Lycobetaine acts as a selective topoisomerase II beta poison and inhibits the growth of human tumour cells.
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 microM). The growth of human leukaemia cell lines was also potently inhibited (mean IC(50) = 1.3 microM). 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 II beta poison. In the presence of calf thymus DNA, pure recombinant human topoisomerase II beta protein was selectively depleted from SDS-gels, whereas no depletion of topoisomerase II alpha protein was observed. In A431 cells immunoband-depletion of topoisomerase II beta 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.
Barthelmes
H U
HU
Department of Chemistry, Division of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Erwin-Schroedinger Str. 52, 67663 Kaiserslautern, Germany.
Niederberger
E
E
Roth
T
T
Schulte
K
K
Tang
W C
WC
Boege
F
F
Fiebig
H H
HH
Eisenbrand
G
G
Marko
D
D
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D047151:Amaryllidaceae Alkaloids; D000818:Animals; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D020552:Comet Assay; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007212:Indolizines; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D000470:Alkaloids; D047151:Amaryllidaceae Alkaloids; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007212:Indolizines; D059005:Topoisomerase II Inhibitors; C016175:ungeremine; D004247:DNA; D004250:DNA Topoisomerases, Type II