Neolignans isolated from Nectandra leucantha induce apoptosis in melanoma cells by disturbance in mitochondrial integrity and redox homeostasis
Neolignans isolated from Nectandra leucantha induce apoptosis in melanoma cells by disturbance in mitochondrial integrity and redox homeostasis
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DOI：
10.1016/j.phytochem.2017.04.024
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发表时间：
2017-08-01
期刊：
影响因子：
3.8
通讯作者：
Lago, Joao Henrique G.
中科院分区：
文献类型：
--
作者：
de Sousa, Fernanda S.;Grecco, Simone S.;Lago, Joao Henrique G.
六种新木脂素，包括三种以前未描述的代谢物：1-[(7R)-hydroxy-8-propeny1]-3-[3‘-methoxy-1’-(8‘-propeny1)-phenoxy]-4，5-dimethoxybenzene，采用生物活性导向分级法从樟科植物银莲花的枝条中分离得到4-hydroxy-5-methoxy-3-[3‘-methoxy-1’-(8‘-propenyl)phenoxyl-1-(7-oxo-8-propenyl)benzene和4，5-dimethoxy-3-[3’-methoxy-1‘-(8’-propenyl)phenoxy]-1-(7-oxo-8-propenyl)benzene。以脱氢二丁香酚B和4-hydroxy-5-methoxy-3-[3‘-methoxy-1’-(8‘-propenyl)phenoxy]-1-(7-oxo-8-propenyl)benzene为活性代谢物，对分离得到的化合物进行了体外细胞毒活性测定。这些化合物对小鼠黑色素瘤的IC50值分别为78.8+/-2.8和82.2+/-3.5mM。两种化合物对该细胞株的体外诱导细胞毒作用机制不同。结果表明，在诱导细胞凋亡的形态、生化和酶学特征方面，如线粒体膜电位(Delta Psi M)的破坏、外膜磷脂酰丝氨酸的暴露、基因组DNA的凝聚和断裂等，均有显著的作用。脱氢二丁香酚B诱导Caspase3和PARP激活，4-hydroxy-5-methoxy-3-[3‘-methoxy-1’-(8‘-propenyl)phenoxy]-1-(7-oxo-8-propenyl)benzene下调Bcl2蛋白水平。伴随着这些效应的是线粒体损伤导致的活性氧水平的增加，以及细胞死亡过程中F-肌动蛋白的聚集。脱氢二丁香酚B显示出氧化性质，两种化合物，特别是4-hydroxy-5-methoxy-3-[3‘-methoxy-1’-(8‘-propenyl)phenoxyl-1-(7-oxo-8-propenyl)benzene，显示出使亲核试剂烷基化的潜力，这表明这些代谢产物具有辅助的肿瘤细胞毒性机制。(C)2017爱思唯尔有限公司。保留所有权利。
Six neolignans including three previously undescribed metabolites: 1-[(7R)-hydroxy-8-propeny1]-3-[3'-methoxy-1'-(8'-propeny1)-phenoxy]-4,5-dimethoxybenzene, 4-hydroxy-5-methoxy-3-[3'-methoxy-1'-(8'-propenyl)phenoxyl-1-(7-oxo-8-propenyl)benzene and 4,5-dimethoxy-3-[3'-methoxy-1'-(8'-propenyl)phenoxy]-1-(7-oxo-8-propenyl)benzene were isolated from twigs of Nectandra leucantha Nees & Mart (Lauraceae) using bioactivity-guided fractionation. Cytotoxic activity of isolated compounds was evaluated in vitro against cancer cell lines (SR BR-3, HCT, U87-MG, A2058, and B16F10), being dehy-drodieugenol B and 4-hydroxy-5-methoxy-3-[3'-methoxy-1'-(8'-propenyl)phenoxy]-1-(7-oxo-8-propenyl)benzene the most active metabolites. These compounds displayed IC50 values of 78.8 +/- 2.8 and 82.2 +/- 3.5 mu M, respectively, against murine melanoma. Different in vitro mechanism of induced cytotoxicity for this cell line is proposed for both compounds. Obtained results indicated a remarkable effect during the induction of morphological, biochemical and enzymatic features of apoptosis, such as disruption of mitochondrial membrane potential (Delta Psi m), exposure of phosphatidylserine in the outer cell membrane, and-genomic DNA condensation and fragmentation. Dehydrodieugenol B induced caspase-3 and PARP activation and 4-hydroxy-5-methoxy-3-[3'-methoxy-1'-(8'-propenyl)phenoxy]-1-(7-oxo-8-propenyl)benzene downregulated the levels of Bcl-2 protein. These effects were accompanied by increased levels of reactive oxygen species as a consequence of mitochondrial damage, followed by F-actin aggregation during the cell death process. Dehydrodieugenol B showed oxidative properties and both compounds, especially 4-hydroxy-5-methoxy-3-[3'-methoxy-1'-(8'-propenyl)phenoxyl-1-(7-oxo-8-propenyl)benzene, displayed potential to alkylate nucleophiles, suggesting an accessory mechanism of tumor-induced cytotoxicity by these metabolites. (C) 2017 Elsevier Ltd. All rights reserved.