| 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
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| 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
|
| リソース情報 |
| ヒト・動物細胞 |
MKN1(RCB1003) |
