Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Nov;85(10):1585–1591. doi: 10.1054/bjoc.2001.2142

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

H U Barthelmes 2, E Niederberger 1, T Roth 4, K Schulte 1, W C Tang 1, F Boege 2, H-H Fiebig 3,4, G Eisenbrand 1, D Marko 1
PMCID: PMC2363954  PMID: 11720449

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 IC 50 = 0.8 μM). The growth of human leukaemia cell lines was also potently inhibited (mean IC 50 = 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

Keywords: lycobetaine, ungeremine, topoisomerase IIβ, cleavable complex, clonogenic assay, gastric carcinoma

Full Text

The Full Text of this article is available as a PDF (109.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boege F. Analysis of eukaryotic DNA topoisomerases and topoisomerase-directed drug effects. Eur J Clin Chem Clin Biochem. 1996 Nov;34(11):873–888. [PubMed] [Google Scholar]
  2. Davies S. M., Robson C. N., Davies S. L., Hickson I. D. Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. J Biol Chem. 1988 Nov 25;263(33):17724–17729. [PubMed] [Google Scholar]
  3. Drees M., Dengler W. A., Roth T., Labonte H., Mayo J., Malspeis L., Grever M., Sausville E. A., Fiebig H. H. Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin Cancer Res. 1997 Feb;3(2):273–279. [PubMed] [Google Scholar]
  4. Gao H., Huang K. C., Yamasaki E. F., Chan K. K., Chohan L., Snapka R. M. XK469, a selective topoisomerase IIbeta poison. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12168–12173. doi: 10.1073/pnas.96.21.12168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gedik C. M., Ewen S. W., Collins A. R. Single-cell gel electrophoresis applied to the analysis of UV-C damage and its repair in human cells. Int J Radiat Biol. 1992 Sep;62(3):313–320. doi: 10.1080/09553009214552161. [DOI] [PubMed] [Google Scholar]
  6. Ghosal S., Singh S. K., Kumar Y., Unnikrishnan S., Chattopadhyay S. The role of ungeremine in the growth-inhibiting and cytotoxic effects of lycorine: evidence and speculation. Planta Med. 1988 Apr;54(2):114–116. doi: 10.1055/s-2006-962364. [DOI] [PubMed] [Google Scholar]
  7. He H. M., Weng Z. Y. [Structure-activity-relationship study of the new anticancer drug lycobetaine (AT-1840)]. Yao Xue Xue Bao. 1989;24(4):302–304. [PubMed] [Google Scholar]
  8. Knudsen B. R., Straub T., Boege F. Separation and functional analysis of eukaryotic DNA topoisomerases by chromatography and electrophoresis. J Chromatogr B Biomed Appl. 1996 Sep 20;684(1-2):307–321. doi: 10.1016/0378-4347(96)00152-1. [DOI] [PubMed] [Google Scholar]
  9. Liu J., Yang S. L., Xu B. Characteristics of the interaction of lycobetaine with DNA. Zhongguo Yao Li Xue Bao. 1989 Sep;10(5):437–442. [PubMed] [Google Scholar]
  10. Marko D., Romanakis K., Zankl H., Fürstenberger G., Steinbauer B., Eisenbrand G. 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. 1998;28(2-3):75–101. doi: 10.1007/BF02737806. [DOI] [PubMed] [Google Scholar]
  11. Marko D., Schätzle S., Friedel A., Genzlinger A., Zankl H., Meijer L., Eisenbrand G. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer. 2001 Jan;84(2):283–289. doi: 10.1054/bjoc.2000.1546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Meyer K. N., Kjeldsen E., Straub T., Knudsen B. R., Hickson I. D., Kikuchi A., Kreipe H., Boege F. Cell cycle-coupled relocation of types I and II topoisomerases and modulation of catalytic enzyme activities. J Cell Biol. 1997 Feb 24;136(4):775–788. doi: 10.1083/jcb.136.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesch H., Kenney S., Boyd M. R. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990 Jul 4;82(13):1107–1112. doi: 10.1093/jnci/82.13.1107. [DOI] [PubMed] [Google Scholar]
  14. Wang X. W., Yu W. J., Shen Z. M., Yang J. L., Xu B. [Cytotoxicity of hydroxycamptothecin and four other antineoplastic agents on KB cells]. Zhongguo Yao Li Xue Bao. 1987 Jan;8(1):86–90. [PubMed] [Google Scholar]
  15. Zhang S. Y., Lu F. L., Yang J. L., Wang L. J., Xu B. [Effect on animal tumors and toxicity of lycobetaine acetate (author's transl)]. Zhongguo Yao Li Xue Bao. 1981 Mar;2(1):41–45. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES