BA-j as a novel CDK1 inhibitor selectively induces apoptosis in cancer cells by regulating ROS

Zhang, Shixuan; Bao, Yongming; Ju, Xiulan; Li, Kangjian; Shang, Huaming; Ha, Lisha; Qian, Yuan; Zou, Liang; Sun, Xiaodan; Li, Jing; Fan, Qingyu

doi:10.1038/srep13626

Cited by 21 publications

(15 citation statements)

References 45 publications

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“…Baicalein has been identified as a selective inhibitor of CDK1 by FRET analysis and structure-activity relationship analysis in the Hep G2 and SMMC-7721 cell lines [39, 40]. A549 and H1299 non-small-cell lung cancer cells and primary cultured heart endothelial cells treated with baicalein have additionally been reported to exhibit downregulated expression of CDK1 [41].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma

Sun

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Liver cancer is the fourth leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) accounts for the greatest proportion of these deaths. Baicalein, a flavonoid isolated from the root of Scutellariae radix, is considered a potential candidate to treat HCC. However, the underlying molecular mechanisms remain poorly understood. In the present study, a network pharmacological approach was combined with microarray data (GSE95504) acquired from the Gene Expression Omnibus database to reveal the therapeutic mechanisms of action of baicalein at a systemic level. We identified 38 baicalein targets and 76 differently expressed genes (DEGs) following treatment with baicalein, including 55 upregulated and 21 downregulated genes. The DEGs were significantly enriched in the biological functions of apoptosis, endoplasmic reticulum stress, and PERK-mediated unfolded protein response. Protein-protein interaction (PPI) network construction and topological screening revealed a core module of PPIs including two baicalein targets, TP53 and CDK1, and two downregulated DEGs, HSPA1A and HSPA1B. Expression and survival data for these genes in the module derived from Gene Expression Profiling Interactive Analysis (GEPIA) were subjected to Kaplan–Meier analysis of overall survival and disease-free survival. Overexpression of CDK1, BRCA1, TUBB, HSPA1A, HSPA1B, and HSPA4 was associated with significantly worse overall survival, while overexpression of CDK1, CLU7, BRCA1, and TUBB was associated with significantly worse disease-free survival. These data suggest that baicalein exerts therapeutic effects against HCC via a PPI network involving TP53, CDK1, HSPA1A, and HSPA1B.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma

Sun

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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“…The cell cycle is another interesting molecular target in AML and cyclin-dependent kinases (CDKs) inhibitors are currently being studied in this respect [ 137 ]. Some work supports the fact that the antiproliferative effect of this type of inhibitors is linked to the induction of oxidative stress [ 151 ].…”

Section: The Use Of Ros As a Therapeutic Target In Haematological Malmentioning

confidence: 96%

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

Prieto-Bermejo

Romo-González

Pérez-Fernández

et al. 2018

J Exp Clin Cancer Res

104

115

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Oxidative stress is related to ageing and degenerative diseases, including cancer. However, a moderate amount of reactive oxygen species (ROS) is required for the regulation of cellular signalling and gene expression. A low level of ROS is important for maintaining quiescence and the differentiation potential of haematopoietic stem cells (HSCs), whereas the level of ROS increases during haematopoietic differentiation; thus, suggesting the importance of redox signalling in haematopoiesis. Here, we will analyse the importance of ROS for haematopoiesis and include evidence showing that cells from leukaemia patients live under oxidative stress. The potential sources of ROS will be described. Finally, the level of oxidative stress in leukaemic cells can also be harnessed for therapeutic purposes. In this regard, the reliance of front-line anti-leukaemia chemotherapeutics on increased levels of ROS for their mechanism of action, as well as the active search for novel compounds that modulate the redox state of leukaemic cells, will be analysed.

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“…The integrity of the mitochondrial membrane was estimated by Rhodamine 123 (Rh 123) assay as described earlier [ 40 ]. Rh 123 is a cationic green fluorescent dye that can enter the mitochondrial matrix and the variation in the accumulation of Rh 123 in the cells is directly related to the change in the mitochondrial electrochemical potential (Δψ M ).…”

Section: Methodsmentioning

confidence: 99%

HSP60 critically regulates endogenous IL-1β production in activated microglia by stimulating NLRP3 inflammasome pathway

Swaroop¹,

Mahadevan²,

Shankar³

et al. 2018

J Neuroinflammation

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BackgroundInterleukin-1β (IL-1β) is one of the most important cytokine secreted by activated microglia as it orchestrates the vicious cycle of inflammation by inducing the expression of various other pro-inflammatory cytokines along with its own production. Microglia-mediated IL-1β production is a tightly regulated mechanism which involves the activation of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome pathway. Our previous study suggests the critical role of heat shock protein 60 (HSP60) in IL-1β-induced inflammation in microglia through TLR4-p38 MAPK axis. However, whether HSP60 regulates endogenous IL-1β production is not known. Therefore, to probe the underlying mechanism, we elucidate the role of HSP60 in endogenous IL-1β production.MethodsWe used in vitro (N9 murine microglial cells) and in vivo (BALB/c mouse) models for our study. HSP60 overexpression and knockdown experiment was done to elucidate the role of HSP60 in endogenous IL-1β production by microglia. Western blotting and quantitative real-time PCR was performed using N9 cells and BALB/c mice brain, to analyze various proteins and transcript levels. Reactive oxygen species levels and mitochondrial membrane depolarization in N9 cells were analyzed by flow cytometry. We also performed caspase-1 activity assay and enzyme-linked immunosorbent assay to assess caspase-1 activity and IL-1β production, respectively.ResultsHSP60 induces the phosphorylation and nuclear localization of NF-κB both in vitro and in vivo. It also induces perturbation in mitochondrial membrane potential and enhances reactive oxygen species (ROS) generation in microglia. HSP60 further activates NLRP3 inflammasome by elevating NLRP3 expression both at RNA and protein levels. Furthermore, HSP60 enhances caspase-1 activity and increases IL-1β secretion by microglia. Knockdown of HSP60 reduces the IL-1β-induced production of IL-1β both in vitro and in vivo. Also, we have shown for the first time that knockdown of HSP60 leads to decreased IL-1β production during Japanese encephalitis virus (JEV) infection, which eventually leads to decreased inflammation and increased survival of JEV-infected mice.ConclusionHSP60 mediates microglial IL-1β production by regulating NLRP3 inflammasome pathway and reduction of HSP60 leads to reduction of inflammation in JEV infection.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1214-5) contains supplementary material, which is available to authorized users.

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BA-j as a novel CDK1 inhibitor selectively induces apoptosis in cancer cells by regulating ROS

Cited by 21 publications

References 45 publications

Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma

Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

HSP60 critically regulates endogenous IL-1β production in activated microglia by stimulating NLRP3 inflammasome pathway

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