Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lycobetaine acts as a selective topoisomerase IIβ poison and inhibits the growth of human tumour cells

This article has been updated

Abstract

The phenanthridine alkaloid lycobetaine is a minor constituent of Amaryllidaceae. Inhibition of cell growth was studied in the clonogenic assay on 21 human tumour xenografts (mean IC50 = 0.8 μM). The growth of human leukaemia cell lines was also potently inhibited (mean IC50 = 1.3 μM). Athymic nude mice, carrying s.c. implanted human gastric tumour xenograft GXF251, were treated i.p. with lycobetaine for 4 weeks, resulting in a marked tumour growth delay. Lycobetaine was found to act as a specific topoisomerase IIβ poison. In the presence of calf thymus DNA, pure recombinant human topoisomerase IIβ protein was selectively depleted from SDS-gels, whereas no depletion of topoisomerase IIα protein was observed. In A431 cells immunoband-depletion of topoisomerase IIβ was induced, suggesting stabilization of the covalent catalytic DNA-intermediate in living cells. It is reasonable to assume that this mechanism will cause or at least contribute significantly to the antitumour activity. © 2001 Cancer Research Campaign http://www.bjcancer.com

Change history

  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  1. Berger DP, Winterhalter BR and Fiebig HH (1992) Establishment and characterization of human tumor xenografts in thymus aplastic nude mice. Contr Oncol 42: 23–46

    Google Scholar 

  2. Boege F (1996) Analysis of eukaryotic DNA topoisomerases and topoisomerase-directed drug effects. Eur J Clin Chem Clin Biochem 34: 873–888

    CAS  PubMed  Google Scholar 

  3. Chen AY, Chiang Y, Gatto B and Liu LF (1993) DNA minor groove binding ligands: a different class of mammalian DNA topoisomerase I inhibitors. Proc Natl Acad Sci USA 90: 131–135

    Google Scholar 

  4. Chen JZ, Chen KX, Jiang HL, Lin MW and Ji RY (1997) Theoretical investigation on interaction binding of analogs of AT-1840 to double-stranded polynucleotide. Proc Natl Sci 7: 329–335

    Google Scholar 

  5. Davies SM, Robson CN, Davies SL and Hickson ID (1988) Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. J Biol Chem 263, (33):17724–17729

    CAS  PubMed  Google Scholar 

  6. Drees M, Dengler WA, Roth T, Labonte H, Mayo J, Malspeis L, Grever M, Sausville EA and Fiebig HH (1997) Selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin Cancer Res 3: 273–279

    CAS  Google Scholar 

  7. Evidente A, Iasiello I and Randazzo G (1984) An improved method for the large-scale preparation of lycorine. Chem & Ind, 348–349

  8. Gan L, Liu XJ, Chen KL and Ji YY (1992) Computer simulation on the interaction between antitumor agent lycobetaine and DNA. Gaojishu Tongxun 2: 30–33

    CAS  Google Scholar 

  9. Gao H, Huang KC, Yamasaki EF, Chan KK, Chohan L and Snapka RM (1999) XK469, a selective topoisomerase IIβ poison. Proc Natl Acad Sci USA 96: 12168–12173

    CAS  Article  Google Scholar 

  10. Gedik CM, Ewen SWB and Collins AR (1992) Single-cell gel electrophoresis applied to the analysis of UV-C damage and its repair in human cells. Int J Radiat Biol 62: 313–320

    CAS  Article  Google Scholar 

  11. Ghosal S, Kumar Y, Singh SK and Kumar A (1986) Chemical constituents of Amaryllidaceae. Part 21. Ungeremine and criasbetaine, two antitumor alkaloids from Crinum asiaticum. J Chem Res Synop, 112–113

  12. Ghosal S, Singh SK, Kumar Y, Unnikrishnan S and Chattopadhyay S (1988) Chemical constituents of Amaryllidaceae. Part 26. The role of ungeremine in the growth-inhibiting and cytotoxic effects of lycorine: evidence and speculation. Planta Med 54: 114–116

    CAS  Article  Google Scholar 

  13. He HM and Weng ZY (1989) Structure-activity-relationship study of the new anticancer drug lycobetaine (AT-1840). Acta Pharm Sinica 24: 302–304

    CAS  Google Scholar 

  14. Knudsen BR, Straub T and Boege F (1996) Separation and functional analysis of eukaryotic DNA topoisomerases by chromatography and electrophoresis. J Chromatogr B Biomed Appl 684: 307–321

    CAS  Article  Google Scholar 

  15. Lee KH, Sun L and Wang HK (1994) Antitumor agents. 147. Antineoplastic alkaloids from Chinese medicinal plants and their analogs. J Chin Chem Soc 41: 371–384

    CAS  Article  Google Scholar 

  16. Liu J, Yang SL and Xu B (1989) Characteristics of the interaction of lycobetaine with DNA. Acta Pharmacol Sinica 10: 437–442

    CAS  Google Scholar 

  17. Marko D, Romanakis K, Zankl H, Fürstenberger G, Steinbauer B and Eisenbrand G (1998) Induction of apoptosis by an inhibitor of cAMP-specific PDE in malignant murine carcinoma cells overexpressing PDE activity in comparison to their nonmalignant counterparts. Cell Biochem Biophys 28: 75–101

    CAS  Article  Google Scholar 

  18. Marko D, Schätzle S, Friedel A, Genzlinger A, Zankl H, Meijer L and Eisenbrand G (2001) Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 84, (2):283–289

    CAS  Article  Google Scholar 

  19. Meyer KN, Kjeldsen E, Straub T, Knudsen BR, Hickson ID, Kikuchi A, Kreipe H and Boege F (1997) Cell cycle-coupled relocation of types I and II topoisomerases and modulation of catalytic enzyme activities. J Cell Biol 136: 775–788

    CAS  Article  Google Scholar 

  20. Owen TY, Wang SY, Chang SY, Lu FL, Yang CL and Hsu B (1976) A new antitumor substance lycobetaine (AT-1840). Ko Hsueh Tung Pao 21: 285–287

    CAS  Google Scholar 

  21. Roth T, Burger AM, Dengler W, Willmann H and Fiebig HH (1999) Human tumor cell lines demonstrating the characteristics of patient tumors as useful models for anticancer drug screening. In: Fiebig HH, Burger AM (eds) Relevance of tumor models for anticancer drug development, Contrib Oncol Vol 42. pp: 145–156 Basel: Karger

    Chapter  Google Scholar 

  22. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S and Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82: 1110–1112

    Article  Google Scholar 

  23. Wang XW, Yu WJ, Shen ZM, Yang JL and Xu B (1987) Cytotoxicity of hydroxycamptothecin and four other antineoplastic agents on KB cells. Acta Pharmacol Sinica 8: 86–90

    CAS  Google Scholar 

  24. Workman P, Twentyman P, Balkwill F, Balmain A, Chaplin D, Double J, Embleton J, Newell D, Raymond R, Stables J, Stephens T and Wallace J (1998) United Kingdom Co-ordinating Committee on Cancer Research (UK CCCR) Guidelines for the Welfare of Animals in Experimental Neoplasia (Second Edition). Br J Cancer 77: 1–10

    Google Scholar 

  25. Wu H, Shen CY and Xu B (1987) Effect of lycobetaine on DNA circular dichroism. Chin J Pharmacol Toxicol 1: 272–276

    CAS  Google Scholar 

  26. Wu YL, Wu YX, Yu CS, Zhang SY, Su ZC and Jiang SJ (1988) The cytocidal effect of AT-1840 and parvovirus H-1 on gastric cancer cells. Shanghai Med J 11: 683–688

    CAS  Google Scholar 

  27. Zhang SY, Lu FL, Yang JL, Wang LJ and Xu B (1981) Effect on animal tumors and toxicity of lycobetaine acetate. Acta Pharmacol Sinica 2: 41–45

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Reprints and Permissions

About this article

Cite this article

Barthelmes, H., Niederberger, E., Roth, T. et al. Lycobetaine acts as a selective topoisomerase IIβ poison and inhibits the growth of human tumour cells. Br J Cancer 85, 1585–1591 (2001). https://doi.org/10.1054/bjoc.2001.2142

Download citation

Keywords

  • lycobetaine
  • ungeremine
  • topoisomerase IIβ
  • cleavable complex
  • clonogenic assay
  • gastric carcinoma

Further reading

Search

Quick links