Cynaropicrin Induces Reactive Oxygen Species-Dependent Paraptosis-Like Cell Death in Human Liver Cancer Cells.

IF 3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Min Yeong Kim, Hee-Jae Cha, Su Hyun Hong, Sung-Kwon Moon, Taeg Kyu Kwon, Young-Chae Chang, Gi Young Kim, Jin Won Hyun, A-Young Nam, Jung-Hyun Shim, Yung Hyun Choi
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Abstract

Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.

西那匹克林诱导人肝癌细胞中活性氧依赖性跃迁样细胞死亡
洋蓟素是洋蓟叶中的一种倍半萜内酯,具有多种药理作用。本研究探讨了除了在几种癌细胞系中报道的凋亡效应外,辣木次黄嘌呤是否在人肝癌 Hep3B 细胞中具有类似凋亡的细胞死亡效应。在 Hep3B 细胞中,坏死抑制剂、自噬抑制剂或泛 Caspase 抑制剂都不能改善犬喹啉诱导的细胞毒性和细胞质空泡化(paraptosis 的一个关键特征)。我们的研究表明,卡泊三醇诱导的细胞毒性伴随着线粒体功能障碍和内质网应激以及细胞钙离子水平的升高。内质网应激抑制剂或蛋白质合成抑制剂可明显减轻这些影响。此外,在 Hep3B 细胞中使用卡那霉素会增加活性氧的生成,并下调与细胞凋亡相关的基因 2 交互蛋白 X(Alix)(一种抑制凋亡的蛋白质)。加入活性氧清除剂 N-乙酰-L-半胱氨酸(NAC)可以中和卡诺匹克林诱导的 Alix 表达和内质网应激标志蛋白的变化,从而抵消内质网应激和线粒体损伤。这证明了内质网应激与活性氧生成之间的密切关系。此外,卡泊三醇可激活 p38 丝裂原活化蛋白激酶,而选择性 p38 丝裂原活化蛋白激酶阻断剂可减轻卡泊三醇诱导的生物现象。NAC 预处理能最好地逆转三硝基吡啶诱导的空泡化和细胞失活现象。我们的研究结果表明,氯化苦在 Hep3B 细胞中诱导的氧化应激导致了包括内质网应激和线粒体损伤在内的副aptotic 事件。
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来源期刊
CiteScore
6.60
自引率
8.10%
发文量
72
审稿时长
6-12 weeks
期刊介绍: Biomolecules & Therapeutics (Biomolecules & Therapeutics) (Print ISSN 1976-9148, Online ISSN 2005-4483) is an international, peer-reviewed, open access journal that covers pharmacological and toxicological fields related to bioactive molecules and therapeutics. It was launched in 1993 as "The Journal of Applied Pharmacology (ISSN 1225-6110)", and renamed "Biomolecules & Therapeutics" (Biomol Ther: abbreviated form) in 2008 (Volume 16, No. 1). It is published bimonthly in January, March, May, July, September and November. All manuscripts should be creative, informative, and contribute to the development of new drugs. Articles in the following categories are published: review articles and research articles.
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