奥卡米诺卡二氢黄酮醇和异黄酮对多因素耐药性癌症的细胞毒性。
Cytotoxicity of isoflavones and biflavonoids from Ormocarpum kirkii towards multi-factorial drug resistant cancer.
机构信息
Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya; Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon.
出版信息
Phytomedicine. 2019 May;58:152853. doi: 10.1016/j.phymed.2019.152853. Epub 2019 Jan 30.
BACKGROUND
While incidences of cancer are continuously increasing, drug resistance of malignant cells is observed towards almost all pharmaceuticals. Several isoflavonoids and flavonoids are known for their cytotoxicity towards various cancer cells.
PURPOSE
The aim of this study was to determine the cytotoxicity of isoflavones: osajin (1), 5,7-dihydroxy-4'-methoxy-6,8-diprenylisoflavone (2) and biflavonoids: chamaejasmin (3), 7,7″-di-O-methylchamaejasmin (4) and campylospermone A (5), a dimeric chromene [diphysin(6)] and an ester of ferullic acid with long alkyl chain [erythrinasinate (7)] isolated from the stem bark and roots of the Kenyan medicinal plant, Ormocarpum kirkii. The mode of action of compounds 2 and 4 was further investigated.
METHODS
The cytotoxicity of compounds was determined based on the resazurin reduction assay. Caspases activation was evaluated using the caspase-Glo assay. Flow cytometry was used to analyze the cell cycle (propodium iodide (PI) staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (HDCFH-DA). CCRF-CEM leukemia cells were used as model cells for mechanistic studies.
RESULTS
Compounds 1, 2 and 4 displayed IC values below 20 µM towards CCRF-CEM and CEM/ADR5000 leukemia cells, and were further tested towards a panel of 7 carcinoma cells. The IC values of the compounds against carcinoma cells varied from 16.90 µM (in resistant U87MG.ΔEGFR glioblastoma cells) to 48.67 µM (against HepG2 hepatocarcinoma cells) for 1, from 7.85 µM (in U87MG.ΔEGFR cells) to 14.44 µM (in resistant MDA-MB231/BCRP breast adenocarcinoma cells) for 2, from 4.96 µM (towards U87MG.ΔEGFRcells) to 7.76 µM (against MDA-MB231/BCRP cells) for 4, and from 0.07 µM (against MDA-MB231 cells) to 2.15 µM (against HepG2 cells) for doxorubicin. Compounds 2 and 4 induced apoptosis in CCRF-CEM cells mediated by MMP alteration and increased ROS production.
CONCLUSION
The present report indicates that isoflavones and biflavonoids from Ormocarpum kirkii are cytotoxic compounds with the potential of being exploited in cancer chemotherapy. Compounds 2 and 4 deserve further studies to develop new anticancer drugs to fight sensitive and resistant cancer cell lines.
背景
尽管癌症的发病率持续上升，但恶性细胞对几乎所有药物的耐药性也在不断增加。一些异黄酮和黄酮类化合物因其对各种癌细胞的细胞毒性而闻名。
目的
本研究旨在测定异黄酮(osajin（1）、5,7-二羟基-4'-甲氧基-6,8-二烯基异黄酮（2）和双黄酮：chamaejasmin（3）、7,7″-二-O-甲基chamaejasmin（4）和 campylospermone A（5）、二聚色烯[diphysin（6）]和阿魏酸的酯与长链烷基[erythrinasinate（7）]，这些化合物均从肯尼亚药用植物 Ormocarpum kirkii 的茎皮和根部分离出来。进一步研究了化合物 2 和 4 的作用机制。
方法
根据 Resazurin 还原测定法确定化合物的细胞毒性。使用 caspase-Glo 测定法评估半胱天冬酶的激活。通过碘化丙啶（PI）染色分析细胞周期，通过 Annexin V/PI 染色分析细胞凋亡，通过 JC-1 分析线粒体膜电位（MMP），通过 HDCFH-DA 分析活性氧（ROS）。使用 CCRF-CEM 白血病细胞作为机制研究的模型细胞。
结果
化合物 1、2 和 4 对 CCRF-CEM 和 CEM/ADR5000 白血病细胞的 IC 值低于 20µM，并且进一步对 7 种癌细胞系进行了测试。化合物对癌细胞的 IC 值从 16.90µM（在耐药 U87MG.ΔEGFR 神经胶质瘤细胞中）到 48.67µM（在 HepG2 肝癌细胞中）不等，对 1 为 16.90µM，对 2 为 7.85µM（在 U87MG.ΔEGFR 细胞中）到 14.44µM（在耐药 MDA-MB231/BCRP 乳腺癌细胞中），对 4 为 4.96µM（对 U87MG.ΔEGFR 细胞）到 7.76µM（对 MDA-MB231/BCRP 细胞），对 doxorubicin 为 0.07µM（对 MDA-MB231 细胞）到 2.15µM（对 HepG2 细胞）。化合物 2 和 4 通过 MMP 改变和增加 ROS 产生诱导 CCRF-CEM 细胞凋亡。
结论
本报告表明，来自 Ormocarpum kirkii 的异黄酮和双黄酮是具有细胞毒性的化合物，具有在癌症化疗中应用的潜力。化合物 2 和 4 值得进一步研究，以开发新的抗癌药物来对抗敏感和耐药的癌细胞系。
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