論文 - 詳細
| RRC ID | 63973 |
|---|---|
| 著者 | 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. |
| タイトル | (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. |
| ジャーナル | 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. |
| 巻・号 | 30 |
| ページ | 115904 |
| 公開日 | 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MKN1(RCB1003) |