Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

  • Goldar, Samira ;
  • Khaniani, Mahmoud Shekari ;
  • Derakhshan, Sima Mansoori ;
  • Baradaran, Behzad
  • Published : 2015.04.03


Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.


Apoptosis;apoptotic pathways;cancer;treatment target


  1. Abedini MR, Muller EJ, Brun J, et al (2008). Cisplatin induces p53-dependent FLICE-like inhibitory protein ubiquitination in ovarian cancer cells. Cancer Res, 68, 4511-7.
  2. Acehan D, Jiang X, Morgan DG, et al (2002). Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell, 9, 423-32.
  3. Albershardt TC, Salerni BL, Soderquist RS, et al (2011). Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem, 286, 24882-95.
  4. Allegra D, Bilan V, Garding A, et al (2014). Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia. Leukemia, 28, 2427.
  5. Antonia SJ, Mirza N, Fricke I, et al (2006). Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res, 12, 878-87.
  6. Arbel N, Ben-Hail D, Shoshan-Barmatz V (2012). Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem, 287, 23152-61.
  7. Aron JL, Parthun MR, Marcucci G, et al (2003). Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood, 102, 652-8.
  8. Ashkenazi A, Pai RC, Fong S, et al (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest, 104, 155-62.
  9. Atencio IA, Grace M, Bordens R, et al (2006). Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial. Cancer Gene Ther, 13, 169-81.
  10. Azmi AS, Mohammad RM (2009). Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol, 218, 13-21.
  11. Baron AT, O'Bryant CL,Choi Y, et al (2011). Phase Ib study of drozitumab combined with cetuximab (CET) plus irinotecan (IRI) or with FOLFIRI+/-bevacizumab (BV) in previously treated patients (Pts) with metastatic colorectal cancer (mCRC). J Clin Oncol, 29, [Epub ahead of print].
  12. Bartholomeusz C, Itamochi H, Yuan LX, et al (2005). Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapy in a low HER2-expressing ovarian cancer xenograft model. Cancer Res, 65, 8406-13.
  13. Baud V, Karin M (2009). Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov, 8, 33-40.
  14. Bijangi-Vishehsaraei K, Saadatzadeh MR, Huang S, et al (2010). 4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells. Mol Cell Biochem, 342, 133-42.
  15. Boatright KM, Renatus M, Scott FL, et al (2003). A unified model for apical caspase activation. Mol Cell, 11, 529-41.
  16. Boeckler FM, Joerger AC, Jaggi G, et al (2008). Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci U S A, 105, 10360-5.
  17. Bose P, Grant S (2013). Mcl-1 as a Therapeutic Target in Acute Myelogenous Leukemia (AML). Leuk Res Rep, 2, 12-4.
  18. Bykov VJ, Issaeva N, Zache N, et al (2005a). Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem, 280, 30384-91.
  19. Bykov VJ, Wiman KG (2014). Mutant p53 reactivation by small molecules makes its way to the clinic. FEBS Lett, 588, 2622-7.
  20. Bykov VJ, Zache N, Stridh H, et al (2005b). PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis. Oncogene, 24, 3484-91.
  21. Calin GA, Cimmino A, Fabbri M, et al (2008). MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A, 105, 5166-71.
  22. Carter BZ, Mak DH, Morris SJ, et al (2011). XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34+38- cells in a phase 1/2 study of patients with relapsed/refractory AML. Apoptosis, 16, 67-74.
  23. Chang DW, Xing Z, Pan Y, et al (2002). c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. Embo J, 21, 3704-14.
  24. Chatterjee D, Schmitz I, Krueger A, et al (2001). Induction of apoptosis in 9-nitrocamptothecin-treated DU145 human prostate carcinoma cells correlates with de novo synthesis of CD95 and CD95 ligand and down-regulation of c-FLIP(short). Cancer Res, 61, 7148-54.
  25. Chauhan D, Velankar M, Brahmandam M, et al (2007). A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene, 26, 2374-80.
  26. Chen Y, Gao DY, Huang L (2014). In vivo delivery of miRNAs for cancer therapy: Challenges and strategies. Adv Drug Deliv Rev, 81, 128-41
  27. Cheng Q, Ling X, Haller A, et al (2012). Suppression of survivin promoter activity by YM155 involves disruption of Sp1-DNA interaction in the survivin core promoter. Int J Biochem Mol Biol, 3, 179-97.
  28. Chi KN, Gleave ME, Klasa R, et al (2001). A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin Cancer Res, 7, 3920-7.
  29. Chi SW (2014). Structural insights into the transcription-independent apoptotic pathway of p53. BMB Rep, 47, 167-72.
  30. Chipuk JE, Bouchier-Hayes L, Green DR (2006). Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ, 13, 1396-402.
  31. Chipuk JE, Kuwana T, Bouchier-Hayes L, et al (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science, 303, 1010-4.
  32. Chu ZL, McKinsey TA, Liu L, et al (1997). Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci U S A, 94, 10057-62.
  33. Cimmino A, Calin GA, Fabbri M, et al (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A, 102, 13944-9.
  34. Cohen EE, Rudin CM (2001). ONYX-015. Onyx Pharmaceuticals. Curr Opin Investig Drugs, 2, 1770-5.
  35. Croce CM (2009). Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet, 10, 704-14.
  36. Croci DO, Cogno IS, Vittar NB, et al (2008). Silencing survivin gene expression promotes apoptosis of human breast cancer cells through a caspase-independent pathway. J Cell Biochem, 105, 381-90.
  37. Czabotar PE, Lessene G, Strasser A, et al (2014). Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol, 15, 49-63.
  38. Dai DJ, Lu CD, Lai RY, et al (2005). Survivin antisense compound inhibits proliferation and promotes apoptosis in liver cancer cells. World J Gastroenterol, 11, 193-9.
  39. Dai Y, Liu M, Tang W, et al (2008). Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis. Clin Cancer Res, 14, 7701-10.
  40. Dai Y, Liu M, Tang W, et al (2009). A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB. BMC Cancer, 9, 392.
  41. Day TW, Safa AR (2009). RNA interference in cancer: targeting the anti-apoptotic protein c-FLIP for drug discovery. Mini Rev Med Chem, 9, 741-8.
  42. de Almagro MC, Vucic D (2012). The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol, 34, 200-11.
  43. De Cesare M, Perego P, Righetti SC, et al (2005). Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts. Eur J Cancer, 41, 1213-22.
  44. Demma M, Maxwell E, Ramos R, et al (2010). SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem, 285, 10198-212.
  45. Devarajan E, Sahin AA, Chen JS, et al (2002). Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene, 21, 8843-51.
  46. Dineen SP, Roland CL, Greer R, et al (2010). Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. Cancer Res, 70, 2852-61.
  47. Duan H, Heckman CA, Boxer LM (2005). Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol, 25, 1608-19.
  48. Dubrez L, Berthelet J, Glorian V (2013). IAP proteins as targets for drug development in oncology. Onco Targets Ther, 9, 1285-304.
  49. Duggan BJ, Maxwell P, Kelly JD, et al (2001). The effect of antisense Bcl-2 oligonucleotides on Bcl-2 protein expression and apoptosis in human bladder transitional cell carcinoma. J Urol, 166, 1098-105.
  50. Eckelman BP, Salvesen GS, Scott FL (2006). Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep, 7, 988-94.
  51. Elmore S (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol, 35, 495-516.
  52. Emi M, Kim R, Tanabe K, et al (2005). Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res, 7, 940-52.
  53. Feng W, Zhang B, Cai D, et al (2014). Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer. Cancer Lett, 347, 183-90.
  54. Fong PY, Xue WC, Ngan HY, et al (2006). Caspase activity is downregulated in choriocarcinoma: a cDNA array differential expression study. J Clin Pathol, 59, 179-83.
  55. Fulda S (2009). Tumor resistance to apoptosis. Int J Cancer, 124, 511-5.
  56. Fulda S (2010). Evasion of apoptosis as a cellular stress response in cancer. Int J Cell Biol, 2010, 370835.
  57. Fulda S (2014). Molecular pathways: targeting inhibitor of apoptosis proteins in cancer-from molecular mechanism to therapeutic application. Clin Cancer Res, 20, 289-95.
  58. Fulda S, Debatin KM (2006). 5-Aza-2'-deoxycytidine and IFN-gamma cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8. Oncogene, 25, 5125-33.
  59. Galligan L, Longley DB, McEwan M, et al (2005). Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP. Mol Cancer Ther, 4, 2026-36.
  60. Galluzzi L, Morselli E, Kepp O, et al (2010). Mitochondrial gateways to cancer. Mol Aspects Med, 31, 1-20.
  61. Garofalo M, Condorelli GL, Croce CM, et al (2010). MicroRNAs as regulators of death receptors signaling. Cell Death Differ, 17, 200-8.
  62. Garofalo M, Croce CM (2011). microRNAs: Master regulators as potential therapeutics in cancer. Annu Rev Pharmacol Toxicol, 51, 25-43.
  63. Garofalo M, Quintavalle C, Di Leva G, et al (2008). MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene, 27, 3845-55.
  64. Giaccone G, Zatloukal P, Roubec J, et al (2009). Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J Clin Oncol, 27, 4481-6.
  65. Green DR, Evan GI (2002). A matter of life and death. Cancer Cell, 1, 19-30.
  66. Greer RM, Peyton M, Larsen JE, et al (2011). SMAC mimetic (JP1201) sensitizes non-small cell lung cancers to multiple chemotherapy agents in an IAP-dependent but TNF-alpha-independent manner. Cancer Res, 71, 7640-8.
  67. Grillier-Vuissoz, Isabelle ea (2012). $PPAR{\gamma}$-independent Activity of Thiazolidinediones: A Promising Mechanism of Action for New Anticancer Drugs. J Carcinogene Mutagene
  68. Guicciardi ME, Gores GJ (2009). Life and death by death receptors. FASEB J, 23, 1625-37.
  69. Gustafsson AB, Gottlieb RA (2008). Heart mitochondria: gates of life and death. Cardiovasc Res, 77, 334-43.
  70. Hamanaka RB, Bobrovnikova-Marjon E, Ji X, et al (2009). PERK-dependent regulation of IAP translation during ER stress. Oncogene, 28, 910-20.
  71. Hassan M, Watari H, AbuAlmaaty A, et al (2014). Apoptosis and molecular targeting therapy in cancer. Biomed Res Int, 2014, 150845.
  72. Hassen S, Ali N, Chowdhury P (2012). Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer. World J Gastrointest Pathophysiol, 3, 71-9.
  73. Hawkins CJ, Silke J, Verhagen AM, et al (2001). Analysis of candidate antagonists of IAP-mediated caspase inhibition using yeast reconstituted with the mammalian Apaf-1-activated apoptosis mechanism. Apoptosis, 6, 331-8.
  74. Hernandez A, Wang QD, Schwartz SA, et al (2001). Sensitization of human colon cancer cells to TRAIL-mediated apoptosis. J Gastrointest Surg, 5, 56-65.
  75. Herrero Martin D, Boro A, Schafer BW (2013). Cell-based small-molecule compound screen identifies fenretinide as potential therapeutic for translocation-positive rhabdomyosarcoma. PLoS One, 8, 55072.
  76. Hinds MG, Norton RS, Vaux DL, et al (1999). Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol, 6, 648-51.
  77. Hong B, van den Heuvel AP, Prabhu VV, et al (2014). Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities. Curr Drug Targets, 15, 80-9.
  78. Hotte SJ, Hirte HW, Chen EX, et al (2008). A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res, 14, 3450-5.
  79. Hu Q, Wu D, Chen W, et al (2013). Proteolytic processing of the caspase-9 zymogen is required for apoptosome-mediated activation of caspase-9. J Biol Chem, 288, 15142-7.
  80. Hu Y, Bebb G, Tan S, et al (2004). Antitumor efficacy of oblimersen Bcl-2 antisense oligonucleotide alone and in combination with vinorelbine in xenograft models of human non-small cell lung cancer. Clin Cancer Res, 10, 7662-70.
  81. Huerta S, Gao X, Livingston EH, et al (2010). In vitro and in vivo radiosensitization of colorectal cancer HT-29 cells by the smac mimetic JP-1201. Surgery, 148, 346-53.
  82. Iancu-Rubin C, Mosoyan G, Glenn K, et al (2014). Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp Hematol, 42, 137-45.
  83. Ichikawa K, Liu W, Zhao L, et al (2001). Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med, 7, 954-60.
  84. Jin Z, El-Deiry WS (2005). Overview of cell death signaling pathways. Cancer Biol Ther, 4, 139-63.
  85. Kaminskyy VO, Surova OV, Piskunova T, et al (2013). Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling. Cell Death Dis, 4, 522.
  86. Kang MH, Reynolds CP (2009). Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res, 15, 1126-32.
  87. Kapoor P, Ramakrishnan V, Rajkumar SV (2012). Bortezomib combination therapy in multiple myeloma. Semin Hematol, 49, 228-42.
  88. Karami H, Baradaran B, Esfahani A, et al (2013). siRNA-mediated silencing of survivin inhibits proliferation and enhances etoposide chemosensitivity in acute myeloid leukemia cells. Asian Pac J Cancer Prev, 14, 7719-24.
  89. Karami H, Baradaran B, Esfehani A, et al (2014). Down-regulation of Mcl-1 by small interference RNA induces apoptosis and sensitizes HL-60 leukemia cells to etoposide. Asian Pac J Cancer Prev, 15, 629-35.
  90. Kerr E, Holohan C, McLaughlin KM, et al (2012). Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ, 19, 1317-27.
  91. Kerr JF, Wyllie AH, Currie AR (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26, 239-57.
  92. Khan KH, Blanco-Codesido M, Molife LR (2014). Cancer therapeutics: Targeting the apoptotic pathway. Crit Rev Oncol Hematol, 90, 200-19.
  93. Khosravi-Far R, Esposti MD (2004). Death receptor signals to mitochondria. Cancer Biol Ther, 3, 1051-7.
  94. Kinoshita H, Yoshikawa H, Shiiki K, et al (2000). Cisplatin (CDDP) sensitizes human osteosarcoma cell to Fas/CD95-mediated apoptosis by down-regulating FLIP-L expression. Int J Cancer, 88, 986-91.<986::AID-IJC23>3.0.CO;2-B
  95. Kitada S, Zapata JM, Andreeff M, et al (2000). Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood, 96, 393-7.
  96. Koschny R, Holland H, Sykora J, et al (2007). Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res, 13, 3403-12.
  97. Kroemer G, Dallaporta B, Resche-Rigon M (1998). The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol, 60, 619-42.
  98. Kuball J, Schuler M, Antunes Ferreira E, et al (2002). Generating p53-specific cytotoxic T lymphocytes by recombinant adenoviral vector-based vaccination in mice, but not man. Gene Ther, 9, 833-43.
  99. Kudchadkar R, Ernst S, Chmielowski B, et al (2014). A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. Cancer Med [Epub ahead of print].
  100. Lau R, Pratt MA (2012). The opposing roles of cellular inhibitor of apoptosis proteins in cancer. ISRN Oncol, 2012, 928120.
  101. Leffers N, Lambeck AJ, Gooden MJ, et al (2009). Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial. Int J Cancer, 125, 2104-13.
  102. Lehmann S, Bykov VJ, Ali D, et al (2012). Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol, 30, 3633-9.
  103. Leonetti C, Biroccio A, D'Angelo C, et al (2007). Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer. Prostate, 67, 1475-85.
  104. Li J, Yuan J (2008). Caspases in apoptosis and beyond. Oncogene, 27, 6194-206.
  105. Li LY, Luo X, Wang X (2001). Endonuclease G is an apoptotic DNase when released from mitochondria. Nature, 412, 95-9.
  106. Liedtke C, Zschemisch NH, Cohrs A, et al (2005). Silencing of caspase-8 in murine hepatocellular carcinomas is mediated via methylation of an essential promoter element. Gastroenterology, 129, 1602-15.
  107. Lima RT, Busacca S, Almeida GM, et al (2011). MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer, 47, 163-74.
  108. Liu G, Kelly WK, Wilding G, et al (2009). An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res, 15, 3172-6.
  109. Liu Z, Li H, Derouet M, et al (2005). ras Oncogene triggers up-regulation of cIAP2 and XIAP in intestinal epithelial cells: epidermal growth factor receptor-dependent and -independent mechanisms of ras-induced transformation. J Biol Chem, 280, 37383-92.
  110. Liu Z, Li H, Wu X, et al (2006). Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells. Oncogene, 25, 7680-90.
  111. Longley DB, Wilson TR, McEwan M, et al (2006). c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene, 25, 838-48.
  112. Lu J, McEachern D, Sun H, et al (2011). Therapeutic potential and molecular mechanism of a novel, potent, nonpeptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatment. Mol Cancer Ther, 10, 902-14.
  113. Lucas DM, Davis ME, Parthun MR, et al (2004). The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia, 18, 1207-14.
  114. Martinez-Caballero S, Dejean LM, Kinnally MS, et al (2009). Assembly of the mitochondrial apoptosis-induced channel, MAC. J Biol Chem, 284, 12235-45.
  115. Matthew S. Davids M (2013). The single-agent Bcl-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-hodgkin lymphoma (NHL): responses observed in all mantle cell lymphoma (MCL) patients. american society of hematology [Epub ahead of print].
  116. Mawji IA, Simpson CD, Gronda M, et al (2007a). A chemical screen identifies anisomycin as an anoikis sensitizer that functions by decreasing FLIP protein synthesis. Cancer Res, 67, 8307-15.
  117. Mawji IA, Simpson CD, Hurren R, et al (2007b). Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation. J Natl Cancer Inst, 99, 811-22.
  118. Menon AG, Kuppen PJ, van der Burg SH, et al (2003). Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients. Cancer Gene Ther, 10, 509-17.
  119. Micheau O (2003). Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert Opin Ther Targets, 7, 559-73.
  120. Micheau O, Lens S, Gaide O, et al (2001). NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol, 21, 5299-305.
  121. Min KJ, Seo BR, Bae YC, et al (2014). Antipsychotic agent thioridazine sensitizes renal carcinoma Caki cells to TRAIL-induced apoptosis through reactive oxygen species-mediated inhibition of Akt signaling and downregulation of Mcl-1 and c-FLIP(L). Cell Death Dis, 5, 1063.
  122. Mirza A, McGuirk M, Hockenberry TN, et al (2002). Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 21, 2613-22.
  123. Mukhopadhyay S, Panda PK, Sinha N, et al (2014). Autophagy and apoptosis: where do they meet? Apoptosis, 19, 555-66.
  124. Nakahara T, Kita A, Yamanaka K, et al (2007). YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res, 67, 8014-21.
  125. Nemunaitis J, Ganly I, Khuri F, et al (2000). Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. Cancer Res, 60, 6359-66.
  126. O'Brien S, Moore J, Boyd T, et al (2009). 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol, 5208-12.
  127. Oliner JD, Pietenpol JA, Thiagalingam S, et al (1993). Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature, 362, 857-60.
  128. Oltersdorf T, Elmore SW, Shoemaker AR, et al (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 435, 677-81.
  129. Ouyang L, Shi Z, Zhao S, et al (2012). Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif, 45, 487-98.
  130. P: C (2001). p53 as a drug target in cancer therapy. Expert Opin Ther Patents, 923-35.
  131. Park SJ, Kim MJ, Kim HB, et al (2009). Trichostatin a sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by down-regulation of c-FLIPL via inhibition of EGFR pathway. Biochem Pharmacol, 77, 1328-36.
  132. Pathil A, Armeanu S, Venturelli S, et al (2006). HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology, 43, 425-34.
  133. Pei XY, Dai Y, Grant S (2004). 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, 3, 1513-24.
  134. Perez LE, Parquet N, Meads M, et al (2010). Bortezomib restores stroma-mediated APO2L/TRAIL apoptosis resistance in multiple myeloma. Eur J Haematol, 84, 212-22.
  135. Philchenkov A, Zavelevich M, Kroczak TJ, et al (2004). Caspases and cancer: mechanisms of inactivation and new treatment modalities. Exp Oncol, 26, 82-97.
  136. Plati J, Bucur O, Khosravi-Far R (2011). Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb), 3, 279-96.
  137. Prezma T, Shteinfer A, Admoni L, et al (2013). VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia. Cell Death Dis, 4, 809.
  138. Qiu J, Gao Z, Shima H (2012). Growth of human prostate cancer cells is significantly suppressed in vitro with sodium butyrate through apoptosis. Oncol Rep, 27, 160-7.
  139. Rao-Bindal K, Koshkina NV, Stewart J, et al (2013). The histone deacetylase inhibitor, MS-275 (entinostat), downregulates c-FLIP, sensitizes osteosarcoma cells to FasL, and induces the regression of osteosarcoma lung metastases. Curr Cancer Drug Targets, 13, 411-22.
  140. Reesink-Peters N, Hougardy BM, van den Heuvel FA, et al (2005). Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study. Gynecol Oncol, 96, 705-13.
  141. Riley JS, Hutchinson R, McArt DG, et al (2013). Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell Death Dis, 4, 951.
  142. Rohn JL, Noteborn MH (2004). The viral death effector Apoptin reveals tumor-specific processes. Apoptosis, 9, 315-22.
  143. Rossi MN, Antonangeli F (2014). LncRNAs: New Players in Apoptosis Control. Intern J Cell Biology, 2014.
  144. Roy MJ, Vom A, Czabotar PE, et al (2014). Cell death and the mitochondria: therapeutic targeting of the BCL-2 family-driven pathway. Br J Pharmacol, 171, 1973-87.
  145. Rudin CM, Hann CL, Garon EB, et al (2012). Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res, 18, 3163-9.
  146. Safa AR, Day TW, Wu CH (2008). Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets, 8, 37-46.
  147. Safa AR, Pollok KE (2011). Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers (Basel), 3, 1639-71.
  148. Saleem M, Qadir MI, Perveen N, et al (2013). Inhibitors of apoptotic proteins: new targets for anticancer therapy. Chem Biol Drug Des, 82, 243-51.
  149. Schimmer AD, Thomas MP, Hurren R, et al (2006). Identification of small molecules that sensitize resistant tumor cells to tumor necrosis factor-family death receptors. Cancer Res, 66, 2367-75.
  150. Sevrioukova IF (2011). Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal, 14, 2545-79.
  151. Sharma S, de Vries EG, Infante JR, et al (2014). Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors. Invest New Drugs, 32, 135-44.
  152. Shiau CW, Yang CC, Kulp SK, et al (2005). Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma. Cancer Res, 65, 1561-9.
  153. Shin H, Lee YS, Lee YC (2012a). Sodium butyrate-induced DAPK-mediated apoptosis in human gastric cancer cells. Oncol Rep, 27, 1111-5.
  154. Shin JS, Ha JH, Chi SW (2014). Targeting of p53 peptide analogues to anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy. Biochem Biophys Res Commun, 443, 882-7.
  155. Shin JS, Ha JH, He F, et al (2012b). Structural insights into the dual-targeting mechanism of Nutlin-3. Biochem Biophys Res Commun, 420, 48-53.
  156. Shirley S, Micheau O (2013). Targeting c-FLIP in cancer. Cancer Lett, 332, 141-50.
  157. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, et al (2010). VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med, 31, 227-85.
  158. Shoshan-Barmatz V, Mizrachi D (2012). VDAC1: from structure to cancer therapy. Front Oncol, 2, 164.
  159. Sikic BI et al (2007,). A phase Ib study toassess the safety of lexatumumab, a human monoclonal antibody thatactivates TRAIL-R2, in combination with gemcitabine, pemetrexed,doxorubicin or FOLFIRI.
  160. Singh R, Saini N (2012). Downregulation of BCL2 by miRNAs augments drug-induced apoptosis-a combined computational and experimental approach. J Cell Sci, 125, 1568-78.
  161. Song JH, Song DK, Herlyn M, et al (2003). Cisplatin down-regulation of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-like inhibitory proteins to restore tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human melanoma cells. Clin Cancer Res, 9, 4255-66.
  162. Sosin AM, Burger AM, Siddiqi A, et al (2012). HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol, 5, 57.
  163. Speetjens FM, Kuppen PJ, Welters MJ, et al (2009). Induction of p53-specific immunity by a p53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin Cancer Res, 15, 1086-95.
  164. Spierings DC, de Vries EG, Vellenga E, et al (2004). Tissue distribution of the death ligand TRAIL and its receptors. J Histochem Cytochem, 52, 821-31.
  165. Subramaniam K, Hirpara JL, Tucker-Kellogg L, et al (2013). FLIP: a flop for execution signals. Cancer Lett, 332, 151-5.
  166. Sun H, Kapuria V, Peterson LF, et al (2011). Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood, 117, 3151-62.
  167. Sun H, Liu L, Lu J, et al (2010). Cyclopeptide Smac mimetics as antagonists of IAP proteins. Bioorg Med Chem Lett, 20, 3043-6.
  168. Sun Y, Peng ZL (2009). Programmed cell death and cancer. Postgrad Med J, 85, 134-40.
  169. Sung B, Park B, Yadav VR, et al (2010). Celastrol, a triterpene, enhances TRAIL-induced apoptosis through the down-regulation of cell survival proteins and up-regulation of death receptors. J Biol Chem, 285, 11498-507.
  170. Svane IM, Pedersen AE, Johansen JS, et al (2007). Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers. Cancer Immunol Immunother, 56, 1485-99.
  171. Svane IM, Pedersen AE, Johnsen HE, et al (2004). Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother, 53, 633-41.
  172. Szegezdi E, Logue SE, Gorman AM, et al (2006). Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep, 7, 880-5.
  173. Tabernero J, Dirix L, Schoffski P, et al (2011). A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors. Clin Cancer Res, 17, 6313-21.
  174. Tagscherer KE, Fassl A, Campos B, et al (2008). Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene, 27, 6646-56.
  175. Tajeddine N, Galluzzi L, Kepp O, et al (2008). Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death. Oncogene, 27, 4221-32.
  176. Tanioka M, Nokihara H, Yamamoto N, et al (2011). Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors. Cancer Chemother Pharmacol, 68, 505-11.
  177. Tchoghandjian A, Jennewein C, Eckhardt I, et al (2013). Identification of non-canonical NF-kappaB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells. Cell Death Dis, 4, 564.
  178. Tiberio P, Cavadini E, Abolafio G, et al (2010). 4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells. PLoS One, 5, 13362.
  179. Tolcher AW, Mita M, Meropol NJ, et al (2007). Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol, 25, 1390-5.
  180. Tolcher AW, Quinn DI, Ferrari A, et al (2012). A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer. Ann Oncol, 23, 968-73.
  181. Touzeau C, Dousset C, Le Gouill S, et al (2014). The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia, 28, 210-2.
  182. Travert M, Ame-Thomas P, Pangault C, et al (2008). CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL. J Immunol, 181, 1001-11.
  183. Trudel S, Stewart AK, Li Z, et al (2007). The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res, 13, 621-9.
  184. Vaillant F, Merino D, Lee L, et al (2013). Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell, 24, 120-9.
  185. Van Poznak C, Seidman AD, Reidenberg MM, et al (2001). Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat, 66, 239-48.
  186. Vande Walle L, Lamkanfi M, Vandenabeele P (2008). The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ, 15, 453-60.
  187. Varfolomeev E, Blankenship JW, Wayson SM, et al (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell, 131, 669-81.
  188. Venza I, Visalli M, Oteri R, et al (2014). Class I-specific histone deacetylase inhibitor MS-275 overrides TRAIL-resistance in melanoma cells by downregulating c-FLIP. Int Immunopharmacol, 21, 439-46.
  189. Vermeij R, Leffers N, van der Burg SH, et al (2011). Immunological and clinical effects of vaccines targeting p53-overexpressing malignancies. J Biomed Biotechnol, 2011, 702146.
  190. Vici P, Mariani L, Pizzuti L, et al (2014). Emerging biological treatments for uterine cervical carcinoma. J Cancer, 5, 86-97.
  191. Wacheck V, Heere-Ress E, Halaschek-Wiener J, et al (2001). Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model. J Mol Med (Berl), 79, 587-93.
  192. Wakelee HA, Patnaik A, Sikic BI, et al (2010). Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol, 21, 376-81.
  193. Wang S, Zhao Y, Bernard D, et al (2012). Targeting the MDM2-p53 protein-protein interaction for new cancer therapeutics. Springer Berlin Heidelberg??, 57-79.
  194. Wang Y, Lee CG (2009). MicroRNA and cancer--focus on apoptosis. J Cell Mol Med, 13, 12-23.
  195. Watanabe K, Okamoto K, Yonehara S (2005). Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Cell Death Differ, 12, 10-8.
  196. Wea RA (2012). Selective inhibition of BCL-2 is active against chronic lymphocytic leukemia (CLL): first clinical experience with the BH3-mimetic ABT-199. Haematologica, 97, 257-8.
  197. Wei Y, Fan T, Yu M (2008). Inhibitor of apoptosis proteins and apoptosis. Acta Biochim Biophys Sin (Shanghai), 40, 278-88.
  198. Weyhenmeyer B, Murphy AC, Prehn JH, et al (2012). Targeting the anti-apoptotic Bcl-2 family members for the treatment of cancer. Exp Oncol, 34, 192-9.
  199. Whitehead KA, Langer R, Anderson DG (2009). Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov, 8, 129-38.
  200. Wright CW, Duckett CS (2005). Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function. J Clin Invest, 115, 2673-8.
  201. Wu HH, Wu JY, Cheng YW, et al (2010). cIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancer. Clin Cancer Res, 16, 5200-10.
  202. Wuilleme-Toumi S, Robillard N, Gomez P, et al (2005). Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia, 19, 1248-52.
  203. Xiao C, Srinivasan L, Calado DP, et al (2008). Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol, 9, 405-14.
  204. Yamabe K, Shimizu S, Ito T, et al (1999). Cancer gene therapy using a pro-apoptotic gene, caspase-3. Gene Ther, 6, 1952-9.
  205. Yang L, Cao Z, Yan H, et al (2003). Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res, 63, 6815-24.
  206. Yerbes R, Lopez-Rivas A (2012). Itch/AIP4-independent proteasomal degradation of cFLIP induced by the histone deacetylase inhibitor SAHA sensitizes breast tumour cells to TRAIL. Invest New Drugs, 30, 541-7.
  207. Yuan S, Akey CW (2013). Apoptosome structure, assembly, and procaspase activation. Structure, 21, 501-15.
  208. Zhang S, Ding F, Luo A, et al (2007). XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics. Cancer Biol Ther, 6, 973-80.
  209. Zhuang J, Laing N, Oates M, et al (2014). Selective IAP inhibition results in sensitization of unstimulated but not CD40-stimulated chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis. Pharmacology Res Perspect, 2, 6.
  210. Zou H, Henzel WJ, Liu X, et al (1997). Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell, 90, 405-13.

Cited by

  1. T cells vol.11, pp.11, 2015,
  2. Berberine induces apoptosis by suppressing the arachidonic acid metabolic pathway in hepatocellular carcinoma vol.12, pp.3, 2015,
  3. Molecular Links between Alcohol and Tobacco Induced DNA Damage, Gene Polymorphisms and Patho-physiological Consequences: A Systematic Review of Hepatic Carcinogenesis vol.16, pp.12, 2015,
  4. Nuclear DNA Damage and Repair in Normal Ovarian Cells Caused by Epothilone B vol.16, pp.15, 2015,
  5. Inhibition of B-cell apoptosis is mediated through increased expression of Bcl-2 in patients with rheumatoid arthritis vol.19, pp.2, 2015,
  6. -Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells vol.30, pp.4, 2015,
  7. In vitro evaluation of the anti-apoptotic drug Z-VAD-FMK on human ovarian granulosa cell lines for further use in ovarian tissue transplantation vol.32, pp.10, 2015,
  8. CD90 is upregulated in gastric cancer tissues and inhibits gastric cancer cell apoptosis by modulating the expression level of SPARC protein vol.34, pp.5, 2015,
  9. Fra-1 is upregulated in lung cancer tissues and inhibits the apoptosis of lung cancer cells by the P53 signaling pathway vol.35, pp.1, 2015,
  10. Suppression of c-FLIPL promotes JNK activation in malignant melanoma cells vol.13, pp.3, 2016,
  11. Lycopene inhibits the cell proliferation and invasion of human head and neck squamous cell carcinoma vol.14, pp.4, 2016,
  12. Early Activation of Apoptosis and Caspase-independent Cell Death Plays an Important Role in Mediating the Cytotoxic and Genotoxic Effects of WP 631 in Ovarian Cancer Cells vol.16, pp.18, 2016,
  13. Combination Therapy with AKT3 and PI3KCA siRNA Enhances the Antitumor Effect of Temozolomide and Carmustine in T98G Glioblastoma Multiforme Cells vol.30, pp.2, 2016,
  14. Regulation of cell apoptosis and proliferation in pancreatic cancer through PI3K/Akt pathway via Polo-like kinase 1 vol.36, pp.1, 2016,
  15. Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis vol.36, pp.6, 2016,
  16. Influence of the interaction between long noncoding RNAs and hypoxia on tumorigenesis vol.37, pp.2, 2016,
  17. Upregulated LASP-1 correlates with a malignant phenotype and its potential therapeutic role in human cholangiocarcinoma vol.37, pp.6, 2016,
  18. Disulfiram chelated with copper promotes apoptosis in human breast cancer cells by impairing the mitochondria functions vol.38, pp.6, 2016,
  19. Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma vol.49, pp.3, 2016,
  20. Caudatin targets TNFAIP1/NF-κB and cytochrome c/caspase signaling to suppress tumor progression in human uterine cancer vol.49, pp.4, 2016,
  21. miR-378 inhibits cell growth and enhances apoptosis in human myelodysplastic syndromes vol.49, pp.5, 2016,
  22. YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo vol.77, pp.6, 2016,
  23. Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway vol.177, pp.2, 2017,
  24. The induction of apoptosis and autophagy in human hepatoma SMMC-7721 cells by combined treatment with vitamin C and polysaccharides extracted from Grifola frondosa vol.22, pp.11, 2017,
  25. Oblongifolin C and guttiferone K extracted from Garcinia yunnanensis fruit synergistically induce apoptosis in human colorectal cancer cells in vitro vol.38, pp.2, 2017,
  26. Biological evaluation of octahydropyrazin[2,1-a:5,4-a′]diisoquinoline derivatives as potent anticancer agents vol.39, pp.6, 2017,
  27. CADASIL mutant NOTCH3(R90C) decreases the viability of HS683 oligodendrocytes via apoptosis vol.44, pp.3, 2017,
  28. Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3 vol.73, pp.2, 2017,
  29. Rumex dentatus Inhibits Cell Proliferation, Arrests Cell Cycle, and Induces Apoptosis in MDA-MB-231 Cells through Suppression of the NF-κB Pathway vol.8, pp.1663-9812, 2017,
  30. Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis vol.16, pp.11, 2015,
  31. Overexpression of short TRPM8 variant α promotes cell migration and invasion, and decreases starvation-induced apoptosis in prostate cancer LNCaP cells vol.10, pp.3, 2015,
  32. An Aqueous Extract of Tuberaria lignosa Inhibits Cell Growth, Alters the Cell Cycle Profile, and Induces Apoptosis of NCI-H460 Tumor Cells vol.21, pp.5, 2016,
  33. Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP vol.37, pp.12, 2016,
  34. Decreased LRIG1 in Human Ovarian Cancer Cell SKOV3 Upregulates MRP-1 and Contributes to the Chemoresistance of VP16 vol.31, pp.4, 2016,
  35. MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells vol.38, pp.3, 2017,
  36. Significance of dynamic changes in gastric smooth muscle cell apoptosis, PI3K-AKT-mTOR and AMPK-mTOR signaling in a rat model of diabetic gastroparesis vol.16, pp.2, 2017,
  37. High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas vol.75, pp.12, 2017,
  38. Apoptosis: A Target for Anticancer Therapy vol.19, pp.2, 2018,
  39. Physicochemical Characterization and Functional Analysis of the Polysaccharide from the Edible Microalga Nostoc sphaeroides vol.23, pp.2, 2018,
  40. The Role of Caspase Genes Polymorphisms in Genetic Susceptibility to Philadelphia-Negative Myeloproliferative Neoplasms in a Portuguese Population pp.1532-2807, 2018,
  41. Delivery of a TNF-α–derived peptide by nanoparticles enhances its antitumor activity by inducing cell-cycle arrest and caspase-dependent apoptosis vol.32, pp.12, 2018,
  42. Evaluation of Z-VAD-FMK as an anti-apoptotic drug to prevent granulosa cell apoptosis and follicular death after human ovarian tissue transplantation pp.1573-7330, 2018,
  43. Key microRNAs in the biology of breast cancer; emerging evidence in the last decade pp.00219541, 2018,
  44. Paeoniflorin inhibits the growth of bladder carcinoma via deactivation of STAT3 vol.68, pp.2, 2018,
  45. extract in HeLa and MDA-MB-231 cells by a caspase-3 pathway vol.93, pp.5, 2018,
  46. ): A Comprehensive Mechanistic Review vol.2018, pp.1942-0994, 2018,
  47. Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe vol.11, pp.2, 2019,
  48. The X-linked inhibitor of apoptosis protein (XIAP) is involved in melanoma invasion by regulating cell migration and survival pp.2211-3436, 2019,
  49. Immunohistochemical Characterization of Procaspase-3 Overexpression as a Druggable Target With PAC-1, a Procaspase-3 Activator, in Canine and Human Brain Cancers vol.9, pp.2234-943X, 2019,
  50. Realizing the Clinical Potential of Immunogenic Cell Death in Cancer Chemotherapy and Radiotherapy vol.20, pp.4, 2019,
  51. Mechanisms underlying isoliquiritigenin-induced apoptosis and cell cycle arrest via ROS-mediated MAPK/STAT3/NF-κB pathways in human hepatocellular carcinoma cells pp.02724391, 2019,