RRC ID 63973
Author Hikita K, Yamakage Y, Okunaga H, Motoyama Y, Matsuyama H, Matsuoka K, Murata T, Nakayoshi T, Oda A, Kato K, Tanaka H, Asao N, Dan S, Kaneda N.
Title (S)-Erypoegin K, an isoflavone isolated from Erythrina poeppigiana, is a novel inhibitor of topoisomerase IIα: Induction of G2 phase arrest in human gastric cancer cells.
Journal Bioorg Med Chem
Abstract Erypoegin K, an isoflavone isolated from the stem bark of Erythrina poeppigiana, has a single chiral carbon in its structure and exists naturally as a racemic mixture. Our previous study showed (S)-erypoegin K selectively exhibits potent anti-proliferative and apoptosis-inducing activity against human leukemia HL-60 cells. To identify the target molecule of (S)-erypoegin K, we employed the human cancer cell panel analysis (termed JFCR39) coupled with a drug sensitivity database of pharmacologically well-characterized drugs for comparison using the COMPARE algorithm. (S)-erypoegin K exhibited a similar profile to that of etoposide, suggesting the molecular target for erypoegin K may be topoisomerase II (Topo II). Subsequent experiments using purified human Topo IIα established that the (S)-isomer selectively stabilizes the cleavage complex composed of double-stranded plasmid DNA and the enzyme. Moreover, (S)-erypoegin K inhibited decatenation of kinetoplast DNA. Molecular docking studies clearly indicated specific binding of the (S)-isomer to the active site of Topo IIα involving hydrogen bonds that help stabilize the cleavage complex. (S)-erypoegin K displayed potent cytotoxic activity against two human gastric cancer cells GCIY and MKN-1 with IC50 values of 0.270 and 0.327 μM, respectively, and induced enzyme activities of caspase 3 and 9. Cell cycle analysis showed marked cell cycle arrest at G2 phase in both cell lines. (S)-erypoegin K also displayed significant antitumor activity toward GCIY xenografted mice. The present study suggests (S)-erypoegin K acts as a Topo II inhibitor to block the G2/M transition of cancer cells.
Volume 30
Pages 115904
Published 2021-1-15
DOI 10.1016/j.bmc.2020.115904
PII S0968-0896(20)30734-3
PMID 33341500
MeSH Antineoplastic Agents, Phytogenic / chemistry Antineoplastic Agents, Phytogenic / isolation & purification Antineoplastic Agents, Phytogenic / pharmacology* Cell Proliferation / drug effects Cell Survival / drug effects DNA Topoisomerases, Type II / metabolism* Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Erythrina / chemistry* G2 Phase Cell Cycle Checkpoints / drug effects Humans Molecular Docking Simulation Molecular Structure Stomach Neoplasms / drug therapy* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Structure-Activity Relationship Topoisomerase II Inhibitors / chemistry Topoisomerase II Inhibitors / isolation & purification Topoisomerase II Inhibitors / pharmacology* Tumor Cells, Cultured
IF 3.073
Human and Animal Cells MKN1(RCB1003)