA, Kumar B, Chen J, Carey TE, Bradford CR, D’Silva NJ (2006) (−)-gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo. Neoplasia 8:163–172PubMedCentralPubMedCrossRefGoogle Scholar
  85. Zeitlin BD, Joo E, Dong Z, Warner K, Wang G, Nikolovska-Coleska Z, Wang S, Nor JE (2006) Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res 66:8698–8706PubMedCrossRefGoogle Scholar
  86. Zhai D, Jin C, Satterthwait AC, Reed JC (2006) Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ 13:1419–1421PubMedCrossRefGoogle Scholar
  87. Zhang Z, Song T, Zhang T, Gao J, Wu G, An L, Du G (2011) A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1. Int J Cancer 128:1724–1735PubMedCrossRefGoogle Scholar
  88. Zimmermann AK, Loucks FA, Schroeder EK, Bouchard RJ, Tyler KL, Linseman DA (2007) Glutathione binding to the Bcl-2 homology-3 domain groove: a molecular basis for Bcl-2 antioxidant function at mitochondria. J Biol Chem 282:29296–29304PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Experimental Neurosurgery, Center for Neurology and Neurosurgery, Neuroscience CenterGoethe University HospitalFrankfurt am MainGermany

Personalised recommendations