Pharmacological manipulation of Bcl-2 family members to control cell death

Journal of Clinical Investigation

Volumn 115, Issue 10, 2005, Pages 2648-2655

  Letai, Anthony ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; ANTIMYCIN A1; BH3 PROTEIN; CYCLOPHOSPHAMIDE; DACARBAZINE; DEXAMETHASONE; FLUDARABINE; GOSSYPOL; GX 01; NATURAL PRODUCT; OBLIMERSEN; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; PROTEIN INHIBITOR; PROTEIN R8BIDBH3; PURPUROGALLIN; RECOMBINANT PROTEIN; TETROCARCIN A; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BACKACHE; BRAIN ISCHEMIA; CANCER; CELL DEATH; CELL PERMEABILIZATION; CLINICAL TRIAL; DEHYDRATION; DISEASE MODEL; DRUG EFFECT; DRUG EFFICACY; FATIGUE; HEART MUSCLE ISCHEMIA; HUMAN; MELANOMA; MITOCHONDRIAL MEMBRANE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIDE EFFECT; THROMBOCYTOPENIA; WEIGHT REDUCTION;

ANIMALS; BRAIN ISCHEMIA; CELL DEATH; CELL MEMBRANE PERMEABILITY; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; MITOCHONDRIA; MYOCARDIAL ISCHEMIA; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-BCL-2;

EID: 26444558130     PISSN: 00219738     EISSN: None     Source Type: Journal    
DOI: 10.1172/JCI26250     Document Type: Review

References (119)

1. Tsujimoto, Y., Cossman, J., Jaffe, E., and Croce, C.M. 1985. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 228:1440-1443.
2. Cleary, M.L., and Sklar, J. 1985. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl. Acad. Sci. U. S. A. 82:7439-7443.
3. Bakhshi, A., et al. 1985. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. 41:899-906.
4. McDonnell, T.J., et al. 1989. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 57:79-88.
5. Vaux, D.L., Cory, S., and Adams, J.M. 1988. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 335:440-442.
6. McDonnell, T.J., and Korsmeyer, S.J. 1991. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature. 349:254-256.
7. Boise, L.H., et al. 1993. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 74:597-608.
8. Gibson, L., et al. 1996. bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene. 13:665-675.
9. Kozopas, K.M., Yang, T., Buchan, H.L., Zhou, P., and Craig, R.W. 1993. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc. Natl. Acad. Sci. U.S.A. 90:3516-3520.
10. Choi, S.S., et al. 1995. A novel Bcl-2 related gene, Bfl-1, is overexpressed in stomach cancer and preferentially expressed in bone marrow. Oncogene. 11:1693-1698.
11. Oltvai, Z.N., Milliman, C.L., and Korsmeyer, S.J. 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609-619.
12. Chittenden, T., et al. 1995. Induction of apoptosis by the Bcl-2 homologue Bak. Nature. 374:733-736.
13. Huang, D.C., and Strasser, A. 2000. BH3-only proteins-essential initiators of apoptotic cell death. Cell. 103:839-842.
14. Wang, K., Yin, X.M., Chao, D.T., Milliman, C.L., and Korsmeyer, S.J. 1996. BID: a novel BH3 domain-only death agonist. Genes Dev. 10:2859-2869.
15. Boyd, J.M., et al. 1995. Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene. 11:1921-1928.
16. Chittenden, T., et al. 1995. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 14:5589-5596.
17. Green, D.R., and Kroemer, G. 2004. The pathophysiology of mitochondrial cell death. Science. 305:626-629.
18. Lindsten, T., et al. 2000. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol. Cell. 6:1389-1399.
19. Wei, M.C., et al. 2000. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14:2060-2071.
20. Wei, M.C., et al. 2001. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 292:727-730.
21. Suzuki, M., Youle, R.J., and Tjandra, N. 2000. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell. 103:645-654.
22. Griffiths, G.J., et al. 1999. Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. J. Cell Biol. 144:903-914.
23. Desagher, S., et al. 1999. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J. Cell Biol. 144:891-901.
24. Hsu, Y.T., and Youle, R.J. 1997. Nonionic detergents induce dimerization among members of the Bcl-2 family. J. Biol. Chem. 272:13829-13834.
25. Wolter, K.G., et al. 1997. Movement of Bax from the cytosol to mitochondria during apoptosis. J. Cell Biol. 139:1281-1292.
26. Cheng, E.H., et al. 2001. BCL-2, Bcl-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell. 8:705-711.
27. Gross, A., Jockel, J., Wei, M.C., and Korsmeyer, S.J. 1998. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17:3878-3885.
28. Liu, X., Kim, C.N., Yang, J., Jemmerson, R., and Wang, X. 1996. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147-157.
29. Li, L.Y., Luo, X., and Wang, X. 2001. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 412:95-99.
30. Du, C., Fang, M., Li, Y., Li, L, and Wang, X. 2000. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 102:33-42.
31. Verhagen, A.M., et al. 2000. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 102:43-53.
32. Susin, S.A., et al. 1999. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 397:441-446.
33. Danial, N.N., and Korsmeyer, S.J. 2004. Cell death: critical control points [review]. Cell. 116:205-219.
34. Saito, M., Korsmeyer, S.J., and Schlesinger, P.H. 2000. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat. Cell Biol. 2:553-555.
35. Kuwana, T., et al. 2002. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331-342.
36. Kuwana, T., et al. 2005. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell. 17:525-535.
37. Letai, A., et al. 2002. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2:183-192.
38. Eskes, R., Desagher, S., Antonsson, B., and Martinou, J.C. 2000. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol. Cell. Biol. 20:929-935.
39. Marani, M., Tenev, T., Hancock, D., Downward, J., and Lemoine, N.R. 2002. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol. Cell. Biol. 22:3577-3589.
40. Harada, H., Quearry, B., Ruiz-Vela, A., and Korsmeyer, S.J. 2004. Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc. Natl. Acad. Sci. U. S. A. 101:15313-15317.
41. Cartron, P.F., et al. 2004. The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol. Cell. 16:807-818.
42. Li, H., Zhu, H., Xu, C.J., and Yuan, J. 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 94:491-501.
43. Luo, X., Budihardjo, I., Zou, H., Slaughter, C., and Wang, X. 1998. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 94:481-490.
44. Zha, J., Weiler, S., Oh, K.J., Wei, M.C., and Korsmeyer, S.J. 2000. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science. 290:1761-1765.
45. Terradillos, O., Montessuit, S., Huang, D.C., and Martinou, J.C. 2002. Direct addition of BimL to mitochondria does not lead to cytochrome c release. FEBS Lett. 522:29-34.
46. Sawada, M., et al 2003. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat. Cell Biol. 5:320-329.
47. Guo, B., et al. 2003. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 423:456-461.
48. Ohtsuka, T., et al. 2004. ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nat. Cell Biol. 6:121-128.
49. Cheng, E.H., Sheiko, T.V., Fisher, J.K., Craigen, W.J., and Korsmeyer, S.J. 2003. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science. 301:513-517.
50. Muchmore, S.W., et al. 1996. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature. 381:335-341.
51. Sattler, M., et al. 1997. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science. 275:983-986.
52. Petros, A.M., et al. 2001. Solution structure of the antiapoptotic protein bcl-2, Proc. Natl. Acad. Sci. U. S. A. 98:3012-3017.
53. Petros, A.M., et al. 2000. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 9:2528-2534.
54. Cheng, E.H., Levine, B., Boise, L.H., Thompson, C.B., and Hardwick, J.M. 1996. Bax-independent inhibition of apoptosis by Bel-XL Nature. 379:554-556.
55. Murphy, K.M., Streips, U.N., and Lock, R.B. 2000. Bcl-2 inhibits a Fas-induced conformational change in the Bax N terminus and Bax mitochondrial translocation. J. Biol. Chem. 275:17225-17228.
56. Mikhailov, V., et al. 2001. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J. Biol Chem. 276:18361-18374.
57. Chipuk, J.E., et al. 2004. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 303:1010-1014.
58. Letai, A. 2003. BH3 domains as BCL-2 inhibitors: prototype cancer therapeutics. Expert Opin. Biol Ther. 3:293-304.
59. Opferman, J.T., et al. 2003. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 426:671-676.
60. Chen, L., et al. 2005. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 17:393-403.
61. Puthalakath, H., and Strasser, A. 2002. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins [review]. Cell Death Differ. 9:505-512.
62. Oda, E., et al. 2000. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 288:1053-1058.
63. Nakano, K., and Vousden, K.H. 2001. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell. 7:683-694.
64. Yu, J., Zhang, L., Hwang, P.M., Kinzler, K.W., and Vogelstein, B. 2001. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell 7:673-682.
65. Han, J., et al. 2001. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc. Natl. Acad. Sci. U. S. A. 98:11318-11323.
66. Jeffers, J.R., et al. 2003. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell. 4:321-328.
67. Dijkers, P.F., Medema, R.H., Lammers, J.W., Koenderman, L., and Coffer, P.J. 2000. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10:1201-1204.
68. Putcha, G.V., et al. 2001. Induction of BIM, a pro-apoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron. 29:615-628.
69. Puthalakath, H., Huang, D.C., O'Reilly, L.A., King, S.M., and Strasser, A. 1999. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell. 3:287-296.
70. Tan, T.T., et al. 2005. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell. 7:227-238.
71. Ley, R., et al. 2004. Extracellular signal-regulated kinases 1/2 are serum-stimulated "Bim(EL) kinases" that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. J. Biol. Chem. 279:8837-8847.
72. Luciano, F., et al. 2003. Phosphorylation of Bim-EL by Erk 1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its pro-apoptotic function. Oncogene. 22:6785-6793.
73. Zha, J., Harada, H., Yang, E., Jockel, J., and Korsmeyer, S.J. 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not Bcl-X(L). Cell. 87:619-628.
74. Danial, N.N., et al. 2003. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature. 424:952-956.
75. Cory, S., and Adams, J.M. 2002. The Bcl2 family: regulators of the cellular life-or-death switch [review]. Nat. Rev. Cancer. 2:647-656.
76. Adams, J.M. 2003. Ways of dying: multiple pathways to apoptosis [review]. Genes Dev. 17:2481-2495.
77. Gibson, M.E., et al. 2001. BAX contributes to apoptotic-like death following neonatal hypoxia-ischemia: evidence for distinct apoptosis pathways. Mol. Med. 7:644-655.
78. Plesnila, N., et al. 2001. BID mediates neuronal cell death after oxygen/glucose deprivation and focal cerebral ischemia. Proc. Natl. Acad. Sci. U. S. A. 98:15318-15323.
79. Gustafsson, A.B., Tsai, J.G., Logue, S.E., Crow, M.T., and Gottlieb, R.A. 2004. Apoptosis repressor with caspase recruitment domain protects against cell death by interfering with Bax activation. J. Biol. Chem. 279:21233-21238.
80. Chen, Z., Chua, C.C., Ho, Y.S., Hamdy, R.C., and Chua, B.H. 2001. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am. J. Physiol. Heart Circ. Physiol. 280:H2313-H2320.
81. Hochhauser, E., et al. 2003. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am. J. Physiol. Heart Circ. Physiol. 284:H2351-H2359.
82. Hattori, R, et al. 2001. An essential role of the anti-oxidant gene Bcl-2 in myocardial adaptation to ischemia: an insight with antisense Bcl-2 therapy. Antioxid. Redox Signal. 3:403-413.
83. Azzouz, M., et al. 2000. Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2. Hum. Mol. Genet. 9:803-811.
84. Kostic, V., Jackson-Lewis, V., de Bilbao, F., Dubois-Dauphin, M., and Przedborski, S. 1997. Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science. 277:559-562.
85. Weisleder, N., Taffet, G.E., and Capetanaki, Y. 2004. Bcl-2 Overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. 101:769-774.
86. Lawrence, M.S., Ho, D.Y., Sun, G.H., Steinberg, G.K., and Sapolsky, R.M. 1996. Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo. J. Neurosci. 16:486-496.
87. Bombrun, A., et al. 2003. 3,6-Dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome c release via Bax channel modulation. J. Med. Chem. 46:4365-4368.
88. Sawada, M., Hayes, P., and Matsuyama, S. 2003. Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70. Nat. Cell Biol. 5:352-357.
89. Becattini, B., et al. 2004. Targeting apoptosis via chemical design: inhibition of bid-induced cell death by small organic molecules. Chem. Biol. 11:1107-1117.
90. Green, D.R., and Evan, G.I. 2002. A matter of life and death. Cancer Cell. 1:19-30.
91. Shipp, M.A., et al. 2002. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat. Med. 8:68-74.
92. Derenne, S., et al. 2002. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 100:194-199.
93. Berrieman, H.K., et al. 2005. The expression of Bcl-2 family proteins differs between nonsmall cell lung carcinoma subtypes. Cancer. 103:1415-1419.
94. Henderson, S., et al. 1993. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc. Natl. Acad. Sci. U. S. A. 90:8479-8483.
95. Cheng, E.H., et al. 1997. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc. Natl. Acad. Sci. U. S. A. 94:690-694.
96. Letai, A., Beard, C., Sorcinelli, M., and Korsmeyer, S.J. 2004. Anti-apoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell. 6:241-249.
97. Strasser, A., Harris, A.W., Bath, M.L., and Cory, S. 1990. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature. 348:331-333.
98. Rothbard, J.B., et al. 2000. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat. Med. 6:1253-1257.
99. Wang, J.L., et al. 2000. Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells. Cancer Res. 60:1498-1502.
100. Schimmer, A.D., et al. 2001. The BH3 domain of BAD fused to the Antennapedia peptide induces apoptosis via its alpha helical structure and independent of Bcl-2. Cell Death Differ. 8:725-733.
101. Vieira, H.L., et al. 2000. Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator. Cell Death Differ. 7:1146-1154.
102. Chin, J.W., and Schepartz, A. 2001. Design and evolution of a miniature Bcl-2 binding protein. Angew. Chem. Int. Ed. Engl. 40:3806-3809.
103. Yang, B., Liu, D., and Huang, Z. 2004. Synthesis and helical structure of lactam bridged BH3 peptides derived from pro-apoptotic Bcl-2 family proteins. Bioorg. Med. Chem. Lett. 14:1403-1406.
104. Walensky, L.D., et al. 2004. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 305:1466-1470.
105. Wang, J.L., et al. 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. 97:7124-7129.
106. Enyedy, I.J., et al. 2001. Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J. Med. Chem. 44:4313-4324.
107. Degterev, A., et al. 2001. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat. Cell Biol. 3:173-182.
108. Nakashima, T., Miura, M., and Hara, M. 2000. Tetrocarcin A inhibits mitochondrial functions of Bcl-2 and suppresses its anti-apoptotic activity. Cancer Res. 60:1229-1235.
109. Tzung, S.P., et al. 2001. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat. Cell Biol. 3:183-191.
110. Kim, K.M., et al. 2001. Biophysical characterization of recombinant human Bcl-2 and its interactions with an inhibitory ligand, antimycin A. Biochemistry. 40:4911-4922.
111. Kutzki, O., et al. 2002. Development of a potent Bcl-x(L) antagonist based on alpha-helix mimicry. J. Am. Chem. Soc. 124:11838-11839.
112. Leone, M., et al. 2003. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 63:8118-8121.
113. Kitada, S., et al. 2003. Discovery, characterization, and structure-activity relationships studies of pro-apoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J. Med. Chem. 46:4259-4264.
114. Becattini, B., et al. 2004. Rational design and real time, in-cell detection of the proapoptotic activity of anovel compound targeting Bcl-X(L). Chem. Biol. 11:389-395.
115. Oltersdorf, T., et al. 2005. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677-681.
116. Jansen, B., et al. 1998. bcl-2 antisense therapy chemosensitizes human melanomain SCID mice. Nat. Med. 4:232-234.
117. Waters, J.S., et al. 2000. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J. Clin. Oncol. 18:1812-1823.
118. Konopleva, M., et al. 2000. Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood. 95:3929-3938.
119. Murthy, M.S., et al. 2001. A small molecule inhibitor of BCL-2 protein-protein interactions specifically induces apoptosis in cancer cells [abstract]. Clin. Cancer Res. 7:313.