Remimazolam induced cytotoxicity mediated through multiple stress pathways and acted synergistically with tyrosine kinase inhibitors in hepatocellular carcinoma.

IF 5.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Redox Report Pub Date : 2025-12-01 Epub Date: 2025-03-07 DOI:10.1080/13510002.2025.2475696
Hsiu-Lung Fan, Jia-Lin Chen, Shu-Ting Liu, Jia-Tong Lee, Shih-Ming Huang, Zhi-Fu Wu, Hou-Chuan Lai
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引用次数: 0

Abstract

The primary treatment for hepatocellular carcinoma (HCC) involves surgical removal of the primary tumor, but this creates a favorable environment for the proliferation and spread of residual and circulating cancer cells. The development of remimazolam-based balanced anesthesia is crucial for future antitumor applications. It is important to understand the mechanisms of cytotoxicity for HCC in detail.

We performed cell viability analysis, western blotting analysis, reverse transcription-polymerase chain reaction analysis, and flow cytometry analysis in two HCC cell lines, HepG2 and Hep3B cells.

Our data demonstrated that remimazolam induced cytotoxicity by suppressing cell proliferation, inhibiting G1 phase progression, and affecting mitochondrial reactive oxygen species (ROS) levels, leading to apoptosis, DNA damage, cytosolic ROS elevation, lipid peroxidation, autophagy, mitochondrial depolarization, and endoplasmic reticulum stress. Inhibitors of apoptosis, autophagic cell death, and ferroptosis and a ROS scavenger failed to rescue cell death caused by remimazolam besylate. Our combination index revealed that remimazolam besylate has the potential to act as a sensitizer for targeted tyrosine kinase inhibitor therapy for HCC.

Our findings open up new possibilities for combinatory HCC therapy using remimazolam, leveraging its dual functional roles in surgery and drug therapy for liver cancers.

雷马唑仑通过多种应激途径诱导细胞毒性,并与酪氨酸激酶抑制剂协同作用于肝细胞癌。
肝细胞癌(HCC)的主要治疗包括手术切除原发肿瘤,但这为残余和循环癌细胞的增殖和扩散创造了有利的环境。以雷马唑仑为基础的平衡麻醉的发展是未来抗肿瘤应用的关键。详细了解HCC的细胞毒性机制是很重要的。我们对HepG2和Hep3B两种HCC细胞系进行了细胞活力分析、western blotting分析、逆转录-聚合酶链反应分析和流式细胞术分析。我们的数据表明,雷马唑仑通过抑制细胞增殖、抑制G1期进展和影响线粒体活性氧(ROS)水平诱导细胞毒性,导致细胞凋亡、DNA损伤、胞质ROS升高、脂质过氧化、自噬、线粒体去极化和内质网应激。细胞凋亡、自噬细胞死亡和铁凋亡抑制剂和ROS清除剂未能挽救由苯磺酸雷马唑仑引起的细胞死亡。我们的联合指数显示,苯磺酸雷马唑仑有潜力作为靶向酪氨酸激酶抑制剂治疗HCC的增敏剂。我们的研究结果为利用雷马唑仑在肝癌手术和药物治疗中的双重功能作用,联合肝癌治疗开辟了新的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Redox Report
Redox Report 生物-生化与分子生物学
CiteScore
6.10
自引率
0.00%
发文量
28
审稿时长
>12 weeks
期刊介绍: Redox Report is a multidisciplinary peer-reviewed open access journal focusing on the role of free radicals, oxidative stress, activated oxygen, perioxidative and redox processes, primarily in the human environment and human pathology. Relevant papers on the animal and plant environment, biology and pathology will also be included. While emphasis is placed upon methodological and intellectual advances underpinned by new data, the journal offers scope for review, hypotheses, critiques and other forms of discussion.
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