Skip to main content
SpringerLink
Log in

Topoisomerases Inhibitors: A Paradigm for Interfacial Inhibition

  • Chapter
  • First Online:
DNA Topoisomerases and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Interfacial inhibition is a general mode of inhibition for natural toxins and synthetic molecules to alter the dynamics of biological complexes. Interfacial inhibitors bind at the interface of two or more macromolecules while the multimeric complex undergoes conformational transition. The complex is therefore stabilized and locked in an intermediate conformational state. In this chapter, we describe the interfacial inhibition concept and how it was discovered from studies with DNA topoisomerase inhibitors.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Andoh T (1998) Bis(2,6-dioxopiperazines), catalytic inhibitors of DNA topoisomerase II, as molecular probes, cardioprotectors and antitumor drugs. Biochimie 80: 235–246

    Article  CAS  PubMed  Google Scholar 

  • Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, Giordano I, Hann MM, Hennessy A, Hibbs M, Huang J, Jones E, Jones J, Brown KK, Lewis CJ, May EW, Saunders MR, Singh O, Spitzfaden CE, Shen C, Shillings A, Theobald AJ, Wohlkonig A, Pearson ND, Gwynn MN (2010) Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466(7309): 935–940

    Article  PubMed  Google Scholar 

  • Capranico G, Binaschi M (1998) DNA sequence selectivity of topoisomerases and topoisomerase poisons. Biochim Biophys Acta 1400(1–3): 185–194

    Article  CAS  PubMed  Google Scholar 

  • Capranico G, De Isabella P, Tinelli S, Bigioni S, Zunino F (1993) Similar sequence specificity of mitoxantrone and VM-26 stimulation of in vitro DNA cleavage by mammalian DNA topoisomerase II. Biochemistry 32: 3032–3048

    Google Scholar 

  • Capranico G, Kohn KW, Pommier Y (1990a) Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. Nucleic Acids Res 18(22): 6611–6619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Capranico G, Zunino F, Kohn KW, Pommier Y (1990b) Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity. Biochemistry 29(2): 562–569

    Article  CAS  PubMed  Google Scholar 

  • Chrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, Redinbo MR (2004) Mechanisms of camptothecin resistance by human topoisomerase I mutations. J Mol Biol 339(4): 773–784

    Article  CAS  PubMed  Google Scholar 

  • Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 1(3): 198–210

    Article  CAS  PubMed  Google Scholar 

  • Classen S, Olland S, Berger JM (2003) Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc Natl Acad Sci USA 100(19): 10629–10634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Covey JM, Jaxel C, Kohn KW, Pommier Y (1989) Protein-linked DNA strand breaks induced in Mammalian cells by camptothecin, an inhibitor of topoisomerase I. Cancer Res 49: 5016–5022

    CAS  PubMed  Google Scholar 

  • De Isabella P, Capranico G, Palumbo M, Sissi C, Krapcho AP, Zunino F (1993) Sequence selectivity of topoisomerase II DNA cleavage stimulated by mitoxantrone derivatives: relationship to drug DNA binding and cellular effects. Molecular Pharmacol 43: 715–721

    Google Scholar 

  • De Isabella P, Zunino F, Capranico G (1995) Base sequence determinants of amonafide stimulation of topoisomerase II DNA cleavage. Nucleic Acids Res 23(2): 223–229

    Article  PubMed Central  PubMed  Google Scholar 

  • Fujimori A, Harker WG, Kohlhagen G, Hoki Y, Pommier Y (1995) Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell resistant to camptothecin. Cancer Res 55: 1339–1346

    CAS  PubMed  Google Scholar 

  • Gentry AC, Juul S, Veigaard C, Knudsen BR, Osheroff N (2011) The geometry of DNA supercoils modulates the DNA cleavage activity of human topoisomerase I. Nucleic Acids Res 39(3): 1014–1022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heddle JG, Barnard FM, Wentzell LM, Maxwell A (2000) The interaction of drugs with DNA gyrase: a model for the molecular basis of quinolone action. Nucleosides Nucleotides Nucleic Acids 19(8): 1249–1264

    Article  CAS  PubMed  Google Scholar 

  • Hertzberg RP, Busby RW, Caranfa MJ, Holden KG, Johnson RK, Hecht SM, Kingsbury WD (1990) Irreversible trapping of the DNA-topoisomerase I covalent complex. J Biol Chem 265: 19287–19295

    CAS  PubMed  Google Scholar 

  • Hertzberg RP, Caranfa MJ, Hecht SM (1989) On the mechanism of topoisomerase I inhibition by camptothecin: Evidence for binding to an enzyme-DNA complex. Biochemistry 28: 4629–4638

    Article  CAS  PubMed  Google Scholar 

  • Hsiang Y-H, Liu LF, Wall ME, Wani MC, Nicholas AW, Manikumar G, Kirschenbaum S, Silber R, Potmesil M (1989) DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogs. Cancer Res 49: 4385–4389

    CAS  PubMed  Google Scholar 

  • Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260(27): 14873–14878

    CAS  PubMed  Google Scholar 

  • Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M (2005) Synthesis and Mechanism of Action Studies of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal an Inhibitor with a Flipped Orientation in the Ternary DNA-Enzyme-Inhibitor Complex As Determined by X-ray Crystallographic Analysis. J Med Chem 48(15): 4803–4814

    Article  CAS  PubMed  Google Scholar 

  • Ishida R, Sato M, Narita T, Utsumi KR, Nishimoto T, Morita T, Nagata H, Andoh T (1994) Inhibition of DNA topoisomerase II by ICRF-193 induces polyploidization by uncoupling chromosome dynamics from other cell cycle events. J Cell Biol 126(6): 1341–1351

    Article  CAS  PubMed  Google Scholar 

  • Jaxel C, Capranico G, Kerrigan D, Kohn KW, Pommier Y (1991) Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. J Biol Chem 266(30): 20418–20423

    CAS  PubMed  Google Scholar 

  • Jaxel C, Kohn KW, Pommier Y (1988) Topoisomerase I interaction with SV40 DNA in the presence and absence of camptothecin. Nucleic Acids Res 16: 11157–11170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jaxel C, Kohn KW, Wani MC, Wall ME, Pommier Y (1989) Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 49: 1465–1469

    CAS  PubMed  Google Scholar 

  • Kepler JA, Wani MC, McNaull JN, Wall ME, Levine SG (1969) Plant antitumor agents. IV. An approach toward the synthesis of camptothecin. J Org Chem 34(12): 3853–3858

    Article  CAS  PubMed  Google Scholar 

  • Koster DA, Palle K, Bot ES, Bjornsti MA, Dekker NH (2007) Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448(7150): 213–217

    Article  CAS  PubMed  Google Scholar 

  • Laponogov I, Sohi MK, Veselkov DA, Pan XS, Sawhney R, Thompson AW, McAuley KE, Fisher LM, Sanderson MR (2009) Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. Nat Struct Mol Biol 16(6): 667–669

    Article  CAS  PubMed  Google Scholar 

  • Leteurtre F, Fesen M, Kohlhagen G, Kohn KW, Pommier Y (1993) Specific interaction of camptothecin, a topoisomerase I inhibitor, with guanine residues of DNA detected by photoactivation at 365nm. Biochemistry 32: 8955–8962

    Article  CAS  PubMed  Google Scholar 

  • Leteurtre F, Kohlhagen G, Paull KD, Pommier Y (1994) Topoisomerase II inhibition by anthrapyrazoles, DuP 937 & DuP 941 (Losoxanthrone) and cytotoxicity in the NCI cell screen. J Natl Cancer Inst 86: 1239–1244

    Article  CAS  PubMed  Google Scholar 

  • Marchand C, Antony S, Kohn KW, Cushman M, Ioanoviciu A, Staker BL, Burgin AB, Stewart L, Pommier Y (2006) A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex. Mol Cancer Ther 5(2): 287–295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Monod J, Changeux JP, Jacob F (1963) Allosteric proteins and cellular control systems. J Mol Biol 6: 306–329

    Article  CAS  PubMed  Google Scholar 

  • Pommier Y, Capranico G, Orr A, Kohn KW (1991) Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide. Nucleic Acids Res 19(21): 5973–5980

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pommier Y, Cherfils J (2005) Interfacial inhibition of macromolecular interactions: nature’s paradigm for drug discovery. Trends Pharmacol Sci 26(3): 138–145

    Article  CAS  PubMed  Google Scholar 

  • Pommier Y, Kohlhagen G, Kohn F, Leteurtre F, Wani MC, Wall ME (1995) Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites. Proc Natl Acad Sci USA 92: 8861–8865

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pommier Y, Leo E, Zhang H, Marchand C (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17(5): 421–433

    Article  CAS  PubMed  Google Scholar 

  • Pommier Y, Marchand C (2005) Interfacial inhibitors of protein-nucleic acid interactions. Curr Med Chem Anticancer Agents 5(4): 421–429

    Article  CAS  PubMed  Google Scholar 

  • Pommier Y, Pourquier P, Urasaki Y, Wu J, Laco G (1999) Topoisomerase I inhibitors: selectivity and cellular resistance. Drug Resist Updat 2: 307–318

    Article  CAS  PubMed  Google Scholar 

  • Porter SE, Champoux JJ (1989) The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I. Nucleic Acids Res 17(21): 8521–8532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG (1998) Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 279(5356): 1504–1513

    Article  CAS  PubMed  Google Scholar 

  • Sirikantaramas S, Yamazaki M, Saito K (2008) Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants. Proc Natl Acad Sci USA 105(18): 6782–6786

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sissi C, Bolgan L, Moro S, Zagotto G, Bailly C, Menta E, Capranico G, Palumbo M (1998) DNA-binding preferences of bisantrene analogues: relevance to the sequence specificity of drug-mediated topoisomerase II poisoning. Mol Pharmacol 54(6): 1036–1045

    CAS  PubMed  Google Scholar 

  • Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB (2005) Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J Med Chem 48(7): 2336–2345

    Article  CAS  PubMed  Google Scholar 

  • Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Jr., Stewart L (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci USA 99(24): 15387–15392

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tanizawa A, Fujimori A, Fujimori Y, Pommier Y (1994) Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 86: 836–842

    Article  CAS  PubMed  Google Scholar 

  • Wall ME, Wani MC (1995) Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Res 55(4): 753–760

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Christophe Marchand

  2. Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Yves Pommier

Authors
  1. Christophe Marchand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yves Pommier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christophe Marchand .

Editor information

Editors and Affiliations

  1. Laboratory of Molecular Pharmacology, National Institutes of Health Laboratory of Molecular Pharmacology, Bethesda, Maryland, USA

    Yves Pommier

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Marchand, C., Pommier, Y. (2012). Topoisomerases Inhibitors: A Paradigm for Interfacial Inhibition. In: Pommier, Y. (eds) DNA Topoisomerases and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0323-4_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-0323-4_9

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-0322-7

  • Online ISBN: 978-1-4614-0323-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation