Advertisement

Apoptosis

, Volume 22, Issue 12, pp 1487–1509 | Cite as

Inhibitors of apoptosis: clinical implications in cancer

  • Mervat S. MohamedEmail author
  • Mai K. Bishr
  • Fahad M. Almutairi
  • Ayat G. Ali
Review

Abstract

Inhibitor of apoptosis (IAP) family comprises a group of endogenous proteins that function as main regulators of caspase activity and cell death. They are considered the main culprits in evasion of apoptosis, which is a fundamental hallmark of carcinogenesis. Overexpression of IAP proteins has been documented in various solid and hematological malignancies, rendering them resistant to standard chemotherapeutics and radiation therapy and conferring poor prognosis. This observation has urged their exploitation as therapeutic targets in cancer with promising pre-clinical outcomes. This review describes the structural and functional features of IAP proteins to elucidate the mechanism of their anti-apoptotic activity. We also provide an update on patterns of IAP expression in different tumors, their impact on treatment response and prognosis, as well as the emerging investigational drugs targeting them. This aims at shedding the light on the advances in IAP targeting achieved to date, and encourage further development of clinically applicable therapeutic approaches.

Keywords

Apoptosis Inhibitor of apoptosis Caspases Smac mimetics Cancer target therapy 

Notes

Acknowledgements

This work is supported by a research Grant S—1438-0013 from University of Tabuk, Kingdom of Saudi Arabia to Mervat S. Mohamed.

Compliance with ethical standards

Conflict of interest

Mervat S. Mohamed has received a research Grant S – 1438-0013 from University of Tabuk, Kingdom of Saudi Arabia. Other authors declare that they have no conflict of interest.

References

  1. 1.
    Fulda S (2014) Molecular pathways: targeting inhibitor of apoptosis proteins in cancer—from molecular mechanism to therapeutic application. Clin Cancer Res 20(2):289–295PubMedCrossRefGoogle Scholar
  2. 2.
    Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11(2):109PubMedCrossRefGoogle Scholar
  3. 3.
    Crook NE, Clem RJ, Miller LK (1993) An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67(4):2168–2174PubMedPubMedCentralGoogle Scholar
  4. 4.
    Orme M, Meier P (2009) Inhibitor of apoptosis proteins in drosophila: gatekeepers of death. Apoptosis 14(8):950–960PubMedCrossRefGoogle Scholar
  5. 5.
    Roy N, Mahadevan MS, McLean M et al (1995) The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80(1):167–178PubMedCrossRefGoogle Scholar
  6. 6.
    Duckett CS, Nava VE, Gedrich RW et al (1996) A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J 15(11):2685PubMedPubMedCentralGoogle Scholar
  7. 7.
    Liston P, Roy N, Tamai K, Lefebvre C (1996) Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379(6563):349PubMedCrossRefGoogle Scholar
  8. 8.
    Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV (1995) The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83(7):1243–1252PubMedCrossRefGoogle Scholar
  9. 9.
    Lagacé M, Xuan JY, Young SS, McRoberts C, Maier J, Rajcan-Separovic E, Korneluk RG (2001) Genomic organization of the X-linked inhibitor of apoptosis and identification of a novel testis-specific transcript. Genomics 77(3):181–188PubMedCrossRefGoogle Scholar
  10. 10.
    Richter BW, Mir SS, Eiben LJ et al (2001) Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family. Mol Cell Biol 21(13):4292–4301PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Chen Z, Naito M, Hori S, Mashima T, Yamori T, Tsuruo T (1999) A human IAP-family gene, apollon, expressed in human brain cancer cells. Biochem Biophys Res Commun 264(3):847–854PubMedCrossRefGoogle Scholar
  12. 12.
    Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3(8):917–921PubMedCrossRefGoogle Scholar
  13. 13.
    Kasof GM, Gomes BC (2001) Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 276(5):3238–3246PubMedCrossRefGoogle Scholar
  14. 14.
    Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM (2000) ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 10(21):1359–1366PubMedCrossRefGoogle Scholar
  15. 15.
    Vucic D, Dixit VM, Wertz IE (2011) Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12(7):43CrossRefGoogle Scholar
  16. 16.
    Pop C, Salvesen GS (2009) Human caspases: activation, specificity, and regulation. J Biol Chem 284(33):21777–21781PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Berthelet J, Dubrez L (2013) Regulation of apoptosis by inhibitors of apoptosis (IAPs). Cells 2(1):163–187PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Eckelman BP, Drag M, Snipas SJ, Salvesen GS (2008) The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death Differ 15(5):920PubMedCrossRefGoogle Scholar
  19. 19.
    Wei Y, Fan T, Yu M (2008) Inhibitor of apoptosis proteins and apoptosis. Acta Biochim Biophys Sin 40(4):278–288PubMedCrossRefGoogle Scholar
  20. 20.
    Cossu F, Milani M, Mastrangelo E et al (2009) Structural basis for bivalent Smac-mimetics recognition in the IAP protein family. J Mol Biol 392(3):630–644PubMedCrossRefGoogle Scholar
  21. 21.
    Singh N, D’souza A, Cholleti A, Sastry GM, Bose K (2014) Dual regulatory switch confers tighter control on HtrA2 proteolytic activity. FEBS J 281(10):2456–2470PubMedCrossRefGoogle Scholar
  22. 22.
    Bergmann A (2010) The role of ubiquitylation for the control of cell death in Drosophila. Cell Death Differ 17(1):61PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Lu M, Lin SC, Huang Y et al (2007) XIAP induces NF-κB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell 26(5):689–702PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Mace PD, Smits C, Vaux DL, Silke J, Day CL (2010) Asymmetric recruitment of cIAPs by TRAF2. J Mol Biol 400(1):8–15PubMedCrossRefGoogle Scholar
  25. 25.
    Mace PD, Linke K, Feltham R et al (2008) Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment. J Biol Chem 283(46):31633–31640PubMedCrossRefGoogle Scholar
  26. 26.
    Feltham R, Bettjeman B, Budhidarmo R et al (2011) Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization. J Biol Chem 286(19):17015–17028PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Dueber EC, Schoeffler AJ, Lingel A et al (2011) Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science 334(6054):376–380PubMedCrossRefGoogle Scholar
  28. 28.
    Lopez J, John SW, Tenev T et al (2011) CARD-mediated autoinhibition of cIAP1’s E3 ligase activity suppresses cell proliferation and migration. Mol Cell 42(5):569–583PubMedCrossRefGoogle Scholar
  29. 29.
    Gyrd-Hansen M, Darding M, Miasari M et al (2008) IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis. Nat Cell Biol 10(11):1309–1317PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Blankenship JW, Varfolomeev E, Goncharov T et al (2009) Ubiquitin binding modulates IAP antagonist-stimulated proteasomal degradation of c-IAP1 and c-IAP2 1. Biochem J 417(1):149–165PubMedCrossRefGoogle Scholar
  31. 31.
    Huang Q, Deveraux QL, Maeda S, Salvesen GS, Stennicke HR, Hammock BD, Reed JC (2000) Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9. Proc Natl Acad Sci 97(4):1427–1432PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Marino G, Niso-Santano M, Baehrecke EH, Kroemer G (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15(2):81PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30(1):87PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Giansanti V, Torriglia A, Scovassi AI (2011) Conversation between apoptosis and autophagy: “Is it your turn or mine?” Apoptosis 16(4):321–333PubMedCrossRefGoogle Scholar
  35. 35.
    Chowdhury I, Tharakan B, Bhat GK (2008). Caspases—an update. Comp Biochem Physiol B Biochem Mol Biol 151(1):10–27PubMedCrossRefGoogle Scholar
  36. 36.
    Würstle ML, Laussmann MA, Rehm M (2012) The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome. Exp Cell Res 318(11):1213–1220PubMedCrossRefGoogle Scholar
  37. 37.
    Mace PD, Riedl SJ (2010) Molecular cell death platforms and assemblies. Curr Opin Cell Biol 22(6):828–836PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pinton P, Giorgi C, Pandolfi PP (2011) The role of PML in the control of apoptotic cell fate: a new key player at ER–mitochondria sites. Cell Death Differ 18:1450–1456PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hata AN, Engelman JA, Faber AC (2015) The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov 5(5):475–487PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Volkmann N, Marassi FM, Newmeyer DD, Hanein D (2014) The rheostat in the membrane: BCL-2 family proteins and apoptosis. Cell Death Differ 21(2):206PubMedCrossRefGoogle Scholar
  41. 41.
    Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11(9):621PubMedCrossRefGoogle Scholar
  42. 42.
    Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM (2009) Bak activation for apoptosis involves oligomerization of dimers via their α6 helices. Mol Cell 36(4):696–703PubMedCrossRefGoogle Scholar
  43. 43.
    Flanagan L, Sebastia J, Tuffy LP et al (2010) XIAP impairs Smac release from the mitochondria during apoptosis. Cell Death Dis 1(6), e49PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Walle LV, Lamkanfi M, Vandenabeele P (2008) The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ 15(3):453–460CrossRefGoogle Scholar
  45. 45.
    Bratton SB, Salvesen GS (2010) Regulation of the Apaf-1–caspase-9 apoptosome. J Cell Sci 123(19):3209–3214PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Koff JL, Ramachandiran S, Bernal-Mizrachi L (2015) A time to kill: targeting apoptosis in cancer. Int J Mol Sci 16(2):2942–2955PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Sayers TJ (2011) Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunol Immunother 60(8):1173–1180PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang DW, Shao J, Lin J et al (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332–336PubMedCrossRefGoogle Scholar
  49. 49.
    Long JS, Ryan KM (2012) New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy. Oncogene 31(49):5045PubMedCrossRefGoogle Scholar
  50. 50.
    Puthalakath H, O’Reilly LA, Gunn P et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129(7):1337–1349PubMedCrossRefGoogle Scholar
  51. 51.
    Deniaud A, El Dein OS, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C (2008) Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27(3):285PubMedCrossRefGoogle Scholar
  52. 52.
    Hamanaka RB, Bobrovnikova-Marjon E, Ji X, Liebhaber SA, Diehl JA (2009) PERK-dependent regulation of IAP translation during ER stress. Oncogene 28(6):910PubMedCrossRefGoogle Scholar
  53. 53.
    Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13(3):184–190PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Moenner M, Pluquet O, Bouchecareilh M, Chevet E (2007) Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67(22):10631–10634PubMedCrossRefGoogle Scholar
  55. 55.
    Cheung HH, Kelly NL, Liston P, Korneluk RG (2006) Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: a role for the IAPs. Exp Cell Res 312(12):2347–2357PubMedCrossRefGoogle Scholar
  56. 56.
    Baig S, Seevasant I, Mohamad J, Mukheem A, Huri HZ, Kamarul T (2016). Potential of apoptotic pathway-targeted cancer therapeutic research: where do we stand?. Cell Death Dis 7(1):e2058PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Silke J, Meier P (2013) Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harb Perspect Biol 5(2):a008730PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Estornes Y, Bertrand MJ (2015) IAPs, regulators of innate immunity and inflammation. Semin Cell Dev Biol 39:106–114PubMedCrossRefGoogle Scholar
  59. 59.
    Gyrd-Hansen M, Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-[kappa] B, inflammation and cancer. Nat Rev Cancer 10(8):561PubMedCrossRefGoogle Scholar
  60. 60.
    Kao WP, Yang CY, Su TW, Wang YT, Lo YC, Lin SC (2015) The versatile roles of CARDs in regulating apoptosis, inflammation, and NF-κB signaling. Apoptosis 20(2):174–195PubMedCrossRefGoogle Scholar
  61. 61.
    Choi YE, Butterworth M, Malladi S, Duckett CS, Cohen GM, Bratton SB (2009) The E3 ubiquitin ligase cIAP1 binds and ubiquitinates caspase-3 and-7 via unique mechanisms at distinct steps in their processing. J Biol Chem 284(19):12772–12782PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Marivin A, Berthelet J, Plenchette S, Dubrez L (2012) The inhibitor of apoptosis (IAPs) in adaptive response to cellular stress. Cells 1(4):711–737PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Chang H, Schimmer AD (2007) Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy. Mol Cancer Ther 6(1):24–30PubMedCrossRefGoogle Scholar
  64. 64.
    Davoodi J, Ghahremani MH, Es-haghi A, Mohammad-gholi A, MacKenzie A (2010) Neuronal apoptosis inhibitory protein, NAIP, is an inhibitor of procaspase-9. Int J Biochem Cell Biol 42(6):958–964PubMedCrossRefGoogle Scholar
  65. 65.
    Hunter AM, LaCasse EC, Korneluk RG (2007) The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12(9):1543–1568PubMedCrossRefGoogle Scholar
  66. 66.
    Shiozaki EN, Chai J, Rigotti DJ et al (2003) Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell 11(2):519–527PubMedCrossRefGoogle Scholar
  67. 67.
    Ho AT, Li QH, Okada H, Mak TW, Zacksenhaus E (2007) XIAP activity dictates Apaf-1 dependency for caspase 9 activation. Mol Cell Biol 27(16):5673–5685PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Tait SW, Green DR (2008) Caspase independent cell death: leaving the set without the final cut. Oncogene 27(50):6452–6461PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC (1999) Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J 18(19):5242–5251PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Garg H, Suri P, Gupta JC, Talwar GP, Dubey S (2016) Survivin: a unique target for tumor therapy. Cancer Cell Int 16(1):49PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Altieri DC (2010) Survivin and IAP proteins in cell-death mechanisms. Biochem J 430(2):199–205PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Dohi T, Xia F, Altieri DC (2007) Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection. Mol Cell 27(1):17–28PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    van der Horst A, Lens SM (2014) Cell division: control of the chromosomal passenger complex in time and space. Chromosoma 123(1–2):25–42PubMedCrossRefGoogle Scholar
  74. 74.
    Wheatley SP (2015) The functional repertoire of survivin’s tails. Cell Cycle 14(2):261–268PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229PubMedCrossRefGoogle Scholar
  76. 76.
    Huang X, Dixit VM (2016) Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res 26(4):484–498PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Conze DB, Albert L, Ferrick DA, Goeddel DV, Yeh WC, Mak T, Ashwell JD (2005) Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol Cell Biol 25(8):3348–3356PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Cheung HH, Plenchette S, Kern CJ, Mahoney DJ, Korneluk RG (2008) The RING domain of cIAP1 mediates the degradation of RING-bearing inhibitor of apoptosis proteins by distinct pathways. Mol Biol Cell 19(7):2729–2740PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Huang HK, Joazeiro CA, Bonfoco E, Kamada S, Leverson JD, Hunter T (2000) The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J Biol Chem 275(35):26661–26664PubMedGoogle Scholar
  80. 80.
    Galbán S, Duckett CS (2010) XIAP as a ubiquitin ligase in cellular signaling. Cell Death Differ 17(1):54–60PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Schile AJ, García-Fernández M, Steller H (2008) Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes Dev 22(16):2256–2266PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Damgaard RB, Nachbur U, Yabal M et al (2012) The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell 46(6):746–758PubMedCrossRefGoogle Scholar
  83. 83.
    Oberoi TK, Dogan T, Hocking JC et al (2012) IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation. EMBO J 31(1):14–28PubMedCrossRefGoogle Scholar
  84. 84.
    Pohl C, Jentsch S (2008) Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell 132(5):832–845PubMedCrossRefGoogle Scholar
  85. 85.
    Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JPR, Melendez-Zajgla J (2008) Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res 27(1):48PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8(3):613–621PubMedCrossRefGoogle Scholar
  87. 87.
    Liston P, Fong WG, Kelly NL et al (2001) Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol 3(2):128PubMedCrossRefGoogle Scholar
  88. 88.
    Hegde R, Srinivasula SM, Datta P et al (2003) The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein. J Biol Chem 278(40):38699–38706PubMedCrossRefGoogle Scholar
  89. 89.
    Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S (2004) The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J 23(7):1627–1635PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Edison N, Zuri D, Maniv I et al (2012) The IAP-antagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo. Cell Death Differ 19(2):356–368PubMedCrossRefGoogle Scholar
  91. 91.
    Verhagen AM, Kratina TK, Hawkins CJ, Silke J, Ekert PG, Vaux DL (2007) Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ 14(2):348PubMedCrossRefGoogle Scholar
  92. 92.
    Tenev T, Bianchi K, Darding M et al (2011) The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell 43(3):432–448PubMedCrossRefGoogle Scholar
  93. 93.
    Varfolomeev E, Blankenship JW, Wayson SM et al (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131(4):669–681PubMedCrossRefGoogle Scholar
  94. 94.
    Fu J, Jin Y, Arend LJ (2003) Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. J Biol Chem 278(52):52660–52672PubMedCrossRefGoogle Scholar
  95. 95.
    Yamauchi S, Hou YY, Guo AK, Hirata H, Nakajima W, Yip AK, Tanaka N (2014) p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. J Cell Biol 204(7):1191–1207PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Arora V, Cheung HH, Plenchette S, Micali OC, Liston P, Korneluk RG (2007) Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex. J Biol Chem 282(36):26202–26209PubMedCrossRefGoogle Scholar
  97. 97.
    Micali OC, Cheung HH, Plenchette S, Hurley SL, Liston P, LaCasse EC, Korneluk RG (2007) Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-β. BMC Cancer 7(1):52PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Huang J, Yao WY, Zhu Q et al (2010) XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer. Cancer Sci 101(2):559–567PubMedCrossRefGoogle Scholar
  99. 99.
    Choo ZE, Koh RYL, Wallis K et al (2016) XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis. Oncotarget 7(23):34229PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wang Y, Mao H, Hao Q, Wang Y, Yang Y, Shen L, Liu P (2012) Association of expression of XIAP-associated factor 1 (XAF1) with clinicopathologic factors, overall survival, microvessel density and cisplatin-resistance in ovarian cancer. Regul Pept 178(1):36–42PubMedCrossRefGoogle Scholar
  101. 101.
    Zhu LM, Shi DM, Dai Q et al (2014) Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma. Oncotarget 5(14):5403–5415PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Shibata T, Mahotka C, Wethkamp N, Heikaus S, Gabbert HE, Ramp U (2007) Disturbed expression of the apoptosis regulators XIAP, XAF1, and Smac/DIABLO in gastric adenocarcinomas. Diagn Mol Pathol 16(1):1–8PubMedCrossRefGoogle Scholar
  103. 103.
    Zou B, Chim CS, Pang R et al (2012) XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification. Mol Carcinog 51(5):422–432PubMedCrossRefGoogle Scholar
  104. 104.
    Plenchette S, Cheung HH, Fong WG, LaCasse EC, Korneluk RG (2007) The role of XAF1 in cancer. Curr Opin Investig Drugs 8(6):469PubMedGoogle Scholar
  105. 105.
    Bornstein B, Gottfried Y, Edison N, Shekhtman A, Lev T, Glaser F, Larisch S (2011) ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonists. Apoptosis 16(9):869PubMedCrossRefGoogle Scholar
  106. 106.
    Garrison JB, Correa RG, Gerlic M et al (2011) ARTS and Siah collaborate in a pathway for XIAP degradation. Mol Cell 41(1):107–116PubMedCrossRefGoogle Scholar
  107. 107.
    García-Fernández M, Kissel H, Brown S et al (2010) Sept4/ARTS is required for stem cell apoptosis and tumor suppression. Genes Dev 24(20):2282–2293PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Vassina EM, Yousefi S, Simon D, Zwicky C, Conus S, Simon HU (2006) cIAP-2 and survivin contribute to cytokine-mediated delayed eosinophil apoptosis. Eur J Immunol 36(7):1975–1984PubMedCrossRefGoogle Scholar
  109. 109.
    Gordon GJ, Mani M, Mukhopadhyay L, Dong L, Yeap BY, Sugarbaker DJ, Bueno R (2007) Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-α in malignant pleural mesothelioma. J Pathol 211(4):439–446PubMedCrossRefGoogle Scholar
  110. 110.
    Vince JE, Wong WWL, Khan N et al (2007) IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131(4):682–693PubMedCrossRefGoogle Scholar
  111. 111.
    Church DN, Talbot DC (2012) Survivin in solid tumors: rationale for development of inhibitors. Curr Oncol Rep 14(2):120–128PubMedCrossRefGoogle Scholar
  112. 112.
    Rodríguez-Berriguete G, Torrealba N, Ortega MA et al (2015) Prognostic value of inhibitors of apoptosis proteins (IAPs) and caspases in prostate cancer: caspase-3 forms and XIAP predict biochemical progression after radical prostatectomy. BMC Cancer 15(1):809PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Altieri B, Sbiera S, Della Casa S et al (2017) Livin/BIRC7 expression as malignancy marker in adrenocortical tumors. Oncotarget 8(6):9323PubMedGoogle Scholar
  114. 114.
    Sbiera S, Kroiss M, Thamm T et al (2013) Survivin in adrenocortical tumors–pathophysiological implications and therapeutic potential. Horm Metab Res 45(02):137–146PubMedGoogle Scholar
  115. 115.
    Che X, Yang D, Zong H et al (2012) Nuclear cIAP1 overexpression is a tumor stage-and grade-independent predictor of poor prognosis in human bladder cancer patients. Urol Oncol 30(4):450–456PubMedCrossRefGoogle Scholar
  116. 116.
    Yang D, Song X, Zhang J et al (2010) Therapeutic potential of siRNA-mediated combined knockdown of the IAP genes (Livin, XIAP, and Survivin) on human bladder cancer T24 cells. Acta Biochim Biophys Sin 42(2):137–144PubMedCrossRefGoogle Scholar
  117. 117.
    Poli G, Brancorsini S, Cochetti G, Barillaro F, Egidi MG, Mearini E (2015) Expression of inflammasome-related genes in bladder cancer and their association with cytokeratin 20 messenger RNA. Urol Oncol 33(12):505-e1CrossRefGoogle Scholar
  118. 118.
    Ziegler DS, Keating J, Kesari S et al (2011) A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo. Neuro Oncol 13(8):820–829PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Zhang H, Xu F, Xie T, Jin H, Shi L (2012) β-elemene induces glioma cell apoptosis by downregulating survivin and its interaction with hepatitis B X-interacting protein. Oncol Rep 28(6):2083–2090PubMedCrossRefGoogle Scholar
  120. 120.
    Li G, Zhang H, Liu Y, Kong L, Guo Q, Jin F (2015) Effect of temozolomide on livin and caspase-3 in U251 glioma stem cells. Exp Ther Med 9(3):744–750PubMedCrossRefGoogle Scholar
  121. 121.
    Peng XH, Karna P, O’Regan RM et al (2007) Down-regulation of inhibitor of apoptosis proteins by deguelin selectively induces apoptosis in breast cancer cells. Mol Pharmacol 71(1):101–111PubMedCrossRefGoogle Scholar
  122. 122.
    Zhang Y, Zhu J, Tang Y et al (2011) X-linked inhibitor of apoptosis positive nuclear labeling: a new independent prognostic biomarker of breast invasive ductal carcinoma. Diagn Pathol 6(1):49PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Choi J, Hwang YK, Choi YJ et al (2007) Neuronal apoptosis inhibitory protein is overexpressed in patients with unfavorable prognostic factors in breast cancer. J Korean Med Sci 22(Suppl):S17–S23PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Li F, Yin X, Luo X et al (2013) Livin promotes progression of breast cancer through induction of epithelial–mesenchymal transition and activation of AKT signaling. Cell Signal 25(6):1413–1422PubMedCrossRefGoogle Scholar
  125. 125.
    Yaqin M, Runhua L, Fuxi Z (2007) Analyses of Bcl-2, Survivin, and CD44v6 expressions and human papillomavirus infection in cervical carcinomas. Scand J Infect Dis 39(5):441–448PubMedCrossRefGoogle Scholar
  126. 126.
    Imoto I, Tsuda H, Hirasawa A, Miura M, Sakamoto M, Hirohashi S, Inazawa J (2002) Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy. Cancer Res 62(17):4860–4866PubMedGoogle Scholar
  127. 127.
    Burstein DE, Idrees MT, Li G, Wu M, Kalir T (2008) Immunohistochemical detection of the X-linked inhibitor of apoptosis protein (XIAP) in cervical squamous intraepithelial neoplasia and squamous carcinoma. Ann Diagn Pathol 12(2):85–89PubMedCrossRefGoogle Scholar
  128. 128.
    Huerta S, Heinzerling JH, Anguiano-Hernandez YM et al (2007) Modification of gene products involved in resistance to apoptosis in metastatic colon cancer cells: Roles of Fas, Apaf-1, NFκB, IAPs, Smac/DIABLO, and AIF. J Surg Res 142(1):184–194PubMedCrossRefGoogle Scholar
  129. 129.
    Wang X, Xu J, Ju S, Ni H, Zhu J, Wang H (2010) Livin gene plays a role in drug resistance of colon cancer cells. Clin Biochem 43(7):655–660PubMedCrossRefGoogle Scholar
  130. 130.
    Krajewska M, Kim H, Kim C et al (2005) Analysis of apoptosis protein expression in early-stage colorectal cancer suggests opportunities for new prognostic biomarkers. Clin Cancer Res 11(15):5451–5461PubMedCrossRefGoogle Scholar
  131. 131.
    Xu X, Wu X, Jiang Q et al (2015) Downregulation of microRNA-1 and microRNA-145 contributes synergistically to the development of colon cancer. Int J Mol Med 36(6):1630–1638PubMedCrossRefGoogle Scholar
  132. 132.
    Lambropoulou M, Papadopoulos N, Tripsianis G et al (2010) Co-expression of survivin, c-erbB2, and cyclooxygenase-2 (COX-2): prognostic value and survival of endometrial cancer patients. J Cancer Res Clin Oncol 136(3):427–435PubMedCrossRefGoogle Scholar
  133. 133.
    Gagnon V, Van Themsche C, Turner S, Leblanc V, Asselin E (2008) Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol. Apoptosis 13(2):259–271PubMedCrossRefGoogle Scholar
  134. 134.
    Gagnon V, St-Germain ME, Parent S, Asselin E (2003) Akt activity in endometrial cancer cells: regulation of cell survival through cIAP-1. Int J Oncol 23(3):803–810PubMedGoogle Scholar
  135. 135.
    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(6):974–979CrossRefGoogle Scholar
  136. 136.
    Upadhyay R, Khurana R, Kumar S, Ghoshal UC, Mittal B (2011) Role of survivin gene promoter polymorphism (– 31G > C) in susceptibility and survival of esophageal cancer in northern India. Ann Surg Oncol 18(3):880–887PubMedCrossRefGoogle Scholar
  137. 137.
    Zhang S, Tang W, Weng S et al (2014) Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma. Oncotarget 5(16):7183PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Wang TT, Qian XP, Liu BR (2007) Survivin: potential role in diagnosis, prognosis and targeted therapy of gastric cancer. World J Gastroenterol 13(20):2784PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Wang DG, Sun YB, Ye F et al (2014) Anti-tumor activity of the X-linked inhibitor of apoptosis (XIAP) inhibitor embelin in gastric cancer cells. Mol Cell Biochem 386(1–2):143–152PubMedCrossRefGoogle Scholar
  140. 140.
    Chung CY, Park YL, Kim N et al (2013) Expression and prognostic significance of Livin in gastric cancer. Oncol Rep 30(5):2520–2528PubMedCrossRefGoogle Scholar
  141. 141.
    Falkenhorst J, Grunewald S, Mühlenberg T et al (2016) Inhibitor of apoptosis proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib. Oncotarget 7(27):41390–41403PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Shi YH, Ding WX, Zhou J et al (2008) Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology 48(2):497–507PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Fan L, Sun G, Ma T, Zhong F, Wei W (2013) Melatonin overcomes apoptosis resistance in human hepatocellular carcinoma by targeting survivin and XIAP. J Pineal Res 55(2):174–183PubMedCrossRefGoogle Scholar
  144. 144.
    Guo H, Gao YT, Zhang Q et al (2013) Expression and clinical significance of livin protein in hepatocellular carcinoma. Dis Markers 35(5):489–496PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Tanimoto T, Tsuda H, Imazeki N, Ohno Y, Imoto I, Inazawa J, Matsubara O (2005) Nuclear expression of cIAP-1, an apoptosis inhibiting protein, predicts lymph node metastasis and poor patient prognosis in head and neck squamous cell carcinomas. Cancer Lett 224(1):141–151PubMedCrossRefGoogle Scholar
  146. 146.
    Scheper MA, Nikitakis NG, Sauk JJ (2007) Survivin is a downstream target and effector of sulindac-sensitive oncogenic Stat3 signalling in head and neck cancer. Int J Oral Maxillofac Surg 36(7):632–639PubMedCrossRefGoogle Scholar
  147. 147.
    Qi G, Kudo Y, Ando T, Tsunematsu T, Shimizu N, Siriwardena SB, Takata T (2010) Nuclear survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B. Oral Oncol 46(4):263–270PubMedCrossRefGoogle Scholar
  148. 148.
    Yang XH, Feng ZE, Yan M et al (2012) XIAP is a predictor of cisplatin-based chemotherapy response and prognosis for patients with advanced head and neck cancer. PloS ONE, 7(3):e31601PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Lévy P, Vidaud D, Leroy K et al (2004) Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. Mol Cancer 3(1):20PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Chen SM, Li YY, Tu CH et al (2016) Blockade of inhibitors of apoptosis proteins in combination with conventional chemotherapy leads to synergistic antitumor activity in medulloblastoma and cancer stem-like cells. PloS ONE, 11(8):e0161299PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Abdel-Aziz A, Mohamed MAA, Akl FMF, Taha ANM (2013) Survivin expression in medulloblastoma: a possible marker for survival. Pathol Oncol Res 19(3):413–419PubMedCrossRefGoogle Scholar
  152. 152.
    Kluger HM, McCarthy MM, Alvero AB et al (2007) The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization. J Transl Med 5(1):6PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    McKenzie JA, Liu T, Goodson AG, Grossman D (2010) Survivin enhances motility of melanoma cells by supporting Akt activation and α5 integrin upregulation. Cancer Res 70(20):7927–7937PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Mckenzie JA, Grossman D (2012) Role of the apoptotic and mitotic regulator survivin in melanoma. Anticancer Res 32(2):397–404PubMedGoogle Scholar
  155. 155.
    Lazar I, Perlman R, Lotem M, Peretz T, Ben-Yehuda D, Kadouri L (2012) The clinical effect of the inhibitor of apopotosis protein livin in melanoma. Oncology 82(4):197–204PubMedCrossRefGoogle Scholar
  156. 156.
    Tassi E, Zanon M, Vegetti C et al (2012) Role of apollon in human melanoma resistance to antitumor agents that activate the intrinsic or the extrinsic apoptosis pathways. Clin Cancer Res 18(12):3316–3327PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Cregan IL, Dharmarajan AM, Fox SA (2013) Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: Role of inhibitor of apoptosis proteins (IAPs) and caspases. Int J Oncol 42(2):444–452PubMedCrossRefGoogle Scholar
  158. 158.
    Dasgupta A, Alvarado CS, Xu Z, Findley HW (2010) Expression and functional role of inhibitor-of-apoptosis protein livin (BIRC7) in neuroblastoma. Biochem Biophys Res Commun 400(1):53–59PubMedCrossRefGoogle Scholar
  159. 159.
    Eschenburg G, Eggert A, Schramm A, Lode HN, Hundsdoerfer P (2012) Smac mimetic LBW242 sensitizes XIAP-overexpressing neuroblastoma cells for TNF-α–independent apoptosis. Cancer Res 72(10):2645–2656PubMedCrossRefGoogle Scholar
  160. 160.
    Najem S, Langemann D, Appl B, Trochimiuk M, Hundsdoerfer P, Reinshagen K, Eschenburg G (2016) Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L. Oncotarget 7(45):72634PubMedPubMedCentralGoogle Scholar
  161. 161.
    Lamers F, van der Ploeg I, Schild L et al (2011) Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe. Endocr Relat Cancer 18(6):657–668PubMedCrossRefGoogle Scholar
  162. 162.
    Cheng YJ, Jiang HS, Hsu SL, Lin LC, Wu CL, Ghanta VK, Hsueh CM (2010) XIAP-mediated protection of H460 lung cancer cells against cisplatin. Eur J Pharmacol 627(1):75–84PubMedCrossRefGoogle Scholar
  163. 163.
    Fan J, Wang L, Jiang GN, He WX, Ding JA (2008) The role of survivin on overall survival of non-small cell lung cancer, a meta-analysis of published literatures. Lung Cancer 61(1):91–96PubMedCrossRefGoogle Scholar
  164. 164.
    Sun JG, Liao RX, Zhang SX et al (2011) Role of inhibitor of apoptosis protein Livin in radiation resistance in nonsmall cell lung cancer. Cancer Biother Radiopharm 26(5):585–592PubMedCrossRefGoogle Scholar
  165. 165.
    Dong X, Lin D, Low C et al (2013) Elevated expression of BIRC6 protein in non–small-cell lung cancers is associated with cancer recurrence and chemoresistance. J Thorac Oncol 8(2):161–170PubMedCrossRefGoogle Scholar
  166. 166.
    Osaka E, Suzuki T, Osaka S et al (2007) Survivin expression levels as independent predictors of survival for osteosarcoma patients. J Orthop Res 25(1):116–121PubMedCrossRefGoogle Scholar
  167. 167.
    Nedelcu T, Kubista B, Koller A et al (2008) Livin and Bcl-2 expression in high-grade osteosarcoma. J Cancer Res Clin Oncol 134(2):237–244PubMedCrossRefGoogle Scholar
  168. 168.
    Qu Y, Xia P, Zhang S, Pan S, Zhao J (2015) Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin. Oncol Rep 33(3):1177–1184PubMedGoogle Scholar
  169. 169.
    Shaw TJ, Lacasse EC, Durkin JP, Vanderhyden BC (2008) Downregulation of XIAP expression in ovarian cancer cells induces cell death in vitro and in vivo. Int J Cancer 122(6):1430–1434PubMedCrossRefGoogle Scholar
  170. 170.
    Chen L, Liang L, Yan X et al (2013) Survivin status affects prognosis and chemosensitivity in epithelial ovarian cancer. Int J Gynecol Cancer 23(2):256–263PubMedCrossRefGoogle Scholar
  171. 171.
    Liu X, Wang A, Gao H, Yuan Z, Jiao Y (2012) Expression and role of the inhibitor of apoptosis protein livin in chemotherapy sensitivity of ovarian carcinoma. Int J Oncol 41(3):1021–1028PubMedCrossRefGoogle Scholar
  172. 172.
    Cohen S, Bruchim I, Graiver D et al (2013) Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2. J Mol Med 91(3):357–368PubMedCrossRefGoogle Scholar
  173. 173.
    Wang L, Chen YJ, Hou J, Wang YY, Tang WQ, Shen XZ, Tu RQ (2014) Expression and clinical significance of BIRC6 in human epithelial ovarian cancer. Tumor Biol 35(5):4891–4896CrossRefGoogle Scholar
  174. 174.
    Esposito I, Kleeff J, Abiatari I et al (2007) Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer. J Clin Pathol 60(8):885–895PubMedCrossRefGoogle Scholar
  175. 175.
    Lopes RB, Gangeswaran R, McNeish IA, Wang Y, Lemoine NR (2007) Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer 120(11):2344–2352PubMedCrossRefGoogle Scholar
  176. 176.
    Han Z, Lee S, Je S, Eom CY, Choi HJ, Song JJ, Kim JH (2016) Survivin silencing and TRAIL expression using oncolytic adenovirus increase anti-tumorigenic activity in gemcitabine-resistant pancreatic cancer cells. Apoptosis 21(3):351–364PubMedCrossRefGoogle Scholar
  177. 177.
    Seligson DB, Hongo F, Huerta-Yepez S et al (2007) Expression of X-linked inhibitor of apoptosis protein is a strong predictor of human prostate cancer recurrence. Clin Cancer Res 13(20):6056–6063PubMedCrossRefGoogle Scholar
  178. 178.
    Rodríguez-Berriguete G, Fraile B, de Bethencourt FR et al (2010) Role of IAPs in prostate cancer progression: immunohistochemical study in normal and pathological (benign hyperplastic, prostatic intraepithelial neoplasia and cancer) human prostate. BMC Cancer 10(1):18PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Mizutani Y, Nakanishi H, Li YN et al (2007) Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis. Int J Oncol 30(4):919–925PubMedGoogle Scholar
  180. 180.
    Lei Y, Geng Z, Guo-Jun W, He W, Jian-Lin Y (2010) Prognostic significance of survivin expression in renal cell cancer and its correlation with radioresistance. Mol Cell Biochem 344(1–2):23–31PubMedCrossRefGoogle Scholar
  181. 181.
    Kempkensteffen C, Hinz S, Christoph F et al (2007) Expression of the apoptosis inhibitor livin in renal cell carcinomas: correlations with pathology and outcome. Tumor Biol 28(3):132–138CrossRefGoogle Scholar
  182. 182.
    Simon-Keller K, Paschen A, Hombach AA et al (2013) Survivin blockade sensitizes rhabdomyosarcoma cells for lysis by fetal acetylcholine receptor–redirected T cells. Am J Pathol 182(6):2121–2131PubMedCrossRefGoogle Scholar
  183. 183.
    Tirrò E, Consoli ML, Massimino M et al (2006) Altered expression of c-IAP1, survivin, and Smac contributes to chemotherapy resistance in thyroid cancer cells. Cancer Res 66(8):4263–4272PubMedCrossRefGoogle Scholar
  184. 184.
    Antonaci A, Consorti F, Mardente S, Natalizi S, Giovannone G, Della Rocca C (2008) Survivin and cyclin D1 are jointly expressed in thyroid papillary carcinoma and microcarcinoma. Oncol Rep 20(1):63–67PubMedGoogle Scholar
  185. 185.
    Yim JH, Kim WG, Jeon MJ et al (2014) Association between expression of X-linked inhibitor of apoptosis protein and the clinical outcome in a BRAFV600E-prevalent papillary thyroid cancer population. Thyroid 24(4):689–694PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    El-Mesallamy HO, Hegab HM, Kamal AM (2011) Expression of inhibitor of apoptosis protein (IAP) livin/BIRC7 in acute leukemia in adults: correlation with prognostic factors and outcome. Leuk Res 35(12):1616–1622PubMedCrossRefGoogle Scholar
  187. 187.
    Hundsdoerfer P, Dietrich I, Schmelz K, Eckert C, Henze G (2010) XIAP expression is post-transcriptionally upregulated in childhood ALL and is associated with glucocorticoid response in T-cell ALL. Pediatr Blood Cancer 55(2):260–266PubMedCrossRefGoogle Scholar
  188. 188.
    Park E, Gang EJ, Hsieh YT et al (2011) Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood 118(8):2191–2199PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Ismail EAR, Mahmoud HM, Tawfik LM et al (2012) BIRC6/Apollon gene expression in childhood acute leukemia: impact on therapeutic response and prognosis. Eur J Haematol 88(2):118–127PubMedCrossRefGoogle Scholar
  190. 190.
    Moreno-Martínez D, Nomdedeu M, Lara-Castillo MC et al (2014) XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells. Oncotarget 5(12):4337–4346PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Carter BZ, Qiu Y, Huang X et al (2012) Survivin is highly expressed in CD34 + 38 – leukemic stem/progenitor cells and predicts poor clinical outcomes in AML. Blood 120(1):173–180PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Loeder S, Zenz T, Schnaiter A et al (2009) A novel paradigm to trigger apoptosis in chronic lymphocytic leukemia. Cancer Res 69(23):8977–8986PubMedCrossRefGoogle Scholar
  193. 193.
    Silva KL, de Souza PS, de Moraes GN et al (2013) XIAP and P-glycoprotein co-expression is related to imatinib resistance in chronic myeloid leukemia cells. Leuk Res 37(10):1350–1358PubMedCrossRefGoogle Scholar
  194. 194.
    Stella S, Tirro E, Conte E et al (2013) Suppression of survivin induced by a BCR-ABL/JAK2/STAT3 pathway sensitizes imatinib-resistant CML cells to different cytotoxic drugs. Mol Cancer Ther 12(6):1085–1098PubMedCrossRefGoogle Scholar
  195. 195.
    Okumu DO, East MP, Levine M et al (2017) BIRC6 mediates imatinib resistance independently of Mcl-1. PloS ONE 12(5):e0177871PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Akyurek N, Ren Y, Rassidakis GZ, Schlette EJ, Medeiros LJ (2006) Expression of inhibitor of apoptosis proteins in B-cell non-Hodgkin and Hodgkin lymphomas. Cancer 107(8):1844–1851PubMedCrossRefGoogle Scholar
  197. 197.
    Garcıa JF, Camacho FI, Morente M et al (2003) Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays. Blood 101(2):681–689PubMedCrossRefGoogle Scholar
  198. 198.
    Ramakrishnan V, Painuly U, Kimlinger T, Haug J, Rajkumar SV, Kumar S (2014) Inhibitor of apoptosis proteins (IAPs) as therapeutic targets in multiple myeloma (MM). Leukemia 28(7):1519PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Tsubaki M, Takeda T, Ogawa N et al (2015) Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells. Leuk Res 39(4):445–452PubMedCrossRefGoogle Scholar
  200. 200.
    Cillessen SA, Reed JC, Welsh K et al (2008) Small-molecule XIAP antagonist restores caspase-9–mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells. Blood 111(1):369–375PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Jacquemin G, Granci V, Gallouet AS et al (2012) Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin’s lymphoma B cells. Haematologica 97(1):38–46PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Mobahat M, Narendran A, Riabowol K (2014) Survivin as a preferential target for cancer therapy. Int J Mol Sci 15(2):2494–2516PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Krieg A, Werner TA, Verde PE, Stoecklein NH, Knoefel WT (2013). Prognostic and clinicopathological significance of survivin in colorectal cancer: a meta-analysis. PloS ONE 8(6):e65338PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Chen J, Li T, Liu Q, Jiao H, Yang W, Liu X, Huo Z (2014). Clinical and prognostic significance of HIF-1α, PTEN, CD44v6, and survivin for gastric cancer: a meta-analysis. PloS ONE 9(3):e91842PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Fernández JG, Rodríguez DA, Valenzuela M et al (2014) Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription. Mol Cancer 13(1):209PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Martini E, Schneider E, Neufert C, Neurath MF, Becker C (2016) Survivin is a guardian of the intestinal stem cell niche and its expression is regulated by TGF-β. Cell Cycle 15(21):2875–2881PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Fukuda S, Hoggatt J, Singh P et al (2015) Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1. Leukemia 29(2):433–441PubMedCrossRefGoogle Scholar
  208. 208.
    Feng R, Zhou S, Liu Y et al (2013) Sox2 protects neural stem cells from apoptosis via up-regulating survivin expression. Biochem J 450(3):459–468PubMedCrossRefGoogle Scholar
  209. 209.
    Tamm I, Richter S, Oltersdorf D et al (2004) High expression levels of x-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia. Clin Cancer Res 10(11):3737–3744PubMedCrossRefGoogle Scholar
  210. 210.
    Sung KW, Choi J, Hwang YK et al (2009) Overexpression of X-linked inhibitor of apoptosis protein (XIAP) is an independent unfavorable prognostic factor in childhood de novo acute myeloid leukemia. J Korean Med Sci 24(4):605–613PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Tamm I, Richter S, Scholz F et al (2004) XIAP expression correlates with monocytic differentiation in adult de novo AML: impact on prognosis. Hematol J 5(6):489–495PubMedCrossRefGoogle Scholar
  212. 212.
    Ma JJ, Chen BL, Xin XY (2009) XIAP gene downregulation by small interfering RNA inhibits proliferation, induces apoptosis, and reverses the cisplatin resistance of ovarian carcinoma. Eur J Obstet Gynecol Reprod Biol 146(2):222–226PubMedCrossRefGoogle Scholar
  213. 213.
    Endo T, Abe S, Seidlar HBK et al (2004) Expression of IAP family proteins in colon cancers from patients with different age groups. Cancer Immunol Immunother 53(9):770–776PubMedCrossRefGoogle Scholar
  214. 214.
    Cha JD, Kim HK, Cha IH (2014) Cytoplasmic HuR expression: Correlation with cellular inhibitors of apoptosis protein-2 expression and clinicopathologic factors in oral squamous cell carcinoma cells. Head Neck 36(8):1168–1175PubMedCrossRefGoogle Scholar
  215. 215.
    Mannhold R, Fulda S, Carosati E (2010) IAP antagonists: promising candidates for cancer therapy. Drug Discov Today 15(5):210–219PubMedCrossRefGoogle Scholar
  216. 216.
    Connolly K, Mitter R, Muir M, Jodrell D, Guichard S (2009) Stable XIAP knockdown clones of HCT116 colon cancer cells are more sensitive to TRAIL, taxanes and irradiation in vitro. Cancer Chemother Pharmacol 64(2):307–316PubMedCrossRefGoogle Scholar
  217. 217.
    Holt SV, Brookes KE, Dive C, Makin GW (2011) Down-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents. Oncol Rep 25(4):1177–1181PubMedGoogle Scholar
  218. 218.
    Ohnishi K, Nagata Y, Takahashi A, Taniguchi S, Ohnishi T (2008) Effective enhancement of X-ray-induced apoptosis in human cancer cells with mutated p53 by siRNA targeting XIAP. Oncol Rep 20(1):57–61PubMedGoogle Scholar
  219. 219.
    Yamaguchi Y, Shiraki K, Fuke H et al (2005) Targeting of X-linked inhibitor of apoptosis protein or survivin by short interfering RNAs sensitize hepatoma cells to TNF-related apoptosis-inducing ligand-and chemotherapeutic agent-induced cell death. Oncol Rep 14(5):1311–1316PubMedGoogle Scholar
  220. 220.
    Schimmer AD, Estey EH, Borthakur G et al (2009) Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia. J Clin Oncol 27(28):4741–4746PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Mahadevan D, Chalasani P, Rensvold D et al (2013) Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. Am J Clin Oncol 36(3):239–243PubMedCrossRefGoogle Scholar
  222. 222.
    Lee FA, Zee BCY, Cheung FY et al (2016) Randomized phase II study of the X-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC). Am J Clin Oncol 39(6):609–613PubMedCrossRefGoogle Scholar
  223. 223.
    Schimmer AD, Herr W, Hänel M et al (2011) Addition of AEG35156 XIAP antisense oligonucleotide in reinduction chemotherapy does not improve remission rates in patients with primary refractory acute myeloid leukemia in a randomized phase II study. Clin Lymphoma Myeloma Leuk 11(5):433–438PubMedCrossRefGoogle Scholar
  224. 224.
    Dean EJ, Ward T, Pinilla C et al (2010) A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC. Br J Cancer 102(1):97PubMedCrossRefGoogle Scholar
  225. 225.
    Metwalli AR, Khanbolooki S, Jinesh G et al (2010) Smac mimetic reverses resistance to TRAIL and chemotherapy in human urothelial cancer cells. Cancer Biol Ther 10(9):885–892PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Stadel D, Cristofanon S, Abhari BA et al (2011) Requirement of nuclear factor κB for Smac mimetic–mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. Neoplasia 13(12):1162–1170PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Servida F, Lecis D, Scavullo C et al (2011) Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis. Invest New Drugs 29(6):1264–1275PubMedCrossRefGoogle Scholar
  228. 228.
    Loeder S, Fakler M, Schoeneberger H et al (2012) RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis. Leukemia 26(5):1020–1029CrossRefGoogle Scholar
  229. 229.
    Wagner L, Marschall V, Karl S et al (2013) Smac mimetic sensitizes glioblastoma cells to Temozolomide-induced apoptosis in a RIP1-and NF-[kappa] B-dependent manner. Oncogene 32(8):988PubMedCrossRefGoogle Scholar
  230. 230.
    Finlay D, Vamos M, González-López M et al (2014) Small-molecule IAP antagonists sensitize cancer cells to TRAIL-induced apoptosis: roles of XIAP and cIAPs. Mol Cancer Ther 13(1):5–15PubMedCrossRefGoogle Scholar
  231. 231.
    Schirmer M, Trentin L, Queudeville M et al (2016) Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia. Cell Death Dis 7(1):e2052PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Beug ST, Tang VA, LaCasse EC et al (2014) Smac mimetics and innate immune stimuli synergize to promote tumor death. Nat Biotechnol 32(2):182–190PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Infante JR, Dees EC, Olszanski AJ, Dhuria SV, Sen S, Cameron S, Cohen RB (2014) Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol 32(28):3103–3110PubMedCrossRefGoogle Scholar
  234. 234.
    Dienstmann R, Adamo B, Vidal L, Dees EC, Chia S, Mayer EL et al (2012) Phase Ib study of LCL161, an oral antagonist of inhibitor of apoptosis proteins, in combination with weekly paclitaxel in patients with advanced solid tumors. Cancer Res. doi: 10.1158/0008-5472.SABCS12-P6-11-06 Google Scholar
  235. 235.
    Parton M, Bardia A, Kummel S et al (2015) A phase II, open-label, neoadjuvant, randomized study of LCL161 with paclitaxel in patients with triple-negative breast cancer (TNBC). J Clin Oncol 33(15):1014–1014Google Scholar
  236. 236.
    Hurwitz HI, Smith DC, Pitot HC et al (2015) Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Cancer Chemother Pharmacol 75(4):851–859PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Tolcher AW, Papadopoulos KP, Patnaik A et al (2013) Phase I study of safety and pharmacokinetics (PK) of GDC-0917, an antagonist of inhibitor of apoptosis (IAP) proteins in patients (Pts) with refractory solid tumors or lymphoma. J Clin Oncol 31(15):2503–2503Google Scholar
  238. 238.
    Tolcher A, Bendell JC, Papadopoulos KP et al (2016) A phase I dose escalation study evaluating the safety tolerability and pharmacokinetics of cudc-427, a potent, oral, monovalent IAP antagonist, in patients with refractory solid tumors. Clin Cancer Res 22(18):4567–4573PubMedCrossRefGoogle Scholar
  239. 239.
    Amaravadi RK, Schilder RJ, Martin LP et al (2015) A phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol Cancer Ther 14(11):2569–2575PubMedCrossRefGoogle Scholar
  240. 240.
    Amaravadi RK, Senzer NN, Martin LP et al (2013) A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients. J Clin Oncol 31(15):2504–2504Google Scholar
  241. 241.
    Senzer NN, LoRusso P, Martin LP et al (2013) Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer. J Clin Oncol 31(15):3621–3621Google Scholar
  242. 242.
    Noonan AM, Bunch KP, Chen JQ et al (2016) Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or-refractory epithelial ovarian cancer. Cancer 122(4):588–597PubMedCrossRefGoogle Scholar
  243. 243.
    Hamilton EP, Birrer MJ, DiCarlo BA et al (2015) A phase 1b, open-label, non-randomized multicenter study of birinapant in combination with conatumumab in subjects with relapsed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. J Clin Oncol 33(15):5571–5571Google Scholar
  244. 244.
    Donnellan WB, Diez-Campelo M, Heuser M et al (2016) A phase 2 study of azacitidine (5-AZA) with or without birinapant in subjects with higher risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). J Clin Oncol 34(15):7060–7060Google Scholar
  245. 245.
    Sikic BI, Eckhardt SG, Gallant G et al (2011) Safety, pharmacokinetics (PK), and pharmacodynamics (PD) of HGS1029, an inhibitor of apoptosis protein (IAP) inhibitor, in patients (Pts) with advanced solid tumors: Results of a phase I study. J Clin Oncol 29(15):3008–3008CrossRefGoogle Scholar
  246. 246.
    Nikolovska-Coleska Z, Xu L, Hu Z et al (2004) Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47(10):2430–2440PubMedCrossRefGoogle Scholar
  247. 247.
    Heo JY, Kim HJ, Kim SM et al (2011) Embelin suppresses STAT3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase PTEN. Cancer Lett 308(1):71–80PubMedCrossRefGoogle Scholar
  248. 248.
    Dai Y, DeSano J, Qu Y, Tang W, Meng Y, Lawrence TS, Xu L (2011) Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer. Am J Cancer Res 1(2):128–143PubMedGoogle Scholar
  249. 249.
    Ali AG, Mohamed MF, Abdelhamid AO, Mohamed MS (2017) A novel adamantane thiadiazole derivative induces mitochondria-mediated apoptosis in lung carcinoma cell line. Bioorg Med Chem 25(1):241–253PubMedCrossRefGoogle Scholar
  250. 250.
    Sun H, Liu L, Lu J, Qiu S, Yang CY, Yi H, Wang S (2010) Cyclopeptide Smac mimetics as antagonists of IAP proteins. Bioorg Med Chem Lett 20(10):3043–3046PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    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(5):902–914PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Mitsuuchi Y, Benetatos CA, Deng Y et al (2017) Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-κB signaling by degrading TRAF2-associated cIAP1 in cancer cells. Cell Death Discov 3:16046PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    Grossman D, McNiff JM, Li F, Altieri DC (1999) Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 113(6):1076–1081PubMedCrossRefGoogle Scholar
  254. 254.
    Sharma H, Sen S, Lo Muzio L, Mariggiò MA, Singh N (2005) Antisense-mediated downregulation of anti-apoptotic proteins induces apoptosis and sensitizes head and neck squamous cell carcinoma cells to chemotherapy. Cancer Biol Ther 4(7):720–727PubMedCrossRefGoogle Scholar
  255. 255.
    Rödel F, Frey B, Leitmann W, Capalbo G, Weiss C, Rödel C (2008) Survivin antisense oligonucleotides effectively radiosensitize colorectal cancer cells in both tissue culture and murine xenograft models. Int J Radiat Oncol Biol Phys 71(1):247–255PubMedCrossRefGoogle Scholar
  256. 256.
    Du ZX, Zhang HY, Gao DX, Wang HQ, Li YJ, Liu GL (2006) Antisurvivin oligonucleotides inhibit growth and induce apoptosis in human medullary thyroid carcinoma cells. Exp Mol Med 38(3):230PubMedCrossRefGoogle Scholar
  257. 257.
    Natale R, Blackhall F, Kowalski D et al (2014) Evaluation of antitumor activity using change in tumor size of the survivin antisense oligonucleotide LY2181308 in combination with docetaxel for second-line treatment of patients with non–small-cell lung cancer: a randomized open-label phase II study. J Thorac Oncol 9(11):1704–1708PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Kami K, Doi R, Koizumi M et al (2005) Downregulation of survivin by siRNA diminishes radioresistance of pancreatic cancer cells. Surgery 138(2):299–305PubMedCrossRefGoogle Scholar
  259. 259.
    Yang CT, Li JM, Weng HH, Li YC, Chen HC, Chen MF (2010) Adenovirus-mediated transfer of siRNA against survivin enhances the radiosensitivity of human non-small cell lung cancer cells. Cancer Gene Ther 17(2):120PubMedCrossRefGoogle Scholar
  260. 260.
    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(12):7719–7724PubMedCrossRefGoogle Scholar
  261. 261.
    Liu W, Zhu F, Jiang Y, Sun D, Yang B, Yan H (2013) siRNA targeting survivin inhibits the growth and enhances the chemosensitivity of hepatocellular carcinoma cells. Oncol Rep 29(3):1183–1188PubMedCrossRefGoogle Scholar
  262. 262.
    Vogl TJ, Oppermann E, Qian J et al (2016) Transarterial chemoembolization of hepatocellular carcinoma in a rat model: the effect of additional injection of survivin siRNA to the treatment protocol. BMC Cancer 16(1):325PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Cui M, Au JLS, Wientjes MG, O’donnell MA, Loughlin KR, Lu Z (2015) Intravenous siRNA silencing of survivin enhances activity of mitomycin C in human bladder RT4 xenografts. J Urol 194(1):230–237PubMedPubMedCentralCrossRefGoogle Scholar
  264. 264.
    Salzano G, Navarro G, Trivedi MS, De Rosa G, Torchilin VP (2015) Multifunctional polymeric micelles co-loaded with anti-survivin siRNA and paclitaxel overcome drug resistance in an animal model of ovarian cancer. Mol Cancer Ther 14(4):1075–1084PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Wang T, Gantier MP, Xiang D et al (2015) EpCAM aptamer-mediated survivin silencing sensitized cancer stem cells to doxorubicin in a breast cancer model. Theranostics 5(12):1456PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Pennati M, Folini M, Zaffaroni N (2007) Targeting survivin in cancer therapy: fulfilled promises and open questions. Carcinogenesis 28(6):1133–1139PubMedCrossRefGoogle Scholar
  267. 267.
    Zhang S, Wang X, Gu Z, Wang L (2016) Small molecule survivin inhibitor YM155 displays potent activity against human osteosarcoma cells. Cancer Investig 34(8):401–407CrossRefGoogle Scholar
  268. 268.
    Ueno T, Uehara S, Nakahata K, Okuyama H (2016) Survivin selective inhibitor YM155 promotes cisplatin induced apoptosis in embryonal rhabdomyosarcoma. Int J Oncol 48(5):1847–1854PubMedGoogle Scholar
  269. 269.
    Nakahara T, Takeuchi M, Kinoyama I et al (2007) YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67(17):8014–8021PubMedCrossRefGoogle Scholar
  270. 270.
    Na YS, Yang SJ, Kim SM et al (2012) YM155 induces EGFR suppression in pancreatic cancer cells. PLoS ONE 7(6):e38625PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Ling X, Cao S, Cheng Q, Keefe JT, Rustum YM, Li F (2012) A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity. PloS ONE 7(9):e45571PubMedPubMedCentralCrossRefGoogle Scholar
  272. 272.
    Coumar MS, Tsai FY, Kanwar JR, Sarvagalla S, Cheung CHA (2013) Treat cancers by targeting survivin: just a dream or future reality? Cancer Treat Rev 39(7):802–811PubMedCrossRefGoogle Scholar
  273. 273.
    Grossman SA, Ye X, Peereboom D et al (2012) Phase I study of terameprocol in patients with recurrent high-grade glioma. Neuro-Oncol 14(4):511–517PubMedPubMedCentralCrossRefGoogle Scholar
  274. 274.
    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(27):4481–4486PubMedCrossRefGoogle Scholar
  275. 275.
    Cheson BD, Bartlett NL, Vose JM et al (2012) A phase II study of the survivin suppressant YM155 in patients with refractory diffuse large B-cell lymphoma. Cancer 118(12):3128–3134PubMedCrossRefGoogle Scholar
  276. 276.
    Papadopoulos KP, Lopez-Jimenez J, Smith SE et al (2016) A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. Leuk Lymphoma 57(8):1848–1855PubMedCrossRefGoogle Scholar
  277. 277.
    Kudchadkar R, Ernst S, Chmielowski B et al (2015) 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 4(5):643–650PubMedCrossRefGoogle Scholar
  278. 278.
    Clemens MR, Gladkov OA, Gartner E et al (2015) Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer. Breast Cancer Res Treat 149(1):171–179PubMedCrossRefGoogle Scholar
  279. 279.
    Kelly RJ, Thomas A, Rajan A et al (2013) A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 24(10):2601–2606PubMedPubMedCentralCrossRefGoogle Scholar
  280. 280.
    Raetz EA, Morrison D, Romanos-Sirakis E et al (2014) A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. J Pediatr Hematol Oncol 36(6):458PubMedPubMedCentralCrossRefGoogle Scholar
  281. 281.
    Erba HP, Sayar H, Juckett M et al (2013) Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML). Investig New Drugs 31(4):1023–1034CrossRefGoogle Scholar
  282. 282.
    Wiechno PJ, Chlosta P, Pikiel J et al (2013) Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC). J Clin Oncol 31(15):5019–5019Google Scholar
  283. 283.
    Rohn JL, Noteborn MHM (2004) The viral death effector Apoptin reveals tumor-specific processes. Apoptosis 9(3):315–322PubMedCrossRefGoogle Scholar
  284. 284.
    Ruiz-Martínez S, Castro J, Vilanova M et al (2017) A truncated apoptin protein variant selectively kills cancer cells. Investig New Drugs 35(3):260–268CrossRefGoogle Scholar
  285. 285.
    Philchenkov A, Zavelevich M, Kroczak TJ, Los MJ (2004) Caspases and cancer: mechanisms of inactivation and new treatment modalities. Exp Oncol 26(2):82–97PubMedGoogle Scholar
  286. 286.
    Yamabe K, Shimizu S, Ito T et al (1999) Cancer gene therapy using a pro-apoptotic gene, caspase-3. Gene Ther 6(12):1952–1959PubMedCrossRefGoogle Scholar
  287. 287.
    Li X, Fan R, Zou X et al (2007) Inhibitory effect of recombinant adenovirus carrying immunocaspase-3 on hepatocellular carcinoma. Biochem Biophys Res Commun 358(2):489–494PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of ScienceUniversity of TabukTabukKingdom of Saudi Arabia
  2. 2.Department of Chemistry, Biochemistry Speciality, Faculty of ScienceCairo UniversityGizaEgypt
  3. 3.Department of RadiotherapyChildren’s Cancer Hospital Egypt (CCHE)CairoEgypt
  4. 4.Department of BiochemistryEl Sahel Teaching HospitalCairoEgypt
  5. 5.TabukKingdom of Saudi Arabia

Personalised recommendations