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Programmed Cell Death Pathways and Current Antitumor Targets

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Abstract

Apoptosis and autophagic cell deaths are programmed cell deaths and they play essential roles in cell survival, growth and development and tumorigenesis. The huge increase of publications in both apoptosis and autophagic signaling pathways has contributed to the wealth of knowledge in facilitating the understanding of cancer pathogenesis. Deciphering the molecular pathways and molecules involved in these pathways has helped scientists devise and develop targeted strategies against cancer. Various drugs targeting the apoptotic TRAIL, Bcl-2 and proteasome pathways are already in Phase II/III clinical trials. The first mTOR inhibitor, temsirolimus has already been approved by the FDA, USA for the treatment of advanced renal cell carcinoma and more mTOR inhibitors are expected to be in the market in a few years time. Strategizing against aberrant autophagy activities in various cancers by using either pro-autophagics or autophagy inhibitors are currently been investigated. This review aims to discuss the most recent antitumor strategies targeting the apoptosis and autophagy signaling pathways and the latest outcome of clinical trials of the above drugs.

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References

  1. Bellamy CO, Malcomson RD, Harrison DJ, Wyllie AH. Cell death in health and disease: the biology and regulation of apoptosis. Semin Cancer Biol 1995;6:3–16. doi:10.1006/scbi.1995.0002.

    PubMed  CAS  Google Scholar 

  2. Lockshinand RA, Zakeri Z. Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol 2001;2:545–50. doi:10.1038/35080097.

    Google Scholar 

  3. Kerrand JF, Searle J. A suggested explanation for the paradoxically slow growth rate of basal-cell carcinomas that contain numerous mitotic figures. J Pathol 1972;107:41–4. doi:10.1002/path.1711070107.

    Google Scholar 

  4. Steel GG. Cell loss as a factor in the growth rate of human tumours. Eur J Cancer 1967;3:381–7. doi:10.1016/0014-2964(67)90022-9.

    PubMed  CAS  Google Scholar 

  5. Iversen OH. Kinetics of cellular proliferation and cell loss in human carcinomas. A discussion of methods available for in vivo studies. Eur J Cancer 1967;3:389–94. doi:10.1016/0014-2964(67)90023-0.

    PubMed  CAS  Google Scholar 

  6. Green DR, Evan GI. A matter of life and death. Cancer Cell 2002;1:19–30. doi:10.1016/S1535-6108(02)00024-7.

    PubMed  CAS  Google Scholar 

  7. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. doi:10.1016/S0092-8674(00)81683-9.

    PubMed  CAS  Google Scholar 

  8. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995;267:1456–62. doi:10.1126/science.7878464.

    PubMed  CAS  Google Scholar 

  9. Vaux DL, Flavell RA. Apoptosis genes and autoimmunity. Curr Opin Immunol 2000;12:719–24. doi:10.1016/S0952-7915(00)00168-0.

    PubMed  CAS  Google Scholar 

  10. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000;407:802–9. doi:10.1038/35037739.

    PubMed  CAS  Google Scholar 

  11. Bold RJ, Termuhlen PM, McConkey DJ. Apoptosis, cancer and cancer therapy. Surg Oncol 1997;6:133–42. doi:10.1016/S0960-7404(97)00015-7.

    PubMed  CAS  Google Scholar 

  12. Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994;73:2013–26. doi:10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J.

    PubMed  CAS  Google Scholar 

  13. Lockshin RA, Williams CM. Programmed cell death—I. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J Insect Physiol 1965;11:123–33. doi:10.1016/0022-1910(65)90099-5.

    PubMed  CAS  Google Scholar 

  14. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–57.

    PubMed  CAS  Google Scholar 

  15. Peter ME, Heufelder AE, Hengartner MO. Advances in apoptosis research. Proc Natl Acad Sci USA 1997;94:12736–7. doi:10.1073/pnas.94.24.12736.

    PubMed  CAS  Google Scholar 

  16. Bowen ID, Bowen SM, Jones AH. Mitosis and apoptosis, matters of life and death. Cardiff, UK: Chapman and Hall; 1998.

    Google Scholar 

  17. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980;68:251–306. doi:10.1016/S0074-7696(08)62312-8.

    PubMed  CAS  Google Scholar 

  18. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995;182:1545–56. doi:10.1084/jem.182.5.1545.

    PubMed  CAS  Google Scholar 

  19. Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME. Apoptosis signaling by death receptors. Eur J Biochem 1998;254:439–59. doi:10.1046/j.1432-1327.1998.2540439.x.

    PubMed  CAS  Google Scholar 

  20. Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770–6. doi:10.1038/35037710.

    PubMed  CAS  Google Scholar 

  21. Wolf BB, Schuler M, Echeverri F, Green DR. Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem 1999;274:30651–6. doi:10.1074/jbc.274.43.30651.

    PubMed  CAS  Google Scholar 

  22. Widlakand P, Garrard WT. Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G. J Cell Biochem 2005;94:1078–87. doi:10.1002/jcb.20409.

    Google Scholar 

  23. Antonssonand B, Martinou JC. The Bcl-2 protein family. Exp Cell Res 2000;256:50–7. doi:10.1006/excr.2000.4839.

    Google Scholar 

  24. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999;13:1899–911. doi:10.1101/gad.13.15.1899.

    PubMed  CAS  Google Scholar 

  25. Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JP, Melendez-Zajgla J. Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res 2008;27:48. doi:10.1186/1756-9966-27-48.

    PubMed  Google Scholar 

  26. James D, Parone PA, Terradillos O, Lucken-Ardjomande S, Montessuit S, Martinou JC. Mechanisms of mitochondrial outer membrane permeabilization. Novartis Found Symp 2007;287:170–6. discussion 176–82.

    PubMed  CAS  Google Scholar 

  27. Rajalingam K, Oswald M, Gottschalk K, Rudel T. Smac/DIABLO is required for effector caspase activation during apoptosis in human cells. Apoptosis 2007;12:1503–10. doi:10.1007/s10495-007-0067-7.

    PubMed  CAS  Google Scholar 

  28. Liptonand SA, Bossy-Wetzel E. Dueling activities of AIF in cell death versus survival: DNA binding and redox activity. Cell 2002;111:147–50. doi:10.1016/S0092-8674(02)01046-2.

    Google Scholar 

  29. Low RL. Mitochondrial Endonuclease G function in apoptosis and mtDNA metabolism: a historical perspective. Mitochondrion 2003;2:225–36. doi:10.1016/S1567-7249(02)00104-6.

    PubMed  CAS  Google Scholar 

  30. Zhang J, Dong M, Li L, Fan Y, Pathre P, Dong J, et al. Endonuclease G is required for early embryogenesis and normal apoptosis in mice. Proc Natl Acad Sci USA 2003;100:15782–7. doi:10.1073/pnas.2636393100.

    PubMed  CAS  Google Scholar 

  31. Tsujimoto Y. Stress-resistance conferred by high level of bcl-2 alpha protein in human B lymphoblastoid cell. Oncogene 1989;4:1331–6.

    PubMed  CAS  Google Scholar 

  32. Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells 1998;3:697–707. doi:10.1046/j.1365-2443.1998.00223.x.

    PubMed  CAS  Google Scholar 

  33. Uren RT, Dewson G, Chen L, Coyne SC, Huang DC, Adams JM, et al. Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak. J Cell Biol 2007;177:277–87. doi:10.1083/jcb.200606065.

    PubMed  CAS  Google Scholar 

  34. Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 2008;4:600–6.

    PubMed  CAS  Google Scholar 

  35. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002;2:183–92. doi:10.1016/S1535-6108(02)00127-7.

    PubMed  CAS  Google Scholar 

  36. Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME. Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 1999;274:22532–8. doi:10.1074/jbc.274.32.22532.

    PubMed  CAS  Google Scholar 

  37. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002;3:401–10. doi:10.1038/nrm830.

    PubMed  CAS  Google Scholar 

  38. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997;388:300–4. doi:10.1038/40901.

    PubMed  CAS  Google Scholar 

  39. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J 1997;16:6914–25. doi:10.1093/emboj/16.23.6914.

    PubMed  CAS  Google Scholar 

  40. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998;17:2215–23. doi:10.1093/emboj/17.8.2215.

    PubMed  CAS  Google Scholar 

  41. Zhang L, Ming L, Yu J. BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist Updat 2007;10:207–17. doi:10.1016/j.drup.2007.08.002.

    PubMed  CAS  Google Scholar 

  42. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789–99. doi:10.1038/nm1087.

    PubMed  CAS  Google Scholar 

  43. Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003;3:17–22. doi:10.1016/S1535-6108(02)00241-6.

    PubMed  CAS  Google Scholar 

  44. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000;12:611–20. doi:10.1016/S1074-7613(00)80212-5.

    PubMed  CAS  Google Scholar 

  45. Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 2002;16:33–45. doi:10.1101/gad.949602.

    PubMed  CAS  Google Scholar 

  46. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155–62. doi:10.1172/JCI6926.

    PubMed  CAS  Google Scholar 

  47. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157–63. doi:10.1038/5517.

    PubMed  CAS  Google Scholar 

  48. El-Deiry WS. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ 2001;8:1066–75. doi:10.1038/sj.cdd.4400943.

    PubMed  CAS  Google Scholar 

  49. Herbst RS, Mendolson DS, Ebbinghaus S, Gordon MS, O’Dwyer P, Lieberman G, et al. A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer. J Clin Oncol 2006;24:3013.

    Google Scholar 

  50. Ling J, Herbst RS, Mendelson DS, Eckhardt SG, O’Dwyer P, Ebbinghaus S, et al. Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma. J Clin Oncol 2006;24:3047.

    Google Scholar 

  51. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 2008;8:782–98. doi:10.1038/nrc2465.

    PubMed  CAS  Google Scholar 

  52. Yee L, Fanale M, Dimick K, Calvert S, Robins C, Ing J, et al. A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma. J Clin Oncol 2007;25:8078.

    Google Scholar 

  53. Soria J, Smit EF, Khayat D, Besse B, Burton J, Yang X, et al. Phase Ib study of recombinant human (rh)Apo2L/TRAIL in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2008;26:3539.

    Google Scholar 

  54. Greco FA, Bonomi P, Crawford J, Kelly K, Oh Y, Halpern W, et al. Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer 2008;61:82–90. doi:10.1016/j.lungcan.2007.12.011.

    PubMed  Google Scholar 

  55. Hotte SJ, Hirte HW, Chen EX, Siu LL, Le LH, Corey A, et al. A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res 2008;14:3450–5. doi:10.1158/1078-0432.CCR-07-1416.

    PubMed  CAS  Google Scholar 

  56. Le LH, Hirte HW, Hotte SJ, Maclean M, Iacobucci A, Corey A, et al. Phase I study of a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 4 (TRAIL-R1) in subjects with advanced solid malignancies or non-Hodgkin’s lymphoma (NHL). J Clin Oncol 2004;22:2533.

    Google Scholar 

  57. Chow LQ, Eckhardt SG, Gustafson DL, O’Bryant C, Hariharan S, Diab S, et al. HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase 1 and PK study. J Clin Oncol 2006;24:2515.

    Google Scholar 

  58. Plummer R, Attard G, Pacey S, Li L, Razak A, Perrett R, et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 2007;13:6187–94. doi:10.1158/1078-0432.CCR-07-0950.

    PubMed  CAS  Google Scholar 

  59. LoRusso P, Hong D, Heath E, Kurzrock R, Wang D, Hsu M, et al. First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors. J Clin Oncol 2007;25:3534.

    Google Scholar 

  60. Camidge D, Herbst RS, Gordon M, Eckhardt S, Kurzroc R, Durbin B, et al. A phase I safety and pharmacokinetic study of apomab, a human DR5 agonist antibody, in patients with advanced cancer. J Clin Oncol 2007;25:3582.

    Google Scholar 

  61. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007;26:1324–37. doi:10.1038/sj.onc.1210220.

    PubMed  CAS  Google Scholar 

  62. Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene 2008;27:6398–406. doi:10.1038/onc.2008.307.

    PubMed  CAS  Google Scholar 

  63. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677–81. doi:10.1038/nature03579.

    PubMed  CAS  Google Scholar 

  64. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116:205–19. doi:10.1016/S0092-8674(04)00046-7.

    PubMed  CAS  Google Scholar 

  65. Baell JB, Huang DC. Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 2002;64:851–63. doi:10.1016/S0006-2952(02)01148-6.

    PubMed  CAS  Google Scholar 

  66. Kirkin V, Joos S, Zornig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 2004;1644:229–49. doi:10.1016/j.bbamcr.2003.08.009.

    PubMed  CAS  Google Scholar 

  67. Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC, Fornace Jr AJ. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res 2000;60:6101–10.

    PubMed  CAS  Google Scholar 

  68. Kitada S, Kress CL, Krajewska M, Jia L, Pellecchia M, Reed JC. 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;111:3211–9. doi:10.1182/blood-2007-09-113647.

    PubMed  CAS  Google Scholar 

  69. Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 2007;104:19512–7. doi:10.1073/pnas.0709443104.

    PubMed  CAS  Google Scholar 

  70. Mohan KV, Gunasekaran P, Varalakshmi E, Hara Y, Nagini S. In vitro evaluation of the anticancer effect of lactoferrin and tea polyphenol combination on oral carcinoma cells. Cell Biol Int 2007;31:599–608. doi:10.1016/j.cellbi.2006.11.034.

    PubMed  CAS  Google Scholar 

  71. 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;10:1387–98. doi:10.2174/1381612043384880.

    PubMed  CAS  Google Scholar 

  72. Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M. Discovery, characterization, and structure–activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem 2003;46:4259–64. doi:10.1021/jm030190z.

    PubMed  CAS  Google Scholar 

  73. Stein RC, Joseph AE, Matlin SA, Cunningham DC, Ford HT, Coombes RC. A preliminary clinical study of gossypol in advanced human cancer. Cancer Chemother Pharmacol 1992;30:480–2. doi:10.1007/BF00685601.

    PubMed  CAS  Google Scholar 

  74. Bushunow P, Reidenberg MM, Wasenko J, Winfield J, Lorenzo B, Lemke S, et al. Gossypol treatment of recurrent adult malignant gliomas. J Neurooncol 1999;43:79–86. doi:10.1023/A:1006267902186.

    PubMed  CAS  Google Scholar 

  75. Van Poznak C, Seidman AD, Reidenberg MM, Moasser MM, Sklarin N, Van Zee K, 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;66:239–48. doi:10.1023/A:1010686204736.

    PubMed  Google Scholar 

  76. James DF, Castro JE, Loria O, Prada CE, Aguillon RA, Kipps TJ. AT-101, a small molecule Bcl-2 antagonist, in treatment naive CLL patients (pts) with high risk features; Preliminary results from an ongoing phase I trial. J Clin Oncol 2006;24:6605.

    Google Scholar 

  77. Sun Y, Wu J, Aboukameel A, Banerjee S, Arnold AA, Chen J, et al. 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 2008;7:1418–26.

    PubMed  CAS  Google Scholar 

  78. Schimmer AD, O’Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, 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;14:8295–301. doi:10.1158/1078-0432.CCR-08-0999.

    PubMed  CAS  Google Scholar 

  79. O’Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, 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 2008;113:299–305.

    PubMed  Google Scholar 

  80. Moreira JN, Santos A, Simoes S. Bcl-2-targeted antisense therapy (oblimersen sodium): towards clinical reality. Rev Recent Clin Trials 2006;1:217–35. doi:10.2174/157488706778250050.

    PubMed  CAS  Google Scholar 

  81. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006;24:4738–45. doi:10.1200/JCO.2006.06.0483.

    PubMed  CAS  Google Scholar 

  82. O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007;25:1114–20. doi:10.1200/JCO.2006.07.1191.

    PubMed  Google Scholar 

  83. Wetzler M, Donohue KA, Odenike OM, Feldman EJ, Hurd DD, Stone RM, et al. Feasibility of administering oblimersen (G3139; Genasense) with imatinib mesylate in patients with imatinib resistant chronic myeloid leukemia—cancer and leukemia group B study 10107. Leuk Lymphoma 2008;49:1274–8. doi:10.1080/10428190802043887.

    PubMed  CAS  Google Scholar 

  84. Rudin CM, Salgia R, Wang X, Hodgson LD, Masters GA, Green M, et al. Randomized phase II Study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol 2008;26:870–6. doi:10.1200/JCO.2007.14.3461.

    PubMed  CAS  Google Scholar 

  85. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002;82:373–428.

    PubMed  CAS  Google Scholar 

  86. Glickman MH, Adir N. The proteasome and the delicate balance between destruction and rescue. PLoS Biol 2004;2:E13. doi:10.1371/journal.pbio.0020013.

    PubMed  Google Scholar 

  87. Ludwig H, Khayat D, Giaccone G, Facon T. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer 2005;104:1794–807. doi:10.1002/cncr.21414.

    PubMed  CAS  Google Scholar 

  88. Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bortezomib etreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin Adv Hematol Oncol 2008;6:755–60.

    PubMed  Google Scholar 

  89. Reece DE, Rodriguez GP, Chen C, Trudel S, Kukreti V, Mikhael J, et al. Phase I–II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 2008;26:4777–83. doi:10.1200/JCO.2007.14.2372.

    PubMed  CAS  Google Scholar 

  90. Fonseca R, Rajkumar SV. Consolidation therapy with bortezomib/lenalidomide/dexamethasone versus bortezomib/dexamethasone after a dexamethasone-based induction regimen in patients with multiple myeloma: a randomized phase III trial. Clin Lymphoma Myeloma 2008;8:315–7. doi:10.3816/CLM.2008.n.046.

    PubMed  CAS  Google Scholar 

  91. Mendler JH, Kelly J, Voci S, Marquis D, Rich L, Rossi RM, et al. Bortezomib and gemcitabine in relapsed or refractory Hodgkin’s lymphoma. Ann Oncol 2008;19:1759–64. doi:10.1093/annonc/mdn365.

    PubMed  CAS  Google Scholar 

  92. Cresta S, Sessa C, Catapano CV, Gallerani E, Passalacqua D, Rinaldi A, et al. Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumours. Eur J Cancer 2008;44:1829–34. doi:10.1016/j.ejca.2008.05.022.

    PubMed  CAS  Google Scholar 

  93. Jatoi A, Dakhil SR, Foster NR, Ma C, Rowland Jr KM, Moore Jr DF, et al. Bortezomib, paclitaxel, and carboplatin as a first-line regimen for patients with metastatic esophageal, gastric, and gastroesophageal cancer: phase II results from the North Central Cancer Treatment Group (N044B). J Thorac Oncol 2008;3:516–20.

    PubMed  Google Scholar 

  94. Cossu F, Mastrangelo E, Milani M, Sorrentino G, Lecis D, Delia D, et al. Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2. Biochem Biophys Res Commun 2009;378:162–7. doi:10.1016/j.bbrc.2008.10.139.

    PubMed  CAS  Google Scholar 

  95. Fandy TE, Shankar S, Srivastava RK. Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells. Mol Cancer 2008;7:60. doi:10.1186/1476-4598-7-60.

    PubMed  Google Scholar 

  96. Lleo A, Invernizzi P, Selmi C, Coppel RL, Alpini G, Podda M, et al. Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun 2007;29:61–8. doi:10.1016/j.jaut.2007.06.003.

    PubMed  CAS  Google Scholar 

  97. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004;6:463–77. doi:10.1016/S1534-5807(04)00099-1.

    PubMed  CAS  Google Scholar 

  98. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005;120:237–48. doi:10.1016/j.cell.2004.11.046.

    PubMed  CAS  Google Scholar 

  99. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature 2004;432:1032–6. doi:10.1038/nature03029.

    PubMed  CAS  Google Scholar 

  100. Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007;8:931–7. doi:10.1038/nrm2245.

    PubMed  CAS  Google Scholar 

  101. Tan ML, Muhammad TS, Najimudin N, Sulaiman SF. Growth arrest and non-apoptotic programmed cell death associated with the up-regulation of c-myc mRNA expression in T-47D breast tumor cells following exposure to Epipremnum pinnatum (L.) Engl. hexane extract. J Ethnopharmacol 2005;96:375–83. doi:10.1016/j.jep.2004.07.005.

    PubMed  CAS  Google Scholar 

  102. Meijer AJ, Codogno P. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 2004;36:2445–62. doi:10.1016/j.biocel.2004.02.002.

    PubMed  CAS  Google Scholar 

  103. Reggiori F, Klionsky DJ. Autophagy in the eukaryotic cell. Eukaryot Cell 2002;1:11–21. doi:10.1128/EC.01.1.11-21.2002.

    PubMed  CAS  Google Scholar 

  104. Suzuki K, Ohsumi Y. Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett 2007;581:2156–61. doi:10.1016/j.febslet.2007.01.096.

    PubMed  CAS  Google Scholar 

  105. Ferraro E, Cecconi F. Autophagic and apoptotic response to stress signals in mammalian cells. Arch Biochem Biophys 2007;462:210–9. doi:10.1016/j.abb.2007.02.006.

    PubMed  CAS  Google Scholar 

  106. Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 2005;5:726–34. doi:10.1038/nrc1692.

    PubMed  CAS  Google Scholar 

  107. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form—II formation. J Cell Sci 2004;117:2805–12. doi:10.1242/jcs.01131.

    PubMed  CAS  Google Scholar 

  108. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000;19:5720–8. doi:10.1093/emboj/19.21.5720.

    PubMed  CAS  Google Scholar 

  109. Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y. Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 2005;16:2544–53. doi:10.1091/mbc.E04-08-0669.

    PubMed  CAS  Google Scholar 

  110. Xue L, Fletcher GC, Tolkovsky AM. Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci 1999;14:180–98. doi:10.1006/mcne.1999.0780.

    PubMed  CAS  Google Scholar 

  111. White E. Autophagic cell death unraveled: pharmacological inhibition of apoptosis and autophagy enables necrosis. Autophagy 2008;4:399–401.

    PubMed  CAS  Google Scholar 

  112. Hornung JP, Koppel H, Clarke PG. Endocytosis and autophagy in dying neurons: an ultrastructural study in chick embryos. J Comp Neurol 1989;283:425–37. doi:10.1002/cne.902830310.

    PubMed  CAS  Google Scholar 

  113. Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene 2004;23:2891–906. doi:10.1038/sj.onc.1207521.

    PubMed  CAS  Google Scholar 

  114. Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 2007;120:4081–91. doi:10.1242/jcs.019265.

    PubMed  CAS  Google Scholar 

  115. Kegel KB, Kim M, Sapp E, McIntyre C, Castano JG, Aronin N, et al. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 2000;20:7268–78.

    PubMed  CAS  Google Scholar 

  116. Qin ZH, Wang Y, Kegel KB, Kazantsev A, Apostol BL, Thompson LM, et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet 2003;12:3231–44. doi:10.1093/hmg/ddg346.

    PubMed  CAS  Google Scholar 

  117. Petersen A, Brundin P. Huntington’s disease: the mystery unfolds? Int Rev Neurobiol 2002;53:315–39. doi:10.1016/S0074-7742(02)53012-9.

    PubMed  CAS  Google Scholar 

  118. Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, et al. Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet 2001;10:1243–54. doi:10.1093/hmg/10.12.1243.

    PubMed  CAS  Google Scholar 

  119. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 1997;12:25–31.

    PubMed  CAS  Google Scholar 

  120. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003;4:117–26. doi:10.1038/nrm1018.

    PubMed  CAS  Google Scholar 

  121. Martin KA, Blenis J. Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res 2002;86:1–39. doi:10.1016/S0065-230X(02)86001-8.

    PubMed  CAS  Google Scholar 

  122. Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Mol Med 2003;9:65–76. doi:10.1007/BF01656257.

    PubMed  Google Scholar 

  123. Wang L, Fraley CD, Faridi J, Kornberg A, Roth RA. Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells. Proc Natl Acad Sci USA 2003;100:11249–54. doi:10.1073/pnas.1534805100.

    PubMed  CAS  Google Scholar 

  124. Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth inhibition. Recent Results Cancer Res 2007;172:99–124. doi:10.1007/978-3-540-31209-3_7.

    PubMed  CAS  Google Scholar 

  125. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004;24:6710–8. doi:10.1128/MCB.24.15.6710-6718.2004.

    PubMed  CAS  Google Scholar 

  126. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815–22. doi:10.1074/jbc.270.2.815.

    PubMed  CAS  Google Scholar 

  127. Takeuchi H, Kondo Y, Fujiwara K, Kanzawa T, Aoki H, Mills GB, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005;65:3336–46.

    PubMed  CAS  Google Scholar 

  128. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 1998;72:8586–96.

    PubMed  CAS  Google Scholar 

  129. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672–6. doi:10.1038/45257.

    PubMed  CAS  Google Scholar 

  130. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003;112:1809–20.

    PubMed  CAS  Google Scholar 

  131. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003;100:15077–82. doi:10.1073/pnas.2436255100.

    PubMed  CAS  Google Scholar 

  132. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science 2004;306:990–5. doi:10.1126/science.1099993.

    PubMed  CAS  Google Scholar 

  133. Kisen GO, Tessitore L, Costelli P, Gordon PB, Schwarze PE, Baccino FM, et al. Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis 1993;14:2501–5. doi:10.1093/carcin/14.12.2501.

    PubMed  CAS  Google Scholar 

  134. Toth S, Nagy K, Palfia Z, Rez G. Changes in cellular autophagic capacity during azaserine-initiated pancreatic carcinogenesis. Acta Biol Hung 2001;52:393–401. doi:10.1556/ABiol.52.2001.4.3.

    PubMed  CAS  Google Scholar 

  135. Toth S, Nagy K, Palfia Z, Rez G. Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res 2002;309:409–16. doi:10.1007/s00441-001-0506-7.

    PubMed  Google Scholar 

  136. Schwarze PE, Seglen PO. Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. Exp Cell Res 1985;157:15–28. doi:10.1016/0014-4827(85)90148-X.

    PubMed  CAS  Google Scholar 

  137. Canuto RA, Tessitore L, Muzio G, Autelli R, Baccino FM. Tissue protein turnover during liver carcinogenesis. Carcinogenesis 1993;14:2581–7. doi:10.1093/carcin/14.12.2581.

    PubMed  CAS  Google Scholar 

  138. Bialik S, Kimchi A. Autophagy and tumor suppression: recent advances in understanding the link between autophagic cell death pathways and tumor development. Adv Exp Med Biol 2008;615:177–200. doi:10.1007/978-1-4020-6554-5_9.

    PubMed  Google Scholar 

  139. Lee HK, Jones RT, Myers RA, Marzella L. Regulation of protein degradation in normal and transformed human bronchial epithelial cells in culture. Arch Biochem Biophys 1992;296:271–8. doi:10.1016/0003-9861(92)90572-E.

    PubMed  CAS  Google Scholar 

  140. Houri JJ, Ogier-Denis E, De Stefanis D, Bauvy C, Baccino FM, Isidoro C, et al. Differentiation-dependent autophagy controls the fate of newly synthesized N-linked glycoproteins in the colon adenocarcinoma HT-29 cell line. Biochem J 1995;309 Pt 2:521–7.

    PubMed  Google Scholar 

  141. Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res 2007;67:9677–84. doi:10.1158/0008-5472.CAN-07-1462.

    PubMed  CAS  Google Scholar 

  142. Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, et al. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 2008;99:1813–9.

    PubMed  CAS  Google Scholar 

  143. Cuervo AM. Autophagy: in sickness and in health. Trends Cell Biol 2004;14:70–7. doi:10.1016/j.tcb.2003.12.002.

    PubMed  Google Scholar 

  144. Lefranc F, Facchini V, Kiss R. Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 2007;12:1395–403. doi:10.1634/theoncologist.12-12-1395.

    PubMed  CAS  Google Scholar 

  145. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2002;2:38–47. doi:10.1038/nrc704.

    PubMed  CAS  Google Scholar 

  146. Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9:685–93. doi:10.1038/nm0603-685.

    PubMed  CAS  Google Scholar 

  147. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001;18:243–59. doi:10.1385/MO:18:4:243.

    PubMed  CAS  Google Scholar 

  148. Levine B. Cell biology: autophagy and cancer. Nature 2007;446:745–7. doi:10.1038/446745.

    PubMed  CAS  Google Scholar 

  149. Ogier-Denis E, Codogno P. Autophagy: a barrier or an adaptive response to cancer. Biochim Biophys Acta 2003;1603:113–28.

    PubMed  CAS  Google Scholar 

  150. Karantza-Wadsworth V, White E. Role of autophagy in breast cancer. Autophagy 2007;3:610–3.

    PubMed  CAS  Google Scholar 

  151. Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Investig Drugs 2008;17:1947–54. doi:10.1517/13543780802556485.

    PubMed  CAS  Google Scholar 

  152. Malizzia LJ, Hsu A. Temsirolimus, an mTOR inhibitor for treatment of patients with advanced renal cell carcinoma. Clin J Oncol Nurs 2008;12:639–46. doi:10.1188/08.CJON.639-646.

    PubMed  Google Scholar 

  153. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–56. doi:10.1016/S0140-6736(08)61039-9.

    PubMed  CAS  Google Scholar 

  154. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008;26:361–7. doi:10.1200/JCO.2007.12.0345.

    PubMed  CAS  Google Scholar 

  155. Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008;14:2756–62. doi:10.1158/1078-0432.CCR-07-1372.

    PubMed  CAS  Google Scholar 

  156. Katayama M, Kawaguchi T, Berger MS, Pieper RO. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ 2007;14:548–58. doi:10.1038/sj.cdd.4402030.

    PubMed  CAS  Google Scholar 

  157. Yokoyama T, Iwado E, Kondo Y, Aoki H, Hayashi Y, Georgescu MM, et al. Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Ther 2008;15:1233–9. doi:10.1038/gt.2008.98.

    PubMed  CAS  Google Scholar 

  158. Milano V, Piao Y, LaFortune T, de Groot J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol Cancer Ther 2009;8:394–406. doi:10.1158/1535-7163.MCT-08-0669.

    PubMed  CAS  Google Scholar 

  159. Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004;11:448–57. doi:10.1038/sj.cdd.4401359.

    PubMed  CAS  Google Scholar 

  160. Naumann SC, Roos WP, Jost E, Belohlavek C, Lennerz V, Schmidt CW, et al. Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53. Br J Cancer 2009;100:322–33. doi:10.1038/sj.bjc.6604856.

    PubMed  CAS  Google Scholar 

  161. Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K. Temozolomide for high grade glioma. Cochrane Database Syst Rev 2008. (4):CD007415.

  162. Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 2009;27:579–84. doi:10.1200/JCO.2008.18.9639.

    PubMed  CAS  Google Scholar 

  163. Kouroussis C, Vamvakas L, Vardakis N, Kotsakis A, Kalykaki A, Kalbakis K, et al. Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study. Oncology 2009;76:112–7. doi:10.1159/000192586.

    PubMed  CAS  Google Scholar 

  164. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008;7:1851–63. doi:10.1158/1535-7163.MCT-08-0017.

    PubMed  CAS  Google Scholar 

  165. Schnell CR, Stauffer F, Allegrini PR, O’Reilly T, McSheehy PM, Dartois C, et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008;68:6598–607. doi:10.1158/0008-5472.CAN-08-1044.

    PubMed  CAS  Google Scholar 

  166. Cao P, Maira SM, Garcia-Echeverria C, Hedley DW. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer 2009;100:1267–76.

    PubMed  CAS  Google Scholar 

  167. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008;68:8022–30. doi:10.1158/0008-5472.CAN-08-1385.

    PubMed  CAS  Google Scholar 

  168. Shingu T, Fujiwara K, Bogler O, Akiyama Y, Moritake K, Shinojima N, et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int J Cancer 2009;124:1060–71. doi:10.1002/ijc.24030.

    PubMed  CAS  Google Scholar 

  169. McLean K, Vandeven NA, Sorenson DR, Daudi S, Liu JR. The HIV protease inhibitor saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells. Gynecol Oncol 2009;112:623–30.

    PubMed  CAS  Google Scholar 

  170. Liu B, Cheng Y, Bian HJ, Bao JK. Molecular mechanisms of Polygonatum cyrtonema lectin-induced apoptosis and autophagy in cancer cells. Autophagy 2009;5:253–5.

    PubMed  Google Scholar 

  171. Moretti L, Cha YI, Niermann KJ, Lu B. Switch between apoptosis and autophagy: radiation-induced endoplasmic reticulum stress? Cell Cycle 2007;6:793–8.

    PubMed  CAS  Google Scholar 

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The main author’s work is supported by the SAGA grant by the Academy of Sciences Malaysia and the Sciencefund grant by MOSTI, Malaysia.

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Tan, M.L., Ooi, J.P., Ismail, N. et al. Programmed Cell Death Pathways and Current Antitumor Targets. Pharm Res 26, 1547–1560 (2009). https://doi.org/10.1007/s11095-009-9895-1

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