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Annals of Oncology Advance Access published online on September 22, 2009
Annals of Oncology, doi:10.1093/annonc/mdp335
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2{alpha} by unique interference with its DNA binding and catalytic cycle

M. Li1, Z.-H. Miao1,{dagger}, Z. Chen2, Q. Chen1, M. Gui1, L.-P. Lin1, P. Sun3, Y.-H. Yi3 and J. Ding1,*,{dagger}

1 Division of Antitumor Pharmacology
2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
3 Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China

* Correspondence to: J. Ding, Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, People's Republic of China. Tel: +86-21-50806722; Fax: +86-21-50806722; E-mail: jding{at}mail.shcnc.ac.cn

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 topoisomerase2{alpha} (Top2{alpha}). Molecular docking analyses were used to demonstrate the direct interaction between echinoside A and Top2{alpha}.

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 Top2{alpha} to DNA by competing with DNA for the DNA-binding domain of the enzyme and of interfering predominantly with the Top2{alpha}-mediated prestrand passage cleavage/religation equilibrium over with the poststrand passage one. These features distinguish echinoside A from other known Top2{alpha} inhibitors. As a result, echinoside A-induced DNA double-strand breaks in a Top2-dependent manner.

Conclusion: Echinoside A targets Top2{alpha} 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.

catalytic cycle, DNA damage, echinoside A, marine-derived anticancer drugs, topoisomerase2 inhibitor

{dagger} Both authors contributed equally to this paper.

Received for publication December 31, 2008. Revision received May 18, 2009. Accepted for publication May 19, 2009.


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