Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2alpha by unique interference with its DNA binding and catalytic cycle.

Abstract

BACKGROUND:

Echinoside A was isolated from sea cucumber. This study demonstrates its anticancer effects and its mechanisms of action.

MATERIALS AND METHODS:

Anticancer effects of echinoside A were evaluated in vitro and in vivo. TUNEL and DNA fragmentation assays were applied to examine its ability to induce apoptosis. A series of biochemical assays were applied to investigate the inhibition of echinoside A on topoisomerase2alpha (Top2alpha). Molecular docking analyses were used to demonstrate the direct interaction between echinoside A and Top2alpha.

RESULTS:

Echinoside A inhibited the growth of tumors in mouse models and human prostate carcinoma xenografts in nude mouse models. Echinoside A shows the unique characteristics of inhibiting the noncovalent binding of Top2alpha to DNA by competing with DNA for the DNA-binding domain of the enzyme and of interfering predominantly with the Top2alpha-mediated prestrand passage cleavage/religation equilibrium over with the poststrand passage one. These features distinguish echinoside A from other known Top2alpha inhibitors. As a result, echinoside A induced DNA double-strand breaks in a Top2-dependent manner.

CONCLUSION:

Echinoside A targets Top2alpha by unique interference with the binding of Top2 to DNA and by imparing the Top2-mediated DNA cleavage and religation, exerting potent in vitro and in vivo antitumor activities.

• Authors: M Li, Z-H Miao, Z Chen, Q Chen, M Gui, L-P Lin, P Sun, Y-H Yi, J Ding
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 21 Issue 3 Pg. 597-607 (Mar 2010) ISSN: 1569-8041 [Electronic] England
• PMID: 19773249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• DNA-Binding Proteins
• Poly-ADP-Ribose Binding Proteins
• Topoisomerase II Inhibitors
• Holothurin
• echinoside A
• DNA
• DNA Topoisomerases, Type II
• TOP2A protein, human
• Top2a protein, mouse

Topics

• Animals
• Antigens, Neoplasm (metabolism)
• Apoptosis (drug effects)
• Blotting, Western
• Catalysis (drug effects)
• Cell Proliferation (drug effects)
• DNA (metabolism)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Topoisomerases, Type II (metabolism)
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Female
• Holothurin (analogs & derivatives, pharmacology)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Neoplasms, Experimental (drug therapy, genetics, pathology)
• Poly-ADP-Ribose Binding Proteins
• Protein Conformation
• Sea Cucumbers (chemistry)
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays