Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Current Opinion in Pharmacology

Volumn 23, Issue , 2015, Pages 74-81

  Vela, Laura ^a   Marzo, Isabel ^a  

^a UNIVERSITY OF ZARAGOZA   (Spain)

Author keywords

ABT 199 (PubChem CID: 49846579); ABT 737 (PubChem CID: 11228183); Chemical compounds studied in this article Navitoclax (PubChem CID: 24978538); Gossypol (PubChem CID: 3503); Obatoclax (PubChem CID: 16681698)

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; A 1155463; A 1210477; ANTINEOPLASTIC AGENT; APOGOSSYPOL; APOGOSSYPOLONE; BAM 7; BH 3M 6; BH3 MIMETIC AGENT; BI 97D 6; BORTEZOMIB; CISPLATIN; DOCETAXEL; ERLOTINIB; GIMERACIL PLUS OTERACIL POTASSIUM PLUS TEGAFUR; GOSSYPOL; GOSSYPOL DERIVATIVE; ISOSORBIDE; MARITOCLAX; MIM 1; NAVITOCLAX; OBATOCLAX; PEPTIDOMIMETIC AGENT; PROTEIN BCL 2; SABUTOCLAX; SORAFENIB; TAXANE DERIVATIVE; TW 37; UNCLASSIFIED DRUG; UNINDEXED DRUG; VENETOCLAX; BID PROTEIN, HUMAN; BIOMIMETIC MATERIAL; PROTEIN BID;

ACUTE MYELOBLASTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; CHRONIC LYMPHATIC LEUKEMIA; DIARRHEA; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SENSITIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; FATIGUE; GLIOBLASTOMA; HUMAN; MULTIPLE MYELOMA; NAUSEA; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; PRIORITY JOURNAL; PROSTATE CANCER; SMALL CELL LUNG CANCER; THROMBOCYTOPENIA; VOMITING; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; DRUG DELIVERY SYSTEM; DRUG EFFECTS; METABOLISM; PHYSIOLOGY; TRENDS;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BH3 INTERACTING DOMAIN DEATH AGONIST PROTEIN; BIOMIMETIC MATERIALS; DRUG DELIVERY SYSTEMS; HUMANS; PROTO-ONCOGENE PROTEINS C-BCL-2;

EID: 84931292235     PISSN: 14714892     EISSN: 14714973     Source Type: Journal    
DOI: 10.1016/j.coph.2015.05.014     Document Type: Review

References (89)

1. L. Pegoraro, A. Palumbo, J. Erikson, M. Falda, B. Giovanazzo, and B.S. Emanuel A 14;18 and an 8;14 chromosome translocation in a cell line derived from an acute B-cell leukemia Proc Natl Acad Sci U S A 81 1984 7166 7170
2. Y. Tsujimoto, J. Cossman, E. Jaffer, and C.M. Croce Involvement of the bcl-2 gene in human follicular lymphoma Science 228 1985 1440 1443
3. D.L. Vaux, S. Cory, and J.M. Adams Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells Nature 335 1988 440 442
4. D. Hanahan, and R.A. Weinberg Hallmarks of cancer: the next generation Cell 144 2011 646 674
5. M. Sattler, H. Liang, D. Nettesheim, R.P. Meadows, J.E. Harlan, and M. Eberstadt Structure of Bcl-XL-Bak peptide complex: recognition between regulators of apoptosis Science 275 1997 983 986
6. F. Llambi, T. Moldoveanu, S.W. Tait, L. Bouchier-Hayes, J. Temirov, and L.L. McCormick A unified model of mammalian BCL-2 protein family interactions at the mitochondria Mol Cell 44 2011 517 531
7. E. Lomonosova, and G. Chinnadurai BH3-only proteins in apoptosis and beyond: an overview Oncogene 27 Suppl 1 2008 S2 S19
8. T. Oltersdorf, S.W. Elmore, A.R. Shoemaker, R.C. Armstrong, D.J. Augeri, and B.A. Belli An inhibitor of Bcl-2 family proteins induces regression of solid tumours Nature 435 2005 677 681
9. G. Wang, Z. Nikolovska-Coleska, C.Y. Yang, R. Wang, G. Tang, and J. Guo Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins J Med Chem 49 2006 6139 6142
10. B. Becattini, S. Kitada, M. Leone, E. Monosov, S. Chandler, and D. Zhai Rational design and real time, in-cell detection of the pro-apoptotic activity of a novel compound targeting Bcl-X(L) Chem Biol 11 2004 389 395
11. S. Kitada, M. Leone, S. Sareth, D. Zhai, J.C. Reed, and M. Pellecchia Discovery, characterization, and structure-activity relationships studies of pro-apoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins J Med Chem 46 2003 4259 4264
12. A. Etxebarria, O. Landeta, B. Antonsson, and G. Basanez Regulation of antiapoptotic MCL-1 function by gossypol: mechanistic insights from in vitro reconstituted systems Biochem Pharmacol 76 2008 1563 1576
13. C. Van Poznak, A.D. Seidman, M.M. Reidenberg, M.M. Moasser, N. Sklarin, and K. Van Zee Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial Breast Cancer Res Treat 66 2001 239 248
14. M.Q. Baggstrom, Y. Qi, M. Koczywas, A. Argiris, E.A. Johnson, and M.J. Millward A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer J Thorac Oncol 6 2011 1757 1760
15. Y. Sun, J. Wu, A. Aboukameel, S. Banerjee, A.A. Arnold, and J. Chen Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo Cancer Biol Ther 7 2008 1418 1426
16. S. Kitada, C.L. Kress, M. Krajewska, L. Jia, M. Pellecchia, and J.C. Reed Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048) Blood 111 2008 3211 3219
17. H. Zhang, P.M. Nimmer, S.K. Tahir, J. Chen, R.M. Fryer, and K.R. Hahn Bcl-2 family proteins are essential for platelet survival Cell Death Differ 14 2007 943 951
18. A.J. Souers, J.D. Leverson, E.R. Boghaert, S.L. Ackler, N.D. Catron, and J. Chen ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets Nat Med 19 2013 202 208
19. G. Lessene, P.E. Czabotar, and P.M. Colman BCL-2 family antagonists for cancer therapy Nat Rev Drug Discov 7 2008 989 1000
20. K. Sadahira, M. Sagawa, T. Nakazato, H. Uchida, Y. Ikeda, and S. Okamoto Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway Int J Oncol 45 2014 2278 2286
21. R.S. Soderquist, A.V. Danilov, and A. Eastman Gossypol increases expression of the pro-apoptotic BH3-only protein NOXA through a novel mechanism involving phospholipase A2, cytoplasmic calcium, and endoplasmic reticulum stress J Biol Chem 289 2014 16190 16199
22. G. Li, L. Liu, C. Shan, Q. Cheng, A. Budhraja, and T. Zhou RhoA/ROCK/PTEN signaling is involved in AT-101-mediated apoptosis in human leukemia cells in vitro and in vivo Cell Death Dis 5 2014 e998
23. J.A. Spijkers-Hagelstein, P. Schneider, S.M. Pinhancos, P. Garrido Castro, R. Pieters, and R.W. Stam Glucocorticoid sensitisation in Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia by the pan-BCL-2 family inhibitors gossypol and AT-101 Eur J Cancer 50 2014 1665 1674
24. Z.Y. Hu, J. Sun, X.F. Zhu, D. Yang, and Y.X. Zeng ApoG2 induces cell cycle arrest of nasopharyngeal carcinoma cells by suppressing the c-Myc signaling pathway J Transl Med 7 2009 74
25. B.C. Koehler, A.L. Scherr, S. Lorenz, C. Elssner, N. Kautz, and S. Welte Pan-Bcl-2 inhibitor obatoclax delays cell cycle progression and blocks migration of colorectal cancer cells PLoS One 9 2014 e106571
26. M. Espona-Fiedler, V. Soto-Cerrato, A. Hosseini, J.M. Lizcano, V. Guallar, and R. Quesada Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: prodigiosin vs. obatoclax Biochem Pharmacol 83 2012 489 496
27. Z. Zhang, T. Song, T. Zhang, J. Gao, G. Wu, L. An, and G. Du A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1 Int J Cancer 128 2011 1724 1735
28. R. Soderquist, A.A. Pletnev, A.V. Danilov, and A. Eastman The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA Apoptosis 19 2014 201 209
29. J.T. Zhong, Y. Xu, H.W. Yi, J. Su, H.M. Yu, and X.Y. Xiang The BH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin 1 interaction in human glioma U251 cells Cancer Lett 323 2012 180 187
30. M. Vogler, K. Weber, D. Dinsdale, I. Schmitz, K. Schulze-Osthoff, M.J. Dyer, and G.M. Cohen Different forms of cell death induced by putative BCL2 inhibitors Cell Death Differ 16 2009 1030 1039
31. K. Balakrishnan, W.G. Wierda, M.J. Keating, and V. Gandhi Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells Blood 112 2008 1971 1980
32. J. Sun, Z.M. Li, Z.Y. Hu, X.B. Lin, N.N. Zhou, and L.J. Xian ApoG2 inhibits antiapoptotic Bcl-2 family proteins and induces mitochondria-dependent apoptosis in human lymphoma U937 cells Anticancer Drugs 19 2008 967 974
33. V. Voss, C. Senft, V. Lang, M.W. Ronellenfitsch, J.P. Steinbach, V. Seifert, and D. Kogel The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma Mol Cancer Res 8 2010 1002 1016
34. J.H. He, X.L. Liao, W. Wang, D.D. Li, W.D. Chen, and R. Deng Apogossypolone, a small-molecule inhibitor of Bcl-2, induces radiosensitization of nasopharyngeal carcinoma cells by stimulating autophagy Int J Oncol 45 2014 1099 1108
35. P. Cheng, Z. Ni, X. Dai, B. Wang, W. Ding, and A. Rae Smith The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma [corrected] cells Cell Death Dis 4 2013 e489
36. M. Konopleva, J. Watt, R. Contractor, T. Tsao, D. Harris, and Z. Estrov Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax) Cancer Res 68 2008 3413 3420
37. D. Wroblewski, C.C. Jiang, A. Croft, M.L. Farrelly, X.D. Zhang, and P. Hersey OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis PLoS One 8 2013 e84073
38. N. Heidari, M.A. Hicks, and H. Harada GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy Cell Death Dis 1 2010 e76
39. K.A. Urtishak, A.Y. Edwards, L.S. Wang, A. Hudome, B.W. Robinson, and J.S. Barrett Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia Blood 121 2013 2689 2703
40. F. Basit, S. Cristofanon, and S. Fulda Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes Cell Death Differ 20 2013 1161 1173
41. M. Rahmani, M.M. Aust, E. Attkisson, D.C. Williams Jr., A. Ferreira-Gonzalez, and S. Grant Inhibition of Bcl-2 anti-apoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process Blood 119 2012 6089 6098
42. M.P. Kline, S.V. Rajkumar, M.M. Timm, T.K. Kimlinger, J.L. Haug, and J.A. Lust ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells Leukemia 21 2007 1549 1560
43. V. Del Gaizo Moore, K.D. Schlis, S.E. Sallan, S.A. Armstrong, and A. Letai BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia Blood 111 2008 2300 2309
44. M. Konopleva, R. Contractor, T. Tsao, I. Samudio, P.P. Ruvolo, and S. Kitada Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia Cancer Cell 10 2006 375 388
45. K.E. Tagscherer, A. Fassl, B. Campos, M. Farhadi, A. Kraemer, and B.C. Bock Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins Oncogene 27 2008 6646 6656
46. P. Hauck, B.H. Chao, J. Litz, and G.W. Krystal Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737 Mol Cancer Ther 8 2009 883 892
47. R. Parrondo, A. de Las Pozas, T. Reiner, and C. Perez-Stable ABT-737, a small molecule Bcl-2/Bcl-xL antagonist, increases antimitotic-mediated apoptosis in human prostate cancer cells PeerJ 1 2013 e144
48. A.R. Shoemaker, M.J. Mitten, J. Adickes, S. Ackler, M. Refici, and D. Ferguson Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models Clin Cancer Res 14 2008 3268 3277
49. C. Tse, A.R. Shoemaker, J. Adickes, M.G. Anderson, J. Chen, and S. Jin ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor Cancer Res 68 2008 3421 3428
50. C.M. Rudin, C.L. Hann, E.B. Garon, M. Ribeiro de Oliveira, P.D. Bonomi, and D.R. Camidge Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer Clin Cancer Res 18 2012 3163 3169
51. S. Peirs, F. Matthijssens, S. Goossens, I. Van de Walle, K. Ruggero, and C.E. de Bock ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia Blood 124 2014 3738 3747
52. R. Pan, L.J. Hogdal, J.M. Benito, D. Bucci, L. Han, and G. Borthakur Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia Cancer Discov 4 2014 362 375
53. C.J. Vandenberg, and S. Cory ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia Blood 121 2013 2285 2288
54. N.A. Cohen, M.L. Stewart, E. Gavathiotis, J.L. Tepper, S.R. Bruekner, and B. Koss A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival Chem Biol 19 2012 1175 1186
55. J.D. Leverson, H. Zhang, J. Chen, S.K. Tahir, D.C. Phillips, and J. Xue Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax) Cell Death Dis 6 2015 e1590
56. M. Wong, N. Tan, J. Zha, F.V. Peale, P. Yue, W.J. Fairbrother, and L.D. Belmont Navitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer models Mol Cancer Ther 11 2012 1026 1035
57. Z.F. Tao, L. Hasvold, L. Wang, X. Wang, A.M. Petros, and C.H. Park Discovery of a potent and selective BCL-XL inhibitor with in vivo activity ACS Med Chem Lett 5 2014 1088 1093
58. D. Park, A.T. Magis, R. Li, T.K. Owonikoko, G.L. Sica, and S.Y. Sun Novel small-molecule inhibitors of Bcl-XL to treat lung cancer Cancer Res 73 2013 5485 5496
59. P. Perez-Galan, G. Roue, N. Villamor, E. Campo, and D. Colomer The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak Blood 109 2007 4441 4449
60. G. Dasmahapatra, D. Lembersky, M. Rahmani, L. Kramer, J. Friedberg, and R.I. Fisher Bcl-2 antagonists interact synergistically with bortezomib in DLBCL cells in association with JNK activation and induction of ER stress Cancer Biol Ther 8 2009 808 819
61. J. Li, J. Viallet, and E.B. Haura A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells Cancer Chemother Pharmacol 61 2008 525 534
62. J. Chen, S. Jin, V. Abraham, X. Huang, B. Liu, and M.J. Mitten 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 2011 2340 2349
63. M.J. Sale, and S.J. Cook That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance Br J Pharmacol 169 2013 1708 1722
64. F. Vaillant, D. Merino, L. Lee, K. Breslin, B. Pal, and M.E. Ritchie Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer Cancer Cell 24 2013 120 129
65. N. Johnson-Farley, J. Veliz, S. Bhagavathi, and J.R. Bertino ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the anti-tumor activity of chemotherapy, bortezomib and JQ1 in "double hit" lymphoma cells Leuk Lymphoma 2015 1 7
66. T.K. Ko, C.T. Chuah, J.W. Huang, K.P. Ng, and S.T. Ong The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors Oncotarget 5 2014 9033 9038
67. X. Zhao, J. Bodo, D. Sun, L. Durkin, J. Lin, M.R. Smith, and E.D. Hsi Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways Br J Haematol 168 2014 765 768
68. G. Sonpavde, V. Matveev, J.M. Burke, J.R. Caton, M.T. Fleming, and T.E. Hutson Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer Ann Oncol 23 2012 1803 1808
69. N. Ready, N.A. Karaseva, S.V. Orlov, A.V. Luft, O. Popovych, and J.T. Holmlund Double-blind, placebo-controlled, randomized phase 2 study of the pro-apoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer J Thorac Oncol 6 2011 781 785
70. A.D. Schimmer, A. Raza, T.H. Carter, D. Claxton, H. Erba, and D.J. DeAngelo A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia PLoS One 9 2014 e108694
71. M.L. Arellano, G. Borthakur, M. Berger, J. Luer, and A. Raza A phase II, multicenter, open-label study of obatoclax mesylate in patients with previously untreated myelodysplastic syndromes with anemia or thrombocytopenia Clin Lymphoma Myeloma Leuk 14 2014 534 539
72. C.J. Langer, I. Albert, H.J. Ross, P. Kovacs, L.J. Blakely, and G. Pajkos Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer Lung Cancer 85 2014 420 428
73. A. Goy, F.J. Hernandez-Ilzaliturri, B. Kahl, P. Ford, E. Protomastro, and M. Berger A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma Leuk Lymphoma 55 2014 2761 2768
74. A. Chiappori, C. Williams, D.W. Northfelt, J.W. Adams, S. Malik, and M.J. Edelman Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer J Thorac Oncol 9 2014 121 125
75. A.A. Chiappori, M.T. Schreeder, M.M. Moezi, J.J. Stephenson, J. Blakely, and R. Salgia A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer Br J Cancer 106 2012 839 845
76. P.K. Paik, C.M. Rudin, M.C. Pietanza, A. Brown, N.A. Rizvi, and N. Takebe A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer Lung Cancer 74 2011 481 485
77. J.M. Cleary, C.M. Lima, H.I. Hurwitz, A.J. Montero, C. Franklin, and J. Yang A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors Invest New Drugs 32 2014 937 945
78. A.W. Roberts, J.F. Seymour, J.R. Brown, W.G. Wierda, T.J. Kipps, and S.L. Khaw 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 2012 488 496
79. L. Gandhi, D.R. Camidge, M. Ribeiro de Oliveira, P. Bonomi, D. Gandara, and D. Khaira Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors J Clin Oncol 29 2011 909 916
80. W.H. Wilson, O.A. O'Connor, M.S. Czuczman, A.S. LaCasce, J.F. Gerecitano, and J.P. Leonard Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity Lancet Oncol 11 2010 1149 1159
81. ABT-199 shows effectiveness in CLL Cancer Discov 4 2014 OF7
82. S. Suryani, H. Carol, T.N. Chonghaile, V. Frismantas, C. Sarmah, and L. High Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts Clin Cancer Res 20 2014 4520 4531
83. T.T. Renault, R. Elkholi, A. Bharti, and J.E. Chipuk B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins J Biol Chem 289 2014 26481 26491
84. T.N. Chonghaile, J.E. Roderick, C. Glenfield, J. Ryan, S.E. Sallan, and L.B. Silverman Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199 Cancer Discov 4 2014 1074 1087
85. S.H. Wei, K. Dong, F. Lin, X. Wang, B. Li, and J.J. Shen Inducing apoptosis and enhancing chemosensitivity to gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell Cancer Chemother Pharmacol 62 2008 1055 1064
86. M. Modugno, P. Banfi, F. Gasparri, R. Borzilleri, P. Carter, and L. Cornelius Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers Exp Cell Res 332 2014 267 277
87. S.A. Malik, I. Orhon, E. Morselli, A. Criollo, S. Shen, and G. Marino BH3 mimetics activate multiple pro-autophagic pathways Oncogene 30 2011 3918 3929
88. E. Gavathiotis, D.E. Reyna, J.A. Bellairs, E.S. Leshchiner, and L.D. Walensky Direct and selective small-molecule activation of pro-apoptotic BAX Nat Chem Biol 8 2012 639 645
89. R.L. Smoot, B.R. Blechacz, N.W. Werneburg, S.F. Bronk, F.A. Sinicrope, A.E. Sirica, and G.J. Gores A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells Cancer Res 70 2010 1960 1969