Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2α by unique interference with its DNA binding and catalytic cycle

• Published in: Annals of oncology Vol. 21; no. 3; pp. 597 - 607
• Main Authors: Li, M., Miao, Z.-H., Chen, Z., Chen, Q., Gui, M., Lin, L.-P., Sun, P., Yi, Y.-H., Ding, J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2010; Oxford University Press
• Subjects: Antineoplastic agents; Biological and medical sciences; catalytic cycle; DNA damage; echinoside A; Holothurioidea; Marine; marine-derived anticancer drugs; Medical sciences; Pharmacology. Drug treatments; topoisomerase2 inhibitor; catalytic cycle; DNA damage; topoisomerase2 inhibitor; marine-derived anticancer drugs; echinoside A; Antineoplastic agent; Drug; Targeting; Cycle; Saponin; Marine environment; Target; DNA; Inhibitor; Lesion
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdp335

Echinoside A was isolated from sea cucumber. This study demonstrates its anticancer effects and its mechanisms of action. 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 topoisomerase2α (Top2α). Molecular docking analyses were used to demonstrate the direct interaction between echinoside A and Top2α. 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 Top2α to DNA by competing with DNA for the DNA-binding domain of the enzyme and of interfering predominantly with the Top2α-mediated prestrand passage cleavage/religation equilibrium over with the poststrand passage one. These features distinguish echinoside A from other known Top2α inhibitors. As a result, echinoside A induced DNA double-strand breaks in a Top2-dependent manner. Echinoside A targets Top2α 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.