Skip to main content
SpringerLink
Log in

Characterization of dequalinium as a XIAP antagonist that targets the BIR2 domain

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Inhibitor of apoptosis proteins (IAPs) regulate the activity of caspases in apoptosis. The human X chromosome-encoded IAP (XIAP) is one of the more potent members of the IAP family and it has been described as a central regulator of apoptosis. Thus, molecules that inhibit XIAP could offer therapeutic opportunities to treat unwanted apoptosis inhibition. In the present study we have applied the selective optimization of side activities (SOSA) approach to the discovery of XIAP inhibitors. In this sense, we have identified dequalinium hydrochloride (Dq) as an inhibitor of the XIAP/caspase-3 interaction both in vitro and in cellular assays.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BIRs:

Baculovirus inhibitor of apoptosis proteins repeats

Bz:

Benzethonium chloride

cIAP:

Cellular inhibitor of apoptosis proteins 1

Dq:

Dequalinium hydrochloride

Gfa:

Glafenine hydrochloride

HeLa:

Human epithelial carcinoma cell line

IAP:

Inhibitor of apoptosis proteins

MBz:

Methyl benzethonium

MTT:

(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)

NMR:

Nuclear magnetic resonance spectroscopy

Smac/DIABLO protein:

Second mitochondria-derived activator of caspases/direct IAP-binding protein with low PI

SOSA:

Selective optimization of side activities

STD:

Saturation transfer difference

water-LOGSY:

Water-ligand observed by gradient spectroscopy

TNF:

Tumor necrosis factor alpha

XIAP:

X chromosome-encoded IAP

References

  1. Birnbaum MJ, Clem RJ, Miller LK (1994) An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs. J Virol 68:2521–2528

    PubMed  CAS  Google Scholar 

  2. Ndubaku C, Varfolomeev E, Wang L et al (2009) Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists. ACS Chem Biol 4:557–566

    Article  PubMed  CAS  Google Scholar 

  3. LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG (2008) IAP-targeted therapies for cancer. Oncogene 27:6252–6275

    Article  PubMed  CAS  Google Scholar 

  4. Lu M, Lin SC, Huang Y et al (2007) XIAP induces NF-kappaB activation via the BIR1/TAB 1 interaction and BIR1 dimerization. Mol Cell 26:689–702

    Article  PubMed  CAS  Google Scholar 

  5. Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388:300–304

    Article  PubMed  CAS  Google Scholar 

  6. Datta R, Oki E, Endo K, Biedermann V, Ren J, Kufe D (2000) XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. J Biol Chem 275:31733–31738

    Article  PubMed  CAS  Google Scholar 

  7. Takahashi R, Deveraux Q, Tamm I et al (1998) A single BIR domain of XIAP sufficient for inhibiting caspases. J Biol Chem 273:7787–7790

    Article  PubMed  CAS  Google Scholar 

  8. Sun C, Cai M, Gunasekera AH et al (1999) NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 401:818–822

    Article  PubMed  CAS  Google Scholar 

  9. Riedl SJ, Renatus M, Schwarzenbacher R et al (2001) Structural basis for the inhibition of caspase-3 by XIAP. Cell 104:791–800

    Article  PubMed  CAS  Google Scholar 

  10. Schimmer A, Dalili S, Batey RA, Riedl SJ (2006) Targeting XIAP for the treatment of malignancy. Cell Death Differ 13:179–188

    Article  PubMed  CAS  Google Scholar 

  11. Sun H, Liu L, Lu J et al (2010) Cyclopeptide Smac mimetics as antagonists of IAP proteins. Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-alpha-dependent manner. Bioorg Med Chem Lett 20:3043–3046

    Article  PubMed  CAS  Google Scholar 

  12. Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG (2004) A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305:1471–1474

    Article  PubMed  CAS  Google Scholar 

  13. Wu TY, Wagner KW, Bursulaya B, Schultz PG, Deveraux QL (2003) Development and characterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction. Chem Biol 10:759–767

    Article  PubMed  CAS  Google Scholar 

  14. Schimmer AD, Welsh K, Pinilla C et al (2004) Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5:25–35

    Article  PubMed  CAS  Google Scholar 

  15. Wermuth CG (2004) Selective optimization of side activities: another way for drug discovery. J Med Chem 47:1303–1314

    Article  PubMed  CAS  Google Scholar 

  16. Fearnhead HO (2001) Cell-free systems to study apoptosis. Methods Cell Biol 66:167–185

    Article  PubMed  CAS  Google Scholar 

  17. Garcia-Calvo M, Peterson EP, Rasper DM et al (1999) Purification and catalytic properties of human caspase family members. Cell Death Differ 6:362–369

    Article  PubMed  CAS  Google Scholar 

  18. Dalvit C, Pevarello P, Tato M, Veronesi M, Vulpetti A, Sundstrom M (2000) Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J Biomol NMR 18:65–68

    Article  PubMed  CAS  Google Scholar 

  19. Meyer B, Peters T (2003) NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angew Chem Int Ed Engl 42:864–890

    Article  PubMed  CAS  Google Scholar 

  20. Pajuelo L, Calvino E, Diez JC, Boyano-Adanez MD, Gil J, Sancho P (2010) Dequalinium induces apoptosis in peripheral blood mononuclear cells isolated from human chronic lymphocytic leukemia. Investig New Drugs

  21. Qin D, Sullivan R, Berkowitz WF, Bittman R, Rotenberg SA (2000) Inhibition of protein kinase C(alpha) by dequalinium analogues: dependence on linker length and geometry. J Med Chem 43:1413–1417

    Article  PubMed  CAS  Google Scholar 

  22. Sancho P, Galeano E, Nieto E, Delgado MD, Garcia-Perez AI (2007) Dequalinium induces cell death in human leukemia cells by early mitochondrial alterations which enhance ROS production. Leuk Res 31:969–978

    Article  PubMed  CAS  Google Scholar 

  23. Probst BL, Liu L, Ramesh V et al (2010) Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-alpha-dependent manner. Cell Death Differ 17:1645–1654

    Article  PubMed  CAS  Google Scholar 

  24. Galeano E, Nieto E, Garcia-Perez AI, Delgado MD, Pinilla M, Sancho P (2005) Effects of the antitumoural dequalinium on NB4 and K562 human leukemia cell lines. Mitochondrial implication in cell death. Leuk Res 29:1201–1211

    Article  PubMed  CAS  Google Scholar 

  25. Bleday R, Weiss MJ, Salem RR, Wilson RE, Chen LB, Steele G Jr (1986) Inhibition of rat colon tumor isograft growth with dequalinium chloride. Arch Surg 121:1272–1275

    Article  PubMed  CAS  Google Scholar 

  26. Modica-Napolitano JS, Aprille JR (2001) Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells. Adv Drug Deliv Rev 49:63–70

    Article  PubMed  CAS  Google Scholar 

  27. Owens TW, Foster FM, Valentijn A, Gilmore AP, Streuli CH (2010) Role for X-linked Inhibitor of apoptosis protein upstream of mitochondrial permeabilization. J Biol Chem 285:1081–1088

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Spanish Ministry of Science and Innovation (MICINN-BIO2007-60066), Generalitat Valenciana Prometeo 2010/005 (partially funded with ERDF) and Consolider-Ingenio 2010 (MICINN-CSD2008-00005C) to E.P.-P. We thank Susana Rubio and Alicia García-Jareño for technical assistance. Y.P.-R. was supported by a postdoctoral fellowship from National Autonomous University of Mexico and Consejo Superior de Investigaciones Científicas of Spain (UNAM-CSIC).

Author information

Authors and Affiliations

  1. Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Avda Autopista Saler, 16, 46012, Valencia, Spain

    Mar Orzáez, Anna Gortat, Mónica Sancho, Yadira Palacios-Rodríguez & Enrique Pérez-Payá

  2. Laboratory of Structural Biochemistry, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain

    Rodrigo J. Carbajo & Antonio Pineda-Lucena

  3. Instituto de Biomedicina de Valencia, IBV-CSIC, 46010, Valencia, Spain

    Yadira Palacios-Rodríguez & Enrique Pérez-Payá

Authors
  1. Mar Orzáez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Gortat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mónica Sancho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rodrigo J. Carbajo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Pineda-Lucena
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yadira Palacios-Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Enrique Pérez-Payá
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mar Orzáez or Enrique Pérez-Payá.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Orzáez, M., Gortat, A., Sancho, M. et al. Characterization of dequalinium as a XIAP antagonist that targets the BIR2 domain. Apoptosis 16, 460–467 (2011). https://doi.org/10.1007/s10495-011-0582-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-011-0582-4

Keywords

Search

Navigation