牛蒡子素在体外通过线粒体自噬激活抑制黑色素瘤,并增强体内达卡巴嗪的敏感性。

IF 2.3 4区 医学 Q3 ONCOLOGY
Ling Jiang, Yang Lu, Hongyan Zhao, Weiyang He
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引用次数: 0

摘要

目的:探讨牛角素(ARG)通过调节线粒体自噬作用对达卡巴嗪(DTIC)增敏的作用及其机制。方法:通过体外实验,探讨ARG对黑色素瘤细胞生物学行为、PINK1/Parkin介导的线粒体自噬的影响,以及活性氧(reactive oxygen species, ROS)-线粒体自噬通过ROS猝灭剂、线粒体自噬抑制剂和激活剂对黑色素瘤细胞生物学行为的调节作用。观察ARG和达卡巴嗪对裸鼠的作用。结果:CCK8检测显示,ARG抑制人黑色素瘤细胞系A375和SK-MEL-2的增殖。亚显微结构观察显示线粒体损伤。流式细胞术进一步证实ARG诱导细胞凋亡。western blot分析显示,cleaved caspase 3和Bax蛋白表达水平升高,而Bcl-2蛋白表达水平降低。此外,ARG增加了ROS水平。LC3II/I、PINK1、Parkin升高。arg诱导的细胞凋亡与线粒体氧化应激增加有关,促进线粒体自噬的发生。添加自噬抑制剂Mdivi-1或ROS猝灭剂n -乙酰半胱氨酸(NAC)后,ARG的抗增殖作用明显减弱。PINK1、Parkin、LC3II/I、cleaved caspase 3、Bax表达量升高,Bcl-2表达量降低。透射电镜观察线粒体自噬体的形成。ARG在体内可抑制mel- anooma细胞的增殖并诱导其凋亡。结论:ARG可通过PINK1/Parkin通路激活自噬介导的细胞凋亡,有效抑制人黑色素瘤细胞的增殖。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Arctigenin Suppresses Melanoma via Mitophagy Activation In vitro and Enhances Dacarbazine Sensitivity In vivo.

Objective: This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.

Methods: In vitro experiments were conducted to explore the effects of ARG on the biologi-cal behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autoph-agy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were as-sessed.

Results: CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. West-ern blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax in-creased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mito-chondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmis-sion electron microscopy. ARG inhibited the proliferation and induced the apoptosis of mel-anoma cells in vivo.

Conclusion: Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.

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来源期刊
Current cancer drug targets
Current cancer drug targets 医学-肿瘤学
CiteScore
5.40
自引率
0.00%
发文量
105
审稿时长
1 months
期刊介绍: Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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