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

  • Ann Oncol. 2010 Mar;21(3):597-607. doi: 10.1093/annonc/mdp335.
M Li  1 ,  Z-H Miao  1 ,  Z Chen  2 ,  Q Chen  1 ,  M Gui  1 ,  L-P Lin  1 ,  P Sun  3 ,  Y-H Yi  3 ,  J Ding  4
Affiliations
  • 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.
  • 4. Division of Antitumor Pharmacology. Electronic address: [email protected].
PMID: 19773249 DOI: 10.1093/annonc/mdp335
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.

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