(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
| Autor: | Shingo Dan, Honoka Okunaga, Kiyomi Hikita, Kenta Matsuoka, Haruka Matsuyama, Yuko Yamakage, Naoki Asao, Tomiyasu Murata, Norio Kaneda, Akifumi Oda, Tomoki Nakayoshi, Kuniki Kato, Yui Motoyama, Hitoshi Tanaka |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cell cycle checkpoint
Cell Survival Clinical Biochemistry Pharmaceutical Science Cleavage (embryo) 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Stomach Neoplasms Drug Discovery Tumor Cells Cultured medicine Humans Topoisomerase II Inhibitors Molecular Biology Etoposide Cell Proliferation Erythrina Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Topoisomerase Organic Chemistry Antineoplastic Agents Phytogenic Molecular biology 0104 chemical sciences G2 Phase Cell Cycle Checkpoints Molecular Docking Simulation 010404 medicinal & biomolecular chemistry DNA Topoisomerases Type II chemistry Cell culture Cancer cell biology.protein Molecular Medicine Drug Screening Assays Antitumor Topoisomerase-II Inhibitor DNA medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 30:115904 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2020.115904 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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