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

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.