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活性氧生成与线粒体拷贝数增加:对极光激酶抑制剂AZD1152-HQPA诱导细胞毒性潜在机制的新见解

Reactive oxygen species generation and increase in mitochondrial copy number: new insight into the potential mechanism of cytotoxicity induced by aurora kinase inhibitor, AZD1152-HQPA.

作者信息

Zekri Ali, Mesbahi Yashar, Ghanizadeh-Vesali Samad, Alimoghaddam Kamran, Ghavamzadeh Ardeshir, Ghaffari Seyed H

机构信息

aPhysiology Research Center bDepartment of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences cHematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

出版信息

Anticancer Drugs. 2017 Sep;28(8):841-851. doi: 10.1097/CAD.0000000000000523.

DOI:10.1097/CAD.0000000000000523
PMID:28639950
Abstract

Aurora-B kinase overexpression plays important roles in the malignant progression of prostate cancer (PCa). AZD1152-HQPA, as an inhibitor of Aurora-B, has recently emerged as a promising agent for cancer treatment. In this study, we aimed to investigate the effects of AZD1152-HQPA on reactive oxygen species (ROS) generation and mitochondrial function in PCa. We used AZD1152-HQPA (Barasertib), a highly potent and selective inhibitor of Aurora-B kinase. The effects of AZD1152-HQPA on cell viability, DNA content, cell morphology, and ROS production were studied in the androgen-independent PC-3 PCa cell line. Moreover, the mitochondrial copy number and the expression of genes involved in cell survival and cancer stem cell maintenance were investigated. We found that AZD1152-HQPA treatment induced defective cell survival, polyploidy, micronuclei formation, cell enlargement, and cell death by significant overexpression of p73, p21 and downregulation of cell cycle-regulatory genes in a drug concentration-dependent manner. Moreover, AZD1152 treatment led to an excessive ROS generation and an increase in the mitochondrial copy number not only in PC-3 but also in several other malignant cells. AZD1152 treatment also led to downregulation of genes involved in the maintenance of cancer stem cells. Our results showed a functional relationship between the aurora kinase inhibition, an increase in mitochondrial copy number, and ROS generation in therapeutic modalities of cancer. This study suggests that the excessive ROS generation may be a novel mechanism of cytotoxicity induced by the aurora kinase inhibitor, AZD1152-HQPA.

摘要

极光激酶B(Aurora-B)过表达在前列腺癌(PCa)的恶性进展中起重要作用。AZD1152-HQPA作为一种Aurora-B抑制剂,最近已成为一种有前景的癌症治疗药物。在本研究中,我们旨在研究AZD1152-HQPA对PCa中活性氧(ROS)生成和线粒体功能的影响。我们使用了AZD1152-HQPA(巴瑞替尼),一种高效且选择性的Aurora-B激酶抑制剂。在雄激素非依赖性PC-3前列腺癌细胞系中研究了AZD1152-HQPA对细胞活力、DNA含量、细胞形态和ROS产生的影响。此外,还研究了线粒体拷贝数以及参与细胞存活和癌症干细胞维持的基因表达。我们发现,AZD1152-HQPA处理通过p73、p21的显著过表达以及细胞周期调节基因的下调,以药物浓度依赖性方式诱导细胞存活缺陷、多倍体形成、微核形成、细胞肿大和细胞死亡。此外,AZD1152处理不仅导致PC-3细胞,还导致其他几种恶性细胞中ROS过度生成和线粒体拷贝数增加。AZD1152处理还导致参与癌症干细胞维持的基因下调。我们的结果表明,在癌症治疗模式中,极光激酶抑制、线粒体拷贝数增加和ROS生成之间存在功能关系。这项研究表明,ROS过度生成可能是极光激酶抑制剂AZD1152-HQPA诱导细胞毒性的一种新机制。

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