(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
(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
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(S)-Erypoegin K 是一种从 Erythrina poeppigiana 中分离出来的异黄酮，是一种新型拓扑异构酶 IIα 抑制剂：诱导人胃癌细胞 G2 期停滞
DOI：
10.1016/j.bmc.2020.115904
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发表时间：
2021
影响因子：
3.5
通讯作者：
Kaneda Norio
中科院分区：
文献类型：
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作者：
Hikita Kiyomi;Yamakage Yuko;Okunaga Honoka;Motoyama Yui;Matsuyama Haruka;Matsuoka Kenta;Murata Tomiyasu;Nakayoshi Tomoki;Oda Akifumi;Kato Kuniki;Tanaka Hitoshi;Asao Naoki;Dan Shingo;Kaneda Norio
Erypoegin K是从刺桐（Erythrina poeppigiana）的茎皮中分离得到的一种手性化合物，其结构中含有一个手性碳，天然存在时为外消旋混合物。我们的前期研究表明（S）-erypoegin K对人白血病HL-60细胞具有选择性的抗增殖和诱导凋亡活性。为了鉴定（S）-erypoegin K的靶分子，我们采用了人类癌细胞组分析（称为JFCR 39），并结合使用COMPARE算法进行比较的药物敏感性数据库，该数据库包含了经过充分表征的药物。（S）-erypoegin K表现出与依托泊苷相似的特征，表明erypoegin K的分子靶标可能是拓扑异构酶II（Topo II）。随后使用纯化的人Topo IIα进行的实验证实，（S）-异构体选择性稳定由双链质粒DNA和酶组成的切割复合物。此外，（S）-erypoegin K抑制动质体DNA的解链。分子对接研究清楚地表明，（S）-异构体与Topo IIα的活性位点特异性结合，涉及有助于稳定切割复合物的氢键。（S）-erypoegin K对两种人胃癌细胞GCIY和MKN-1具有较强的细胞毒活性，IC 50值分别为0.270和0.327 μM，并诱导caspase 3和9的酶活性。细胞周期分析显示，两种细胞系的细胞周期均明显阻滞于G2期。（S）-erypoegin K对GCIY异种移植小鼠也显示出显著的抗肿瘤活性。本研究表明（S）-erypoegin K作为Topo II抑制剂阻断癌细胞的G2/M转换。
Erypoegin K, an isoflavone isolated from the stem bark ofErythrina 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 IC50values 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.