Reactive oxygen species generation and increase in mitochondrial copy number

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.

A Synthetic Pan-Aurora Kinase Inhibitor, 5-Methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one, Triggers Reactive Oxygen Species-Mediated Apoptosis in HCT116 Colon Cancer Cells

“…In this study, we have ascertained the effect of aurora kinase inhibitor on ROS-induced apoptosis in HCT116 colon cancer cells. Similar findings were observed in previous studies demonstrating that Aurora-A inhibitor TCS10 [15] and Aurora-B inhibitor barasertib [40] trigger apoptotic cell death through the excess generation of ROS. Currently, it remains unclear how the aurora kinases inhibition by DK1913 can lead to ROS generation.…”

Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases

“…The impact of mitochondrial activities on cellular physiology is not only restricted to ATP production, but also the generation of reactive oxygen species [43]. Although aurora kinase inhibitors lead to excessive ROS and increased cell death [44][45][46], information regarding tozasertib on glioma has been limited. First, we analyzed whether tozasertib treatment could result in increased hydrogen peroxide (H 2 O 2 ) and superoxide anion (O2 •‾).…”

Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma

“…Aurora B was first demonstrated to be overexpressed in colon cancer in 1998 ( Bischoff et al, 1998 ). Cumulative evidence indicated that the amplification/overexpression and/or hyperactivation of Aurora B kinase is a frequent finding in a panel of human malignancies, such as breast ( Larsen et al, 2015 , Zhang et al, 2015 ), liver ( Liu et al, 2017 ), lung ( Al-Khafaji et al, 2017 , Helfrich et al, 2016 ), prostate ( Schecher et al, 2017 , Zekri et al, 2017 ) cancer and leukemia ( Floc'h et al, 2017 , Song et al, 2017 ). The evidence linking Aurora B overexpression and malignancy has generated significant interest in the development of small-molecule inhibitors against this protein.…”

“…Recently, a growing number of inhibitors of Aurora kinases have been developed for both hematopoietic malignancies and solid tumors, either at preclinical or clinical stages ( Ashton et al, 2016 , Dar et al, 2010 , Floc'h et al, 2017 ). Previous studies have demonstrated that the Aurora B specific inhibitor, AZD1152, significantly suppressed human solid tumors, including prostate ( Zekri et al, 2017 ), lung ( Helfrich et al, 2016 ), breast ( Larsen et al, 2015 ) cancer and nasopharyngeal carcinoma ( Li et al, 2015 ). However, the antitumor effect of Aurora B kinase inhibitors against ESCC is still elusive.…”