Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies

Aging

Volumn 8, Issue 4, 2016, Pages 603-619

  Pistritto, Giuseppa ^a   Trisciuoglio, Daniela ^b   Ceci, Claudia ^a   Alessia Garufi, ^c   D'Orazi, Gabriella ^b,c  

^a UNIVERSITY OF ROME TOR VERGATA   (Italy)

^b REGINA ELENA NATIONAL CANCER INSTITUTE   (Italy)

^c UNIVERSITY OF CHIETI   (Italy)

Author keywords

Apoptosis; Cancer; Defective apoptotic pathways; miRNAs; p53; Small molecules

Indexed keywords

ANTINEOPLASTIC AGENT;

ANIMAL; APOPTOSIS; DISEASE COURSE; DRUG EFFECTS; HUMAN; NEOPLASMS; PATHOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; DISEASE PROGRESSION; HUMANS; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84970007005     PISSN: 19454589     EISSN: None     Source Type: Journal    
DOI: 10.18632/aging.100934     Document Type: Review

References (178)

1. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011; 147:742-758.
2. Wong RSY. Apoptosis in cancer: from pathogenesis to treatment. JECCR. 2011; 30:87.
3. Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer. Molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008; 104:1124-1149.
4. Fulda S. Tumor resistance to apoptosis. Int J Cancer. 2009; 124:515-515.
5. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011; 144:646-674.
6. Gimenez-Bonafe P, Tortosa A, Perez-Tomas R. Overcoming drug resistance by enhancing apoptosis of tumor cells. Curr Cancer Drug Targ. 2009; 9:320-340.
7. Fulda S. Targeting apoptosis for anticancer therapy. Sem Cancer Biol. 2015; 31:84-88.
8. Hacker G. The morphology of apoptosis. Cell Tissue Res. 2000; 301:5-17.
9. Saraste A, Pulkki K. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res. 2000; 45:528-537.
10. Hengartner MO. Apoptosis: corralling the corpses. Cell. 2000; 104:325-328.
11. Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P, Zhivotovsky B, Blagosklonny MV, Malorni W, Knight RA, Piacentini M, Nagata S, Melino G. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Diff. 2005; 12:1463-1467.
12. Bucur O, Nat R, Cretoiu D, Popescu LM. Phagocytosis of apoptotic cells by microglia in vitro. J Cell Mol Med. 2001; 5:438-441.
13. Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008; 27:6194-6206.
14. Thomberry NA, Laxebnik Y. Caspases: enemies within. Science 1998; 281:1312-1316.
15. Nicholson DW. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Diff. 1999; 6:1028-1042.
16. Stennicke HR, Salvesen GS. Caspases - controlling intracellular signals by protease zymogen activation-Biochim Biophys Acta-Port Struct Mol Enzimol. 2000; 1477:299-306.
17. Degterev A, Boyce M, Yuan JY. A decade of caspases. Oncogene. 2003; 22:8543-8567.
18. Pistritto G, Jost M, Srinivasula SM, Baffa R, Poyet JL, Kari C, Lazebnik Y, Rodeck U, Alnemri ES. Expression and transcriptional regulation of caspase-14 in simple and complex epithelia. Cell Death Diff. 2002; 9:995-1006.
19. Pistritto G, Papaleo V, Sanchez P, Ceci C, Barbaccia ML. Divergent modulation of neuronal differentiation by caspase-2 and-9. PLoS ONE. 2012; 7:e36002.
20. Shalini S, Dorstyn L, Dawar S and Kumar S. Old, new and emerging functions of caspases. Cell Death Diff. 2015; 22:526-39.
21. Guicciardi ME, Gores, Gregory J. Life and death by death receptors FASEB J. 2009; 23:1625-1637.
22. Fulda S, Debatin KM. Death receptor signaling in cancer therapy. Curr Med Chem Anticancer Agents. 2003; 3:253-262.
23. Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol. 2003; 6:725-731.
24. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305:626-629.
25. Kroemer G, Galluzzi L, Brenner C: Mitochondrial membrane permeabilisation in cell death. Physiol Rev. 2007; 87:99-163.
26. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004; 116:205-219.
27. Slee EA, Adrain C, Martin SJ. Serial killers: ordering caspase activation events in apoptosis. Cell Death Diff. 1999; 6:1067-1074.
28. Kuribayashi K, Mayes PA, El-Dery WS. What are caspases 3 and 7 doing upstream of the mitochondria? Cancer Biol Ther. 2006; 5:763-765.
29. Giam M, Huang DC, Bouillet P. BH3-only proteins and their roles in programmed cell death. Oncogene. 2008; 27:S128-36.
30. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007; 26:1324-1337.
31. Danial NN. BCL-2 family proteins: Critical checkpoints of apoptotic cell death. Clin Cancer Res. 2007; 13:7254-7263.
32. Lomonosova E and G Chinnadurai. BH3-only proteins in apoptosis and beyond: an overview. Oncogene. 2009; 27:S2-S19.
33. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008; 9:47-59.
34. Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3: Groove interactions. Mol Cell. 2008; 30:369-380.
35. Bleicken St, Classen M, Padmavathi PVL, Ishikawa T, Zeth K, Steinhoff HJ, Bordignon E. Molecular details of Bax activation, oligomerization, and membrane insertion. J Biol Chem. 2010; 285:6636-6647.
36. Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX activation is initiated at a novel interaction site. Nature. 2008; 455:1076-86.
37. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009; 122:437-441.
38. Oakes SA, Scorrano L, Opferman JT, Bassik MC, Nishino M, Pozzan T, Korsmeyer SJ. Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc Natl Acad Sci USA. 2005; 102:105-110.
39. Distelhorst CW, Bootman MD. Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: Role in Ca2+ signaling and disease. Cell Calcium. 2011; 50:234-241.
40. Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem. 2002; 277:432-438.
41. Pop C, Salvesen GS. Human caspases: activation, specificity, and regulation. J Biol Chem. 2009; 284:21777-21781.
42. Salvesen GS and Duckett CS. IAP proteins: Blocking the road to death's door. Nat Rev Mol Cell Biol. 2002; 3:401:410.
43. Berthelet J, Dubrez L. Regulation of apoptosis by inhibitors of apoptosis (IAPs). Cells. 2013; 2:163-87.
44. LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG: IAP-targeted therapies for cancer. Oncogene. 2008; 27:6252-6275.
45. Mace PD, Shirley S, Day CL. Assembling the building blocks: structure and function of inhibitor of apoptosis proteins. Cell Death Differ. 2010; 17:46-53.
46. Müschen M, Beckmann MW. CD95 ligand expression as a criterion of malignant transformation in breast cancer J Pathol. 2000; 191: 468-470.
47. Tourneur L, Buzyn A, Chiocchia G. FADD adaptor in cancer. Med Immunol. 2005; 4:1.
48. Müschen M, Rajewsky K, Krönke M, Küppers R. The origin of CD95-gene mutations in B-cell lymphoma. Trends Immunol. 2002; 23:75-80.
49. Tourneur L, Delluc S, Levy V, Valesi F, Radford-Weiss I, Legrand O, Vargftig J, Boix C, Macintyre EA, Varet B, Chiocchia G, Buzyn A. Absence or low expression of fas-associated protein with death domain in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome. Cancer Res. 2004; 64:8101-8108.
50. Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med. 2000; 6:529-535.
51. Shivapurkar N, Toyooka S, Eby MT, Huang CX, Sathyanarayana UG, Cunningham HT, Reddy JL, Brambilla E, Takahashi T, Minna JD, Chaudhary PM, Gazdar AF. Differential inactivation of caspase-8 in lung cancers. Cancer Biol Ther. 2002; 1:65-69.
52. Zuzak TJ, Steinhoff DF, Sutton LN, Phillips PC, Eggert A, Grotzer MA. Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumor/medulloblastoma. Eur J Cancer. 2002; 38:83-91.
53. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schröter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J. Inhibition of death receptor signals by cellular FLIP. Nature. 1997; 388:190-195.
54. Bagnoli M, Canevari S, Mezzanzanica D. Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol. 2010; 42:210-213.
55. Shirley S, Micheau O. Targeting c-FLIP in cancer. Cancer Lett. 2013; 332:141-150.
56. Gandour-Edwards R, Mack PC, Devere-White RW, Gumerlock PH. Abnormalities of apoptotic and cell cycle regulatory proteins in distinct histopathologic components of benign prostatic hyperplasia. Prost Cancer Prost Dis. 2004; 7:321-326.
57. Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood. 2005; 106:1164-1174.
58. Watanabe A, Yasuhira S, Inoue T, Kasai S, Shibazaki M, Takahashi K, Akasaka T, Masuda T, Maesawa C. BCL2 and BCLxL are key determinants of resistance to antitubulin chemotherapeutics in melanoma cells. Exp Dermatol. 2013; 22:518-523.
59. Raffo AJ, Perlman H, Chen MW, Day ML, Streitman JS, Buttyan R. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res. 1995; 55:4438.
60. Fulda S, Meyer E, Debatin KM. Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene. 2000; 21:2283-2294.
61. Foreman KE, Wrone-Smith T, Boise LH, Thompson CB, Polverini PJ, Simonian PL, Nunez G, Nickoloff BJ. Kaposi's sarcoma tumor cells preferentially express Bcl-xL Am J Pathol. 1996; 149: 795-803.
62. Krajewska M, Moss SF, Krajewski S, Song K, Holt PR, Reed JC. Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas. Cancer Res. 1996; 56:2422-2427.
63. Minn AJ, Rudin CM, Boise LH, Thompson CB. Expression of Bcl-xL can confer a multidrug resistance phenotype. Blood. 1995; 86:1903-1910.
64. Han JY, Hong EK, Choi BG, Park JN, Kim KW, Kang JH, Jin JY, Park SY, Hong YS, Lee KS Death receptor 5 and Bcl-2 protein expression as predictors of tumor response to gemcitabine and cisplatin in patients with advanced non-small-cell lung cancers. Med Oncol. 2003; 20:355-362.
65. Erovic BM, Pelzmann M, Grasl MCh, Pammer J, Kornek G, Brannath W, Selzer E, Thurnher D. Mcl-1, vascular endothelial growth factor-R2, and 14-3-3sigma expression might predict primary response against radiotherapy and chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Clin Cancer Res. 2005; 11:8632-8636.
66. Williams J, Lucas PC, Griffith KA, Choi M, Fogoros S, Hu YY, Liu JR. Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease. Gynecol Oncol. 2005; 96:287-295.
67. Michaud WA, Nichols AC, Mroz EA, Faquin WC, Clark JR, Begum S, Westra WH, Wada H, Busse PM, Ellisen LW, Rocco JW. Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma. Clin Cancer Res. 2009; 15:1645-1654.
68. Yang D, Chen MB, Wang LQ, Yang L, Liu CY, Lu PH. Bcl-2 expression predicts sensitivity to chemotherapy in breast cancer: a systematic review and meta-analysis. JECCR 2013; 32:105.
69. Miquel C, Borrini F, Grandjouan S, Aupérin A, Viguier J, Velasco V, Duvillard P, Praz F, Sabourin JC. Role of bax mutations in apoptosis in colorectal cancers with microsatellite instability. Am J Clin Pathol. 2005; 23:562-570.
70. Pepper C, Hoy T, Bentley DP. Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance. Br J Cancer. 1997; 76:935-938.
71. Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordón-Cardó C, Lowe SW. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature. 2001; 409:207-211.
72. Baldi A, Santini D, Russo P, Catricala' C, Amantea A, Picardo M, Tatangelo F, Botti G, Dragonetti E, Murace R, Tonini G, Natali PG, Baldi F, Paggi MG. Analysis of APAF-1 expression in human cutaneous melanoma progression. Exp Dermatol. 2004; 13:93-97.
73. Schimmer AD. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res. 2004; 64:7183-7190.
74. Fulda S. Inhibitor of apoptosis proteins in hematological malignancies. Leukemia. 2009; 23:467-476.
75. Fulda S, Debatin KM. IFNgamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene. 2002; 21:2295-2308.
76. Subramanian K, Hirpara JL, Tucker-Kellogg L, Tucker-Kellogg G, Pervaiz S. FLIP: A flop for execution signals. Cancer Lett. 2013; 332:151-155.
77. Almasan A, Ashkenazi A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytok Growth Fact Rev. 2003; 14:337-348.
78. Amarante-Mendes GP, Griffith TS. Therapeutic applications of TRAIL receptor agonists in cancer and beyond. Pharmacol Ther. 2015; 155:117-131.
79. Bucur O, Gaidos G, Yatawara A, Pennarum B, Rupasinghe C, Roux J, Andrei S, Guo B, Panaititu A, Pellegrini M, Mierke DF, Khosravi-Far R. A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death. Sci Rep. 2015; 5:9893.
80. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999; 104:155-162.
81. LeBlanc H, Ashkenazi A. Apo2/TRAIL and its death and decoy receptors. Cell Death Diff. 2003; 10:66-75.
82. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009; 15:1126-1132.
83. Sonpavde G, Matveev V, Burke JM, Caton JR, Fleming MT, Hutson TE, Galsky MD, Berry WR, Karlov P, Holmlund JT, Wood BA, Brookes M, Leopold L. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Annal Oncol. 2012; 23:1803-1808.
84. Stein MN, Hussain M, Stadler WM, Liu G, Tereshchenko IV, Goodin S, Jeyamohan C, Kaufman HL, Mehnert J, Di Paola RS. A Phase II study of AT-101 to overcome Bcl-2-mediated resistance to androgen deprivation therapy in patients with newly diagnosed castration-sensitive metastatic prostate cancer. Clin Genitour Cancer. 2016; 14:22-27.
85. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DCS, Hymowitz SG, Jin S, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19:202-208.
86. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature. 2005; 435:677-681.
87. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Mao Y, Yang X, Zhang HC, Fesik S, Rosenberg SH, Elmore SW. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008; 68:3421-3428.
88. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DCS, Xiong H, Cui Y, Busman TA, McKeegan EM, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012; 30:488-496.
89. Chiappori A, Williams C, Northfelt DW, Adams JW, Malik S, Edelman MJ, Rosen P, Van Echo DA, Berger MS, Haura EB. Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer. J Thorac Oncol. 2014; 9:121-125.
90. Theile D, Allendorf D, Koehler BC, Jassowicz A, Weiss J. Obatoclax as a perpetrator in drug-drug interactions and its efficacy in multidrug resistance cell lines. J Pharm Pharmacol. 2015; 67:1575-1584.
91. Zeitlin BD, Joo E, Dong Z, Warner K, Wang G, Nikolovska-Coleska Z, Wang S, Nor JE. Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res. 2006; 66:8698-8706.
92. Tao ZF, Hasvold L, Wang L, Wang X, Petros AM, Park CH, et al. Discovery of a potent and selective Bcl-xL inhibitor with in vivo activity. ACS Med Chem Lett. 2014; 5:1088-1093.
93. Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J Med Chem. 2015; 58:2180-2194.
94. Vervloessem T, La Rovere R, Bultynck G. Antagonizing Bcl-2's BH4 domain in cancer. Aging (Albany NY). 2015; 7:748-749. doi: 10.18632/aging.100828.
95. Trisciuoglio D, Gabellini C, Desideri M, Ragazzoni Y, De Luca T, Ziparo E, Del Bufalo D. Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells. Cell Death Diff. 2011; 18:1024-1035.
96. Trisciuoglio D, De Luca T, Desideri M, Passeri D, Gabellini C, Scarpino S, Liang C, Orlandi A, Del Bufalo D. Removal of the BH4 domain from Bcl-2 protein triggers an autophagic process that impairs tumor growth. Neoplasia. 2013; 15:315-327.
97. Gabellini C, De Luca T, Trisciuoglio D, Desideri M, Di Martile M, Passeri D, Candiloro A, Biffoni M, Rizzo MG, Orlandi A, Del Bufalo D. BH4 domain of bcl-2 protein is required for its proangiogenic function under hypoxic condition. Carcinogenesis. 2013; 34:2558-2567.
98. Han B, Park D, Li R, Xie M, Owonikoko T, Zhang G, Sica GL, Ding C, Zhou J, Magis AT, Chen ZG, Shin DM, Ramalingam S, Khuri FR, Curran WJ, Deng X. Small-molecule Bcl-2 BH4 antagonist for lung cancer therapy. Cancer Cell. 2015; 27:852-863.
99. Dexheimer TS, Sun D, Hurley LH. Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc. 2006; 128:5404-5415.
100. Lin J, Hou JQ, Xiang HD, Yan YY, Gu YC, Tan JH, Li D, Gu LQ, Ou TM, Huang ZS. Stabilization of G-quadruplex DNA by C-5-methyl-cytosine in bcl-2 promoter:implications for epigenetic regulation. Biochem Biophys Res Commun. 2013; 433:368-373.
101. Sun H, Xiang J, Shi Y, Yang Q, Guan A, Li Q, Yu L, Shang Q, Zhang H, Tang Y, Xu G. A newly identified G-quadruplex as a potential target regulating Bcl-2 expression. Biochim Biophys Acta. 2014; 1840:3052-3057.
102. Le Pen J, Laurent M, Sarosiek K, Vuillier C, Gautier F, Montessuit S, Martinou JC, Letaï A, Braun F, Juin PP. Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL. Cell Death Dis. 2016; 7:e2083.
103. Sasaki H, Sheng Y, Kotsuji F, Tsang BK. Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res. 2000; 60:5659-5666.
104. Holcik M, Yeh C, Korneluk RG, Chow T. Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene. 2000; 19:4174-4177.
105. Amantana A, London CA, Iversen PL, Devi GR. X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. Mol Cancer Ther. 2004; 3:699-707.
106. Fulda S. Promises and challenges of Smac mimetics as cancer therapeutics. Clin Cancer Res. 2015; 21:5030-5036.
107. Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD. AZD6244 (ARRY-142886), a potent inhibitor Wong KK, Engelman JA. Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and P13K inhibitors for KRAS-mutant lung cancers. Cancer Res. 2014; 74:3146-3156.
108. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d] pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I P13 kinase for the treatment of cancer. J Med Chem. 2008; 51:5522-5532.
109. Hata AN, Yeo A, Faber AC, Lifshits E, Chen Z, Cheng KA, Walton Z, Sarosiek KA, Letai A, Heist RS, Mino-Kenudson M, Wong KK, Engelman JA. Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and P13K inhibitors for KRAS-mutant lung cancers. Cancer Res. 2014; 74:3146-3156.
110. Okamoto K, Zaanan A, Kawakami H, Huang S, Sinicrope FA. Reversal of mutant KRAS-mediated apoptosis resistance by concurrent Noxa/Bik induction and Bcl-2/Bcl-xL antagonism in colon cancer cells. Mol Cancer Res. 2015; 13:659-669.
111. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell. 2013; 23:121-128.
112. Vousden KH, Lane DP. P53 in health and disease. Nat Rev Mol Cell Biol. 2007;8:275-283.
113. Brooks CL, Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol. 2003; 15:164-171.
114. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci. 2003; 116:4077-4085.
115. Vousden KH. P53: Death Star. Cell. 2000; 103:691-694.
116. Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Matkowitz S, et al. KILLER/DR5 is a DNA damage-induced p53-regulated death receptor gene. Nat Genet. 1997; 17:141-143.
117. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH. P53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med. 1998; 188:2033-2045.
118. Bennet M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg. Cell surface trafficking of Fas: a rapid mechanisms of p53-mediated apoptosis. Science. 1998; 282:290-293.
119. Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T. PERP, an apoptosi-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 2000; 14:704-718.
120. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000; 288:1053-1058.
121. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001; 7:683-694.
122. Thornborrow EC, Patel S, Mastropietro AE, Schwartzfarb EM, Manfredi JJ. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax gene. Oncogene. 2002; 21:990-999.
123. Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A. 2003; 100:1931-1936.
124. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol. 2002; 4:842-849.
125. Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K. Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol. 2001; 3:553-558.
126. MacLachlan TK, and El-Deiry WS. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc Natl Acad Sci. 2002; 99:9492-9497.
127. Sax JK, El-Deiry WS. P53 downstream targets and chemosensitivity. Cell Death Diff. 2003; 10:413-417.
128. Chi SW. Structural insights into the transcription-independent apoptotic pathway of p53. BMB Rep. 2014; 47:167-172.
129. Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C, Pan H, Kessler H, Pancoska P, Moll UM. WT p53, but not tumor-derived mutants, bind to Bc12 via the DNA binding domain and induce mitochondrial permeabilization. JBC 2006; 281:8600-8606.
130. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009; 9:862-873.
131. D'Orazi G, Marchetti A, Crescenzi M, Coen S, Sacchi A, Soddu S: Exogenous wt-p53 protein is active in transformed cells but not in their nontransformed counterparts: implications for cancer gene therapy without tumor targeting. J Gene Med. 2000; 2: 11-21.
132. Momand J, Wu HH, Dasgupta G. MDM2 - master regulator of the p53 tumor suppressor protein. Gene. 2000; 242:15-29.
133. Harris SL, Levine, AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005; 24:2899-2908.
134. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998; 26:3453-3459.
135. Di Stefano V, Blandino G, Sacchi A, Soddu S, D'Orazi G. HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Oncogene. 2004; 23:5185-5192.
136. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y. p53AlP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 2000; 102:849-862.
137. Mayo LD, Seo YR, Jackson MW, Smith ML, Guzman JR, Korgaonkar CK, Donner DB. Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified. J Biol Chem 2005; 280:25953-25959.
138. D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, et al. Homeodomain-interacting protein kinase 2 phosphorylates p53 at Ser46 and mediates apoptosis. Nat Cell Biol. 2002; 4:11-19.
139. Di Stefano V, Rinaldo C, Sacchi A, Soddu S, D'Orazi G. Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. Exp Cell Res. 2004; 293:311-320.
140. Pistritto G, Puca R, Nardinocchi L, Sacchi A, D'Orazi G. HIPK2-induced p53Ser46 phosphorylation activates the KILLER/DR5-mediated caspase-8 extrinsic apoptotic pathway. Cell Death Diff. 2007; 14:1837-1839.
141. Puca R, Nardinocchi L, Sacchi A, Rechavi G, Givol D, D'Orazi G. HIPK2 modulates p53 activity towards pro-apoptotic transcription. Mol Cancer. 2009; 8:85.
142. Garufi A, D'Orazi G. High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity. JECCR. 2014; 33:79.
143. Jin ZG, Shen JF, He JY, Hu CQ. Combination therapy with p53-MDM2 binding inhibitors for malignancies. Med Chem Res. 2015; 24:1369-1379.
144. Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007; 13:23-31.
145. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlot U, Lukacs C, Klein C, Fotouhi N, Liu EA. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303:844-848.
146. Kojima K, Konopleva M, McQueen T, O'Brien S, Plunkett W, Andreeff M. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms that may overcome Atm-mediated resistance to fluodarabine in chronic lymphocytic leukemia. Blood 2006; 108:993-1000.
147. Vaseva AV and Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta. 2009; 1787:414-420.
148. Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu Silvia. MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. Mol Cell. 2007; 25:739-750.
149. Rinaldo C, Prodosmo A, Siepi F, Moncada A, Sacchi A, Selivanova G, Soddu S. HIPK2 regulation by MDM2 determines tumor cell response to the p53-reactivating drugs Nutlin-3 and RITA. Cancer Res. 2009; 69:6241-6248.
150. Nardinocchi L, Puca R, Givol D, D'Orazi G. Counteracting MDM2-induced HIPK2 downregulation restores the HIPK2/p53 apoptotic signaling in cancer cells. FEBS Lett. 2010; 584:4253-4258.
151. Garufi A, Ubertini V, Mancini F, D'Orazi V, Baldari S, Moretti F, Bossi G, D'Orazi G. The beneficial effect of Zinc(II) on low-dose chemotherapeutic sensitivity involves p53 activation in wild-type p53-carrying colorectal cancer cells JECCR. 2015; 34:87.
152. Nardinocchi L, Puca R, D'Orazi G. HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. Aging (Albany NY). 2011; 3:33-43. doi: 10.18632/aging.100254.
153. Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induces mitovhondrial apoptosis in AML. Cell Cycle 2006; 5:2778-2786.
154. Wade M, Rodewald LW, Espinosa JM, Wahl G. BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death. Cell Cycle 2008; 7:1973-1982.
155. Zhao YJ, Aguilar A, Bernard D, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J Med Chem. 2015; 58:1038-1052.
156. Pellegrino M, Mancini F, Lucà R, Coletti A, Giacchè N, Manni I, Arisi I, Florenzano F, Teveroni E, Buttarelli M, Fici L, Brandi R, Bruno T, et al. Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation. Cancer Res. 2015; 75:4560-4572.
157. Mancini F, Di Conza G, Pellegrino M, Rinaldo C, Prodosmo A, Giglio S, D'Agnano I, Florenzano F, Felicioni L, Buttitta F, Marchetti A, Sacchi A, Pontecorvi A, et al. MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway. EMBO J. 2009; 28:1926-1939.
158. Mancini F, Pieroni L, Monteleone V, Luca R, Fici L, Luca E, Urbani A, Xiong S, Soddu S, Masetti R, Lozano G, Pontecorvi A, Moretti F. MDM4/ HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response. Oncogene. 2016; 35:228-240.
159. Hoe KK, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014; 13:217-236.
160. Yu X, Narayanan S, Vazquez A, Carpizo DR. Small molecule compounds targeting the p53 pathway: are we finally making progress? Apoptosis. 2014; 19:1055-1068.
161. Zawancka-Pankau, Selivanova G. Pharmacological reactivation of p53 as a strategy to treat cancer. J Intern Med. 2015; 277:248-259.
162. Lujambio A, Lowe SW. The microcosmos of cancer. Nature. 2012; 482:347-355.
163. Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Helena Vasconcelos M MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer. 2011; 47:163-174.
164. Huang G, Nishimoto K, Zhou Z, Hughes D, Kleinerman ES. miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression. Cancer Res. 2012; 72:908-916.
165. Wang P, Zhuang L, Zhang J, Fan J, Luo J, Chen H, Wang K, Liu L, Chen Z, Meng Z. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol. 2013; 7:334-345.
166. Li Z, Huang H, Chen P, He M, Li Y, Arnovitz S, Jiang X, He C, Hyjek E, Zhang J. miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. Nat Commun. 2012; 2:688.
167. Shaffiey F, Cross E, Sathyanarayana P. Mir-590 is a novel STAT5 regulated oncogenic miRNA and targets FasL in acute myeloid leukemia. Blood. 2013; 122:3811-3811.
168. Guennewig B, Roos M, Dogar AM, Gebert LF, Zagalak JA, Vongrad V, Metzner KJ, Hall J. Synthetic pre-microRNAs reveal dual-strand activity of miR-34a on TNF-α. RNA. 2014; 20:61-75.
169. Zhang L, Dong L, Li Y, Hong Z, Wei W. The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor. J Neuroinflamm. 2012; 9:211.
170. Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, Gasperini S, Mariotti B, De Luca M, Mirolo M, Cassatella MA. IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci USA. 2012; 109:E3101-E3110.
171. Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, Tatsumi T, Ishida H, Noda T, Nagano H, Doki Y, Mori M, Hayashi N. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol. 2010; 52:698-704.
172. Sacconi A, Biagioni F, Canu V, Mori F, Di Benedetto A, Lorenzon L, Ercolani C, Di Agostino S, Cambria AM, Germoni S, Grasso G, Blandino R, Panebianco V, et al. miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer. Cell Death Dis. 2012; 3:e423.
173. Zhang Y, Schiff D, Park D, Abounader R. MicroRNA-608 and MicroRNA-34a regulate chordoma malignancy by targeting EGFR, Bcl-xL and MET. PloS ONE. 2014; 9:e91546.
174. Kurataka O, Takahiro O. Genetic networks lead and follow tumor development: MicroRNA regulation of cell cycle and apoptosis in the p53 pathways. Bio Med Res Intern. 2014; 2014:ID749724.
175. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007; 26:731-743.
176. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007; 26:745-752.
177. Garibaldi F, Falcone E, Trisciuoglio D, Colombo T, Lisek K, Walerych D, Del Sal G, Paci P, Bossi G, Piaggio G, Gurtner A. Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex. Oncogene 2016. doi: 10.1038/onc.2016. 51. [Epub ahead of print].
178. Baig S, Seevasant I, Mohamad J, Mukheem A, Huri HZ, Kamarul T. Potential of apoptotic pathway-targeted cancer thereapeutic research: Where do we stand? Cell Death Dis. 2016; 7:e2058.