Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2alpha 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.


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.


CONCLUSIONS
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.
Division of Antitumor Pharmacology.
M
M
Li
Division of Antitumor Pharmacology.
Z-H
ZH
Miao
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Z
Z
Chen
Division of Antitumor Pharmacology.
Q
Q
Chen
Division of Antitumor Pharmacology.
M
M
Gui
Division of Antitumor Pharmacology.
L-P
LP
Lin
Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
P
P
Sun
Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
Y-H
YH
Yi
Division of Antitumor Pharmacology. Electronic address: jding@mail.shcnc.ac.cn.
J
J
Ding
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002384:Catalysis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D006697:Holothurin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D011487:Protein Conformation; D012616:Sea Cucumbers / Q000737:chemistry; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors; D006697:Holothurin; C043973:echinoside A; D004247:DNA; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse