Targeting Survival Pathways in Lymphoma

  • Luca Paoluzzi
  • Owen A. O’Connor
Part of the Advances in Experimental Medicine and Biology book series (volume 687)


Targeting cellular death pathways including apoptosis is a promising strategy for cancer drug discovery. To date at least three major types of cell death have been distinguished, including: apoptosis, autophagy, and necrosis. Increasing evidence has begun to support a role of Bcl-2-family members in the cellular pathways involved in each of these processes. The induction of apoptosis in different types of tissue and in response to various stressors is a complex process that is controlled by different BCL-2 family members. Pharmacologic modulation of BCL-2 proteins and apoptosis can be achieved through different ways including the use of: (1) Modified peptides; (2) Small molecule inhibitors of anti-apoptotic proteins; (3) Antisense strategies; and (4) TRAIL targeting. Non-peptide based small-molecule inhibitors of signaling pathways are at present the strategy of choice given their low antigenicity and generally more favorable pharmacokinetic and pharmacodynamic features, especially as they pertain to volume of distribution and intracellular accumulation. Bcl2-family inhibitors are showing impressive preclinical efficacy in animal models and are moving rapidly towards phase I and II clinical trials. Appropriate preclinical studies will need to identify the optimal strategies for combining these agents, with an emphasis on the importance of dose and schedule dependency.


Chronic Lymphocytic Leukemia Follicular Lymphoma Mantle Cell Lymphoma Antiapoptotic Protein Refractory Chronic Lymphocytic Leukemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reed JC. BCL-2-family proteins and hematologic malignancies: history and future prospects. Blood 2008; 111(7):3322–30. Review. Erratum in: Blood 2008; 112(2):452.PubMedGoogle Scholar
  2. 2.
    Vaux DL, Cory S, Adams JM. BCL-2 gene promotes haemopoietic cell survival and cooperates with c-Myc to immortalize preB-cells. Nature 1988; 335:440–442.PubMedGoogle Scholar
  3. 3.
    Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26:239–257.PubMedGoogle Scholar
  4. 4.
    Vaux DL, Weissman IL, Kim SK. Prevention of programmed cell death in Caenorhabditis elegans by human BCL-2. Science 1992; 258:1955–1957.PubMedGoogle Scholar
  5. 5.
    Yuan J, Shaham S, Ledoux S et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 1993; 75:641–652.PubMedGoogle Scholar
  6. 6.
    Li P, Nijhawan D, Budihardjo I et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91:479–489.PubMedGoogle Scholar
  7. 7.
    Oltvai ZN, Milliman CL, Korsmeyer SJ. BCL-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74:609–619.PubMedGoogle Scholar
  8. 8.
    Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov 2002; 1(2):111–21. Review.PubMedGoogle Scholar
  9. 9.
    Bredesen DE, Rao RV, Mehlen P. Cell death in the nervous system. Nature 2006; 443(7113):796–802. Review.PubMedGoogle Scholar
  10. 10.
    Waterhouse NJ, Goldstein JC, von Ahsen O et al. Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol 2001; 153(2):319–28.PubMedGoogle Scholar
  11. 11.
    Pattingre S, Tassa A, Qu X et al. BCL-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy, Cell 2005; 122:927–939.PubMedGoogle Scholar
  12. 12.
    Krajewski S, Tanaka S, Takayama S et al. Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum and outer mitochondrial membranes. Cancer Res 1993; 53(19):4701–14.PubMedGoogle Scholar
  13. 13.
    Ron D. Cell biology. Stressed cells cope with protein overload. Science 2006; 313(5783):52–3.PubMedGoogle Scholar
  14. 14.
    Adams JM, Cory S. The BCL-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26:1324–1337.PubMedGoogle Scholar
  15. 15.
    Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9(1):47–59. Review.PubMedGoogle Scholar
  16. 16.
    Wei MC, Zong WX, Cheng EH et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292(5517):727–30.PubMedGoogle Scholar
  17. 17.
    Huang DC, Strasser A. BH3-only proteins-essential initiators of apoptotic cell death. Cell 2000; 103:839–842.PubMedGoogle Scholar
  18. 18.
    Sattler M, Liang H, Nettesheim D et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 1997; 275:983–986.PubMedGoogle Scholar
  19. 19.
    Petros AM, Nettesheim DG, Wang Y et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis and biophysical studies. Protein Sci 2000; 9:2528–2534.PubMedGoogle Scholar
  20. 20.
    Cheng EH, Wei MC, Weiler S et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8:705–711.PubMedGoogle Scholar
  21. 21.
    Danial NN, Korsmeyer SJ. Cell death. Critical control points. Cell 2004; 116:205–219.PubMedGoogle Scholar
  22. 22.
    Zong WX, Lindsten T, Ross AJ et al. BH3-only proteins that bind pro-survival BCL-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15:1481–1486.PubMedGoogle Scholar
  23. 23.
    Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305:626–629.PubMedGoogle Scholar
  24. 24.
    Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15:2922–2933.PubMedGoogle Scholar
  25. 25.
    Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 2008; 7(12):989–1000. Review.PubMedGoogle Scholar
  26. 26.
    Chen L, Willis SN, Wei A et al. Differential targeting of prosurvival BCL-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005; 17:393–403.PubMedGoogle Scholar
  27. 27.
    Kuwana T, Bouchier-Hayes L, Chipuk JE et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005; 17(4):525–35.PubMedGoogle Scholar
  28. 28.
    Letai A, Bassik MC, Walensky LD et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2:183–192.PubMedGoogle Scholar
  29. 29.
    Cartron PF, Gallenne T, Bougras G et al. 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 2004; 16(5):807–18.PubMedGoogle Scholar
  30. 30.
    Certo M, Del Gaizo Moore V, Nishino M et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006; 9:351–365.PubMedGoogle Scholar
  31. 31.
    Kim H, Rafiuddin-Shah M, Tu HC et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 2006; 8:1348–1358.PubMedGoogle Scholar
  32. 32.
    Willis SN, Fletcher JI, Kaufmann T et al. Apoptosis initiated when BH3 ligands engage multiple BCL-2 homologs, not Bax or Bak. Science 2007; 315:856–859.PubMedGoogle Scholar
  33. 33.
    Oda E, Ohki R, Murasawa H et al. Noxa, a BH3-only member of the BCL-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288:1053–1058.PubMedGoogle Scholar
  34. 34.
    Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7:683–694.PubMedGoogle Scholar
  35. 35.
    Strasser A. The role of BH3-only proteins in the immune system. Nature Rev Immunol 2005; 5:189–200.Google Scholar
  36. 36.
    Puthalakath H, O’Reilly LA, Gunn P et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007; 129:1337–1349.PubMedGoogle Scholar
  37. 37.
    Kelley SK, Harris LA, Xie D et al. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics and safety. J Pharmacol Exp Ther 2001; 299:31–38.PubMedGoogle Scholar
  38. 38.
    Motoyama N, Wang F, Roth KA et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 1995; 267:1506–1510.PubMedGoogle Scholar
  39. 39.
    Veis DJ, Sorenson CM, Shutter JR et al. J. BCL-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys and hypopigmented hair. Cell 1993; 75:229–240.PubMedGoogle Scholar
  40. 40.
    Mason KD, Carpinelli MR, Fletcher JI et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128:1173–1186.PubMedGoogle Scholar
  41. 41.
    Rinkenberger JL, Horning S, Klocke B et al. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 2000; 14:23–27.PubMedGoogle Scholar
  42. 42.
    Ross AJ, Waymire KG, Moss JE et al. Testicular degeneration in Bclw-deficient mice. Nature Genet 1998; 18:251–6.PubMedGoogle Scholar
  43. 43.
    Walensky LD, Kung AL, Escher I et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004; 305:1466–1470.PubMedGoogle Scholar
  44. 44.
    Zeitlin BD, Zeitlin IJ, Nör JE. Expanding circle of inhibition: small-molecule inhibitors of BCL-2 as anticancer cell and antiangiogenic agents. J Clin Oncol 2008; 26(25):4180–8. Review.PubMedGoogle Scholar
  45. 45.
    An J, Chen Y, Huang Z. Critical upstream signals of cytochrome C release induced by a novel BCL-2 inhibitor. J Biol Chem 2004; 279(18):19133–40.PubMedGoogle Scholar
  46. 46.
    Milanesi E, Costantini P, Gambalunga A et al. 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 2006; 281(15):10066–72.PubMedGoogle Scholar
  47. 47.
    Wang JL, Liu D, Zhang ZJ et al. Structure-based discovery of an organic compound that binds bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 2000; 97:7124–7129.PubMedGoogle Scholar
  48. 48.
    Hao JH, Yu M, Liu FT et al. 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; 64(10):3607–16.PubMedGoogle Scholar
  49. 49.
    Milella M, Estrov Z, Kornblau SM et al. Synergistic induction of apoptosis by simultaneous disruption of the BCL-2 and MEK/MAPK pathways in acute myelogenous leukemia. Blood 2002; 99(9):3461–4.PubMedGoogle Scholar
  50. 50.
    Pei XY, Dai Y, Grant S. The small-molecule bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and jun NH2-terminal kinase-dependent mechanism. Mol Cancer Ther 2004; 3:1513–1524.PubMedGoogle Scholar
  51. 51.
    Oliver L, Mahé B, Gréé R et al. HA14-1, a small molecule inhibitor of BCL-2, bypasses chemoresistance in leukaemia cells. Leuk Res 2007; 31(6):859–63. Epub 2007.PubMedGoogle Scholar
  52. 52.
    Skommer J, Wlodkowic D, Matto M et al. HA14-1, a small molecule bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B-cells. Leuk Res 2006; 30:322–331.PubMedGoogle Scholar
  53. 53.
    Degterev A, Lugovskoy A, Cardone M et al. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 2001; 3(2):173–82.PubMedGoogle Scholar
  54. 54.
    Feng WY, Liu FT, Patwari Y et al. BH3-domain mimetic compound BH3I-2′ induces rapid damage to the inner mitochondrial membrane prior to the cytochrome c release from mitochondria. Br J Haematol 2003; 121(2):332–40.PubMedGoogle Scholar
  55. 55.
    Tzung SP, Kim KM, Basañez G et al. Antimycin A mimics a cell-death-inducing BCL-2 homology domain 3. Nat Cell Biol 2001; 3(2):183–91.PubMedGoogle Scholar
  56. 56.
    Manion MK, O’Neill JW, Giedt CD et al. BCL-XL mutations suppress cellular sensitivity to antimycin A. J Biol Chem 2004; 279:2159–2165.PubMedGoogle Scholar
  57. 57.
    Kim KM, Giedt CD, Basanez G et al. Biophysical characterization of recombinant human bcl-2 and its interactions with an inhibitory ligand, antimycin A. Biochemistry 2001; 40:4911–4922.PubMedGoogle Scholar
  58. 58.
    Schwartz PS, Manion MK, Emerson CB et al. 2-Methoxy antimycin reveals a unique mechanism for Bcl-x(L) inhibition. Mol Cancer Ther 2007; 6(7):2073–80.PubMedGoogle Scholar
  59. 59.
    Wang H, Li M, Rhie JK et al. Preclinical pharmacology of 2-methoxyantimycin A compounds as novel antitumor agents. Cancer Chemother Pharmacol 2005; 56(3):291–8.PubMedGoogle Scholar
  60. 60.
    Pellecchia M, Reed JC. Inhibition of anti-apoptotic BCL-2 family proteins by natural polyphenols: new avenues for cancer chemoprevention and chemotherapy. Curr Pharm Des 2004; 10(12):1387–98. Review.PubMedGoogle Scholar
  61. 61.
    Kitada S, Leone M, Sareth S et al. Discovery, characterization and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem 2003; 46(20):4259–64.PubMedGoogle Scholar
  62. 62.
    Lei X, Chen Y, Du G et al. Gossypol induces Bax/Bak-independent activation of apoptosis and cytochrome c release via a conformational change in BCL-2. FASEB J 2006; 20(12):2147–9.PubMedGoogle Scholar
  63. 63.
    Mohammad RM, Wang S, Aboukameel A et al. Preclinical studies of a nonpeptidic small-molecule inhibitor of BCL-2 and Bcl-X(L) [(−)-gossypol] against diffuse large cell lymphoma. Mol Cancer Ther 2005; 4(1):13–21.PubMedGoogle Scholar
  64. 64.
    Paoluzzi L, Gonen M, Gardner JR et al. 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 2008; 111(11):5350–8.PubMedGoogle Scholar
  65. 65.
    Castro JE, Loria JO, Aguillon AR et al. A phase II, open label study of AT-101 in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Evaluation of two dose regimens. Blood (ASH Annual Meeting Abstracts) 2007; 110:3119.Google Scholar
  66. 66.
    Castro JE, Loria JO, Aguillon AR et al. A phase II, open label study of AT-101 in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 2006; 108:2838.Google Scholar
  67. 67.
    Van Poznak C, Seidman AD, Reidenberg MM et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat 2001; 66(3):239–48.PubMedGoogle Scholar
  68. 68.
    Becattini B, Kitada S, Leone M et al. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol 2004; 11(3):389–95.PubMedGoogle Scholar
  69. 69.
    Kitada S, Kress CL, Krajewska M et al. 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 2008; 111(6):3211–9.PubMedGoogle Scholar
  70. 70.
    Arnold AA, Aboukameel A, Chen J et al. 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 2008; 7:20.PubMedGoogle Scholar
  71. 71.
    Wang G, Nikolovska-Coleska Z, Yang CY et al. Structure-based design of potent small-molecule inhibitors of anti-apoptotic BCL-2 proteins. J Med Chem 2006; 49(21):6139–42.PubMedGoogle Scholar
  72. 72.
    Mohammad RM, Goustin AS, Aboukameel A et al. 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 2007; 13(7):2226–35.PubMedGoogle Scholar
  73. 73.
    Mohammad RM, Sun Y, Wang S et al. Evaluation of TW-37, a pan BCL-2 proteins small-molecule inhibitor, against spectrum of human B-Cell lines and patient-derived samples. Blood (ASH Annual Meeting Abstracts) 2007; 110:4521.Google Scholar
  74. 74.
    Campàs C, Cosialls AM, Barragán M et al. BCL-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol 2006; 34(12):1663–9.PubMedGoogle Scholar
  75. 75.
    Pérez-Galán P, Roué G, Villamor N et al. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 2007; 109(10):4441–9. Epub 2007.PubMedGoogle Scholar
  76. 76.
    Trudel S, Li ZH, Rauw J et al. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood 2007; 109(12):5430–8.PubMedGoogle Scholar
  77. 77.
    Wei Y, Kadia T, Tong W et al. The combination of a histone deacetylase (HDAC) inhibitor with the BCL-2 inhibitor GX15-070 has synergistic antileukemia effect by inducing both apoptotic and autophagic pathways. Blood (ASH Annual Meeting Abstracts) 2008; 112:1633.Google Scholar
  78. 78.
    O’Brien SM, Claxton DF, Crump M et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 2009; 113(2):299–305. Epub 2008.PubMedGoogle Scholar
  79. 79.
    Schimmer AD, O’Brien S, Kantarjian H et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 2008; 14(24):8295–301.PubMedGoogle Scholar
  80. 80.
    Goy A, Ford P, Feldman T et al. A phase 1 trial of the pan BCL-2 family inhibitor obatoclax mesylate (GX15-070) in combination with bortezomib in patients with relapsed/refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts) 2007; 110:2569.Google Scholar
  81. 81.
    Oltersdorf T, Elmore SW, Shoemaker AR et al. An inhibitor of BCL-2 family proteins induces regression of solid tumours. Nature 2005; 435(7042):677–81.PubMedGoogle Scholar
  82. 82.
    van Delft MF, Wei AH, Mason KD et al. 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; 10(5):389–99.PubMedGoogle Scholar
  83. 83.
    Del Gaizo Moore V, Schlis KD, Sallan SE et al. BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood 2008; 111(4):2300–9.PubMedGoogle Scholar
  84. 84.
    Deng J, Carlson N, Takeyama K et al. A.BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 2007; 12(2):171–85.PubMedGoogle Scholar
  85. 85.
    Konopleva M, Contractor R, Tsao T et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10(5):375–88.PubMedGoogle Scholar
  86. 86.
    Ishitsuka K, Yotsumoto F, Katsuya H et al. A promising therapeutic implication of a novel BCL-2 family inhibitor ABT-737 for adult T-cell leukemia/lymphoma. Blood (ASH Annual Meeting Abstracts) 2008; 112:1584.Google Scholar
  87. 87.
    Jayanthan A, Howard SC, Trippett T et al. Targeting the BCL-2 family of proteins in hodgkin lymphoma: in vitro cytotoxicity, target modulation and drug combination studies of the BH3 mimetic ABT-737. Blood (ASH Annual Meeting Abstracts) 2008; 112:3626.Google Scholar
  88. 88.
    Chauhan D, Velankar M, Brahmandam M et al. A novel BCL-2/Bcl-X(L)/BCL-2 inhibitor ABT-737 as therapy in multiple myeloma. Oncogene 2007; 26(16):2374–80.PubMedGoogle Scholar
  89. 89.
    Kline MP, Rajkumar SV, Timm MM et al. ABT-737, an inhibitor of BCL-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia 2007; 21(7):1549–60.PubMedGoogle Scholar
  90. 90.
    Paoluzzi L, Gonen M, Bhagat G et al. The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 2008; 112(7):2906–16.PubMedGoogle Scholar
  91. 91.
    Kojima K, Konopleva M, Samudio IJ et al. Concomitant inhibition of MDM2 and BCL-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle 2006; 5(23):2778–86.PubMedGoogle Scholar
  92. 92.
    Kang MH, Kang YH, Szymanska B et al. 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; 110(6):2057–66.PubMedGoogle Scholar
  93. 93.
    Kuroda J, Puthalakath H, Cragg MS et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 2006; 103(40):14907–12.PubMedGoogle Scholar
  94. 94.
    Chen S, Dai Y, Harada H et al. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 2007; 67(2):782–91.PubMedGoogle Scholar
  95. 95.
    Ricciardi MR, Milella M, Libotte F et al. Synergistic induction of apoptosis in multiple myeloma cells by simultaneous inhibition of the Raf/MEK/ERK and BCL-2 pathways. Blood (ASH Annual Meeting Abstracts) 2008; 112:5161.Google Scholar
  96. 96.
    Trudel S, Stewart AK, Li Z et al. The BCL-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res 2007; 13(2 Pt 1):621–9.PubMedGoogle Scholar
  97. 97.
    Tahir SK, Yang X, Anderson MG et al. Influence of BCL-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res 2007; 67(3):1176–83.PubMedGoogle Scholar
  98. 98.
    Lin X, Morgan-Lappe S, Huang X et al. ’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; 26(27):3972–9.PubMedGoogle Scholar
  99. 99.
    Olejniczak ET, Van Sant C, Anderson MG et al. Integrative genomic analysis of small-cell lung carcinoma reveals correlates of sensitivity to bcl-2 antagonists and uncovers novel chromosomal gains. Mol Cancer Res 2007; 5(4):331–9.PubMedGoogle Scholar
  100. 100.
    Xia L, Wang R, Qian H et al. Arsenic trioxide plus ABT-737 is synergistic to induce apoptosis in AML cells by repression of Mcl-1 protein and inactivation of BCL-2 protein. Blood (ASH Annual Meeting Abstracts) 2008; 112:2653.Google Scholar
  101. 101.
    Zhang H, Nimmer PM, Tahir SK et al. BCL-2 family proteins are essential for platelet survival. Cell Death Differ 2007; 14(5):943–51.PubMedGoogle Scholar
  102. 102.
    Wilson WH, Tulpule A, Levine AM et al. A phase 1/2a study evaluating the safety, pharmacokinetics and efficacy of ABT-263 in subjects with refractory or relapsed lymphoid malignancies. Blood (ASH Annual Meeting Abstracts) 2007; 110:1371.Google Scholar
  103. 103.
    Klasa RJ, Gillum AM, Klem RE et al. Oblimersen BCL-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002; 12:193–213.PubMedGoogle Scholar
  104. 104.
    Cotter FE, Waters J, Cunningham D. Human BCL-2 antisense therapy for lymphomas. Biochim Biophys Acta 1999; 1489(1):97–106. Review.PubMedGoogle Scholar
  105. 105.
    O’Connor OA, Smith EA, Toner LE et al. The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide. Clin Cancer Res 2006; 12(9):2902–11.PubMedGoogle Scholar
  106. 106.
    Smith MR, Jin F, Joshi I. Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts. Mol Cancer Ther 2004; 3(12):1693–9.PubMedGoogle Scholar
  107. 107.
    Pro B, Leber B, Smith M et al. Phase II multicenter study of oblimersen sodium, a BCL-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell nonHodgkin lymphoma. Br J Haematol 2008; 143(3):355–60.PubMedGoogle Scholar
  108. 108.
    O’Brien S, Wu J, Novick S et al. 5-year follow-up of patients with relapsed/refractory CLL treated with standard chemotherapy with or without oblimersen in randomized phase III trial: prognostic factors and predictive factors for treatment effect. Blood (ASH Annual Meeting Abstracts) 2008; 112:4201.Google Scholar
  109. 109.
    Chuntharapai A, Dodge K, Grimmer K et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166:4891–4898.PubMedGoogle Scholar
  110. 110.
    Ichikawa K, Liu W, Zhao L et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nature Med 2001; 7:954–960.PubMedGoogle Scholar
  111. 111.
    Takeda K, Yamaguchi N, Akiba H et al. Induction of tumor-specific T-cell immunity by anti-DR5 antibody therapy. J Exp Med 2004; 199:437–448.PubMedGoogle Scholar
  112. 112.
    Younes A, Vose JM, Zelenetz AD et al. Results of a phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory nonHodgkin’s lymphoma (NHL). Blood (ASH Annual Meeting Abstracts) 2005; 106:489.Google Scholar
  113. 113.
    Shankar S, Singh TR, Fandy TE et al. Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. Int J Mol Med 2005; 16(6):1125–38.PubMedGoogle Scholar
  114. 114.
    Inoue S, MacFarlane M, Harper N et al. Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ 2004; 11:S193–S206.PubMedGoogle Scholar
  115. 115.
    Mitsiades CS, Treon SP, Mitsiades N et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001; 98:795–804.PubMedGoogle Scholar
  116. 116.
    Ashkenazi A, Pai RC, Fong S et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104:155–162.PubMedGoogle Scholar
  117. 117.
    Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature Rev Cancer 2002; 2:420–421.Google Scholar
  118. 118.
    Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004; 4:333–339.PubMedGoogle Scholar
  119. 119.
    Yee L, Fanale M, Dimick K et al. A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade nonHodgkin lymphoma. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I 2007; 25(18S):8078.Google Scholar
  120. 120.
    Shimizu S, Kanaseki T, Mizushima N et al. Role of BCL-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol 2004; 6:1221–1228.PubMedGoogle Scholar
  121. 121.
    Pattingre S, Tassa A, Qu X et al. BCL-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122(6):927–39.PubMedGoogle Scholar
  122. 122.
    Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27–42.PubMedGoogle Scholar
  123. 123.
    Yoshimori T. Autophagy: paying Charon’s toll. Cell 2007; 128:833–836.PubMedGoogle Scholar
  124. 124.
    Janumyan Y, Cui Q, Yan L et al. G0 function of BCL2 and BCL-xL requires BAX, BAK and p27 phosphorylation by Mirk, revealing a novel role of BAX and BAK in quiescence regulation. J Biol Chem 2008; 283(49):34108–20.PubMedGoogle Scholar
  125. 125.
    Cui Q, Valentin M, Janumyan Y et al. Bax(−/−) bak(−/−) cells exhibit p27 Thr198 phosphorylation and autophagy. Autophagy 2009; 5(2).Google Scholar
  126. 126.
    Yazbeck VY, Buglio D, Georgakis GV et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol 2008; 36(4):443–50.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Department of Medicine and Pharmacology and Department of Clinical Research and Cancer TreatmentNew York Univeristy Cancer InstituteNew York
  2. 2.Division of Hematological Malignancies and Medical OncologyThe New York University Langone Medical CenterNew York
  3. 3.Herbert Irving Comprehensive Cancer Center College of Physicians and Surgeons The New York Presbyterian HospitalColumbia UniversityNew YorkUSA

Personalised recommendations