Targeting Inhibitors of Apoptosis Proteins (IAPs) For New Breast Cancer Therapeutics

  • Shaomeng Wang
  • Longchuan Bai
  • Jianfeng Lu
  • Liu Liu
  • Chao-Yie Yang
  • Haiying Sun
Article

Abstract

Apoptosis resistance is a hallmark of human cancer. Research in the last two decades has identified key regulators of apoptosis, including inhibitor of apoptosis proteins (IAPs). These critical apoptosis regulators have been targeted for the development of new cancer therapeutics. In this article, we will discuss three members of IAP proteins, namely XIAP, cIAP1 and cIAP2, as cancer therapeutic targets and the progress made in developing new cancer therapeutic agents to target these IAP proteins.

Keywords

Apoptosis IAPs Smac Small-molecule drugs 

Abbreviations

AIF

Apoptosis-Inducing Factor

Apaf-1

Apoptotic protease activating factor 1

Apo2L

Apo2 ligand

Apo3L

Apo3 ligand

Bcl-2

B-cell lymphoma 2

BIR

Baculoviral IAP Repeat domain

CARD

Caspase Recruitment Domain

CD95

Cluster of Differentiation 95

cFLIP

cellular FLICE-inhibitory protein

cIAP1

cellular Inhibitor of Apoptosis Protein 1

cIAP2

cellular Inhibitor of Apoptosis Proteins 2

dATP

Deoxyadenosine triphosphate

DIABLO

Direct IAP-Binding protein with Low PI

DISC

Death-Inducing Signaling Complex

DR

Death Receptor

FADD

Fas-Associated protein with Death Domain

FasR

Fas Receptor

IAPs

Inhibitors of Apoptosis Proteins

IHC

Immunohistochemistry

LRIG1

Leucine-Rich repeats and immunoglobulin-like domains protein 1

ML-IAP

Melanoma Inhibitor of Apoptosis Protein

NCI

National Cancer Institute

NFκB

Nuclear Factor kappa-light-chain-enhancer of activated B cells

PMBC

Peripheral Mononuclear Blood cells

RING

Really Interesting New Gene

RIPK1

Receptor-Interacting serine/threonine-protein Kinase 1

RTK

Receptor Tyrosine Kinase

Smac

Second Mitochondria-derived Activator of Caspases

TNF

Tumor Necrosis Factor

TNF-alpha

Tumor Necrosis Factor-alpha

TNFR

Tumor Necrosis Factor Receptor

TRADD

TNFR Associated DEATH Domain

TRAF

TNF Receptor Associated Factor

TRAIL

TNF Related Apoptosis-Inducing Ligand

UBA

Ubiquitin-Associated domain

References

  1. 1.
    Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21:485–95.PubMedCrossRefGoogle Scholar
  2. 2.
    Nicholson DW. From bench to clinic with apoptosis-based therapeutic agents. Nature. 2000;407:810–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov. 2002;1:111–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMedCrossRefGoogle Scholar
  5. 5.
    Fulda S, Debatin K-M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2005;25:4798–811.CrossRefGoogle Scholar
  6. 6.
    Candé CVN, Garrido C, Kroemer G. Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ. 2004;11:591–5.PubMedGoogle Scholar
  7. 7.
    Deveraux QL, Reed JC. IAP family proteinssuppressors of apoptosis. Genes Dev. 1999;13:239–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Shiozaki EN, Shi Y. Caspases, IAPs and Smac/DIABLO: mechanisms from structural biology. Trends Biochem Sci. 2004;29:486–94.PubMedCrossRefGoogle Scholar
  9. 9.
    Schimmer AD. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res. 2004;64:7183–90.PubMedCrossRefGoogle Scholar
  10. 10.
    Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 2002;3:401–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov. 2012;11:109–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Crook NE, Clem RJ, Miller LK. An apoptosis inhibiting baculovirus gene with a zinc finger-like motif. J Virol. 1993;67:2168–74.PubMedGoogle Scholar
  13. 13.
    Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol. 2000;10:1359–66.PubMedCrossRefGoogle Scholar
  14. 14.
    Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 2010;10:561–74.PubMedCrossRefGoogle Scholar
  15. 15.
    Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, Scudiero DA, Tudor G, Qui YH, Monks A, Andreeff M, Reed JC. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000;6:1796–803.PubMedGoogle Scholar
  16. 16.
    Jaffer S, Orta L, Sunkara S, Sabo E, Burstein DE. Immunohistochemical detection of antiapoptotic protein X-linked inhibitor of apoptosis in mammary carcinoma. Hum Pathol. 2007;38:864–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Wang J, Liu Y, Ji R, Gu Q, Zhao X, Sun B. Prognostic value of the X-linked inhibitor of apoptosis protein for invasive ductal breast cancer with triple-negative phenotype. Hum Pathol. 2010;41:1186–95.PubMedCrossRefGoogle Scholar
  18. 18.
    Foster FM, Owens TW, Tanianis-Hughes J, Clarke RB, Brennan K, Bundred NJ, Streuli CH. Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer. Breast Canc Res. 2009;11:R41.CrossRefGoogle Scholar
  19. 19.
    Parton M, Krajewski S, Smith I, Krajewska M, Archer C, Naito M, Ahern R, Reed J, Dowsett M. Coordinate expression of apoptosis-associated proteins in human breast cancer before and during chemotherapy. Clin Cancer Res. 2002;8:2100–8.PubMedGoogle Scholar
  20. 20.
    Yang L, Cao Z, Yan H, Wood WC. Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res. 2003;63:6815–24.PubMedGoogle Scholar
  21. 21.
    Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102:43–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000;406:855–62.PubMedCrossRefGoogle Scholar
  24. 24.
    Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature. 2000;408:1004–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Wang S. Design of small-molecule Smac mimetics as IAP antagonists. Curr Top Microbiol Immunol. 2011;348:89–113.PubMedCrossRefGoogle Scholar
  26. 26.
    Oost TK, Sun C, Armstrong RC, Al-Assaad AS, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak ET, Oleksijew A, Oltersdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H, Fesik SW. Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem. 2004;47:4417–26.PubMedCrossRefGoogle Scholar
  27. 27.
    Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, Liu L, Qiu S, Yang C-Y, Miller R, Yi H, Zhang T, Sun D, Kang S, Guo M, Leopold L, Yang D, Wang S. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem. 2011;54:2714–26.PubMedCrossRefGoogle Scholar
  28. 28.
    Flygare JA, Beresini M, Budha N, Chan H, Chan IT, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt SG, Elliott LO, Feng B, Franklin MC, Reisner SF, Gazzard L, Halladay J, Hymowitz SG, La H, LoRusso P, Maurer B, Murray L, Plise E, Quan C, Stephan JP, Young SG, Tom J, Tsui V, Um J, Varfolomeev E, Vucic D, Wagner AJ, Wallweber HJ, Wang L, Ware J, Wen Z, Wong H, Wong JM, Wong M, Wong S, Yu R, Zobel K, Fairbrother WJ. Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J Med Chem. 2012;55:4101–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Chauhan D, Neri P, Velankar M, Podar K, Hideshima T, Fulciniti M, Tassone P, Raje N, Mitsiades C, Mitsiades N, Richardson P, Zawel L, Tran M, Munshi N, Anderson KC. Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood. 2007;109:1220–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Gaither A, Porter D, Yao Y, Borawski J, Yang G, Donovan J, Sage D, Slisz J, Tran M, Straub C, Ramsey T, Iourgenko V, Huang A, Chen Y, Schlegel R, Labow M, Fawell S, Sellers WR, Zawel L. A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. Cancer Res. 2007;67:11493–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG. A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science. 2004;305:1471–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, Harran P, Wang X. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Canc Cell. 2007;12:445–56.CrossRefGoogle Scholar
  33. 33.
    Sun H, Nikolovska-Coleska Z, Lu J, Meagher JL, Yang CY, Qiu S, Tomita Y, Ueda Y, Jiang S, Krajewski K, Roller PP, Stuckey JA, Wang S. Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP. J Am Chem Soc. 2007;129:15279–94.PubMedCrossRefGoogle Scholar
  34. 34.
    Lu J, Bai L, Sun H, Nikolovska-Coleska Z, McEachern D, Qiu S, Miller RS, Yi H, Shangary S, Sun Y, Meagher JL, Stuckey JA, Wang S. SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. Cancer Res. 2008;68:9384–93.PubMedCrossRefGoogle Scholar
  35. 35.
    Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, Flygare JA, Fairbrother WJ, Deshayes K, Dixit VM, Vucic D. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131:669–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007;131:682–93.PubMedCrossRefGoogle Scholar
  37. 37.
    Dueber EC, Schoeffler AJ, Lingel A, Elliott JM, Fedorova AV, Giannetti AM, Zobel K, Maurer B, Varfolomeev E, Wu P, Wallweber HJ, Hymowitz SG, Deshayes K, Vucic D, Fairbrother WJ. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science. 2011;334:376–80.PubMedCrossRefGoogle Scholar
  38. 38.
    Feltham R, Bettjeman B, Budhidarmo R, Mace PD, Shirley S, Condon SM, Chunduru SK, McKinlay MA, Vaux DL, Silke J, Day CL. Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization. J Biol Chem. 2011;286:17015–28.PubMedCrossRefGoogle Scholar
  39. 39.
    Cheung HH, Mahoney DJ, Lacasse EC, Korneluk RG. Down-regulation of c-FLIP Enhances death of cancer cells by smac mimetic compound. Cancer Res. 2009;69:7729–38.PubMedCrossRefGoogle Scholar
  40. 40.
    Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8:808–15.PubMedGoogle Scholar
  41. 41.
    Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem. 2002;277:44236–43.PubMedCrossRefGoogle Scholar
  42. 42.
    Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T. Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide. Cancer Res. 2003;63:831–7.PubMedGoogle Scholar
  43. 43.
    Bockbrader KM, Tan M, Sun Y. A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells. Oncogene. 2005;24:7381–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Vogler M, Walczak H, Stadel D, Haas TL, Genze F, Jovanovic M, Gschwend JE, Simmet T, Debatin KM, Fulda S. Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo. Cancer Res. 2008;68:7956–65.PubMedCrossRefGoogle Scholar
  45. 45.
    Loeder S, Drensek A, Jeremias I, Debatin KM, Fulda S. Small molecule XIAP inhibitors sensitize childhood acute leukemia cells for CD95-induced apoptosis. Int J Cancer. 2010;126:2216–28.PubMedGoogle Scholar
  46. 46.
    Fakler M, Loeder S, Vogler M, Schneider K, Jeremias I, Debatin KM, Fulda S. Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance. Blood. 2009;113:1710–22.PubMedCrossRefGoogle Scholar
  47. 47.
    Probst BL, Liu L, Ramesh V, Li L, Sun H, Minna JD, Wang L. Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-alpha-dependent manner. Cell Death Differ. 2010;17:1645–54.PubMedCrossRefGoogle Scholar
  48. 48.
    Bai L, McEachern D, Yang CY, Lu J, Sun H, Wang S. LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFalpha expression and receptor tyrosine kinase signaling. Cancer Res. 2012;72:1229–38.PubMedCrossRefGoogle Scholar
  49. 49.
  50. 50.
    Infante JR, Claire Dees EC, Burris IHA, Zawel L, Sager JA, Stevenson C, Clarke K, Dhuria S, Porter D, Sen SK, Zannou E, Sharma S, Cohen RB. A phase I study of LCL161, an oral IAP inhibitor, in patients with advanced cancer. Abstract # 2775, AACR 101st Annual Meeting 2010, April 17–21, 2010, Washington, DC; 2010.Google Scholar
  51. 51.
    Graham MA, Mitsuuchi Y, Burns J, Chunduru S, Benetatos C, McKinlay M, Weng D, Wick MJ, Tolcher AW, Papadopoulos K, Amaravadi R, Schilder RJ, Adjei A, LoRusso P. In Abstract A25: Phase 1 PK/PD analysis of the Smac-mimetic TL32711 demonstrates potent and sustained cIAP1 suppression in patient PBMCs and tumor biopsies, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, San Francisco, CA, Nov 12–16, 2011, 2011; San Francisco, CA; 2011.Google Scholar
  52. 52.
    Sikic BI, Eckhardt SG, Gallant G, Burris HA, Camidge DR, Colevas AD, Jones SF, Messersmith WA, Wakelee HA, Li H, Kaminker PG, Morris S, Infante JR. In 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, 2011 ASCO Annual Meeting 2011; 2011.Google Scholar
  53. 53.
    Wu YT, Wagner KW, Bursulaya B, Schultz PG, Deveraux QL. Development and characterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction. Chem Biol. 2003;10:759–67.PubMedCrossRefGoogle Scholar
  54. 54.
    Schimmer AD, Welsh K, Pinilla C, Wang Z, Krajewska M, Bonneau MJ, Pedersen IM, Kitada S, Scott FL, Bailly-Maitre B, Glinsky G, Scudiero D, Sausville E, Salvesen G, Nefzi A, Ostresh JM, Houghten RA, Reed JC. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Canc Cell. 2004;5:25–35.CrossRefGoogle Scholar
  55. 55.
    Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP, Wang R, Fang X, Guo R, Zhang M, Lippman ME, Yang D, Wang S. 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. 2004;47:2430–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Shaomeng Wang
    • 1
  • Longchuan Bai
    • 1
  • Jianfeng Lu
    • 1
  • Liu Liu
    • 1
  • Chao-Yie Yang
    • 1
  • Haiying Sun
    • 1
  1. 1.Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal ChemistryUniversity of MichiganAnn ArborUSA

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