The effect of danusertib, an Aurora kinase inhibitor, onto the cytotoxicity, cell cycle and apoptosis in pancreatic ductal adenocarcinoma cells

Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

Download Full-text

Cell Cycle Interference Contributes to the Anticancer Synergy Between Radiotherapy and Aurora Kinase Inhibitor VE-465 in Hepatocellular Carcinoma

Annals of Oncology ◽

10.1093/annonc/mdu165.22 ◽

2014 ◽

Vol 25 ◽

pp. ii20

Author(s):

Lin Zhong-Zhe ◽

Chou Chia-Hung ◽

Cheng Ann-Lii ◽

Liu Wei-Lin ◽

Cheng Jason Chia-Hsien

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor

Download Full-text

Erlotinib Promotes Ligand-Induced EGFR Degradation in 3D but Not 2D Cultures of Pancreatic Ductal Adenocarcinoma Cells

Cancers ◽

10.3390/cancers13184504 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4504

Author(s):

Nausika Betriu ◽

Anna Andreeva ◽

Carlos E. Semino

Keyword(s):

Tyrosine Kinase ◽

Pancreatic Ductal Adenocarcinoma ◽

Kinase Inhibitor ◽

3D Culture ◽

Ductal Adenocarcinoma ◽

Normal Fibroblast ◽

Tyrosine Kinase Receptor ◽

3D Cultures ◽

Adenocarcinoma Cells ◽

3D Microenvironment

The epithelial growth factor receptor (EGFR) is a tyrosine kinase receptor that participates in many biological processes such as cell proliferation. In addition, EGFR is overexpressed in many epithelial cancers and therefore is a target for cancer therapy. Moreover, EGFR responds to lots of stimuli by internalizing into endosomes from where it can be recycled to the membrane or further sorted into lysosomes where it undergoes degradation. Two-dimensional cell cultures have been classically used to study EGFR trafficking mechanisms in cancer cells. However, it has been widely demonstrated that in 2D cultures cells are exposed to a non-physiological environment as compared to 3D cultures that provide the normal cellular conformation, matrix dimensionality and stiffness, as well as molecular gradients. Therefore, the microenvironment of solid tumors is better recreated in 3D culture models, and this is why they are becoming a more physiological alternative to study cancer physiology. Here, we develop a new model of EGFR internalization and degradation upon erlotinib treatment in pancreatic ductal adenocarcinoma (PDAC) cells cultured in a 3D self-assembling peptide scaffold. In this work, we show that treatment with the tyrosine kinase inhibitor erlotinib promotes EGFR degradation in 3D cultures of PDAC cell lines but not in 2D cultures. We also show that this receptor degradation does not occur in normal fibroblast cells, regardless of culture dimensionality. In conclusion, we demonstrate not only that erlotinib has a distinct effect on tumor and normal cells but also that pancreatic ductal adenocarcinoma cells respond differently to drug treatment when cultured in a 3D microenvironment. This study highlights the importance of culture systems that can more accurately mimic the in vivo tumor physiology.

Download Full-text

The Evaluation of Effect of Aurora Kinase Inhibitor CCT137690 in Melanoma and Melanoma Cancer Stem Cell

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666201026155101 ◽

2020 ◽

Vol 20 ◽

Author(s):

Fatma Sogutlu ◽

Cagla Kayabasi ◽

Besra Ozmen Yelken ◽

Aycan Asik ◽

Roya Gasimli ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Kinase Inhibitor ◽

Annexin V ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor ◽

Aurora Kinases ◽

Melanoma Cancer

Background: Dysregulation of the cell cycle is one of the main causes of melanomagenesis. Genome-wide studies showed that expression of Aurora -A and -B significantly has been upregulated in melanoma. However, there is no FDA approved drug targeting aurora kinases in the treatment of melanoma. In addition, the development of resistance to chemotherapeutic agents in the treatment of melanoma and, as a result, the relapse due to heterogeneous cell groups in patients is a second phenomenon that causes treatment failure. Therefore, there is an urgent need for therapeutic alternatives targeting both melanoma and melanoma cancer stem cells (MCSCs) in treatments. At this stage, cell cycle regulators become promising targets. Objective: In this study, we aimed to identify the effects of Aurora kinase inhibitor CCT137690 on the cytotoxicity, apoptosis, cell cycle, migration, and colony formation and expression changes of genes related to proliferation, cell death and cell cycle in melanoma and melanoma cancer stem cell. In addition, we investigated the apoptotic and cytostatic effects of CCT137690 in normal fibroblast cells. Methods: We evaluated the cytotoxic effect of CCT137690 in MCSCs, NM2C5 referring as melanoma model cells and WI38 cells by using the WST-1 test. The effect of CCT137690 on apoptosis was detected via Annexin V and JC-1 method; on cell cycle progression by cell cycle test; on gene expression by using RT-PCR, on migration activity by wound healing assay and clonal growth by clonogenic assay in NM2C5 cells and MCSCs. The effects of CCT137690 in WI-38, referring as healthy fibroblast cell, were assessed through Annexin V and cell cycle method. Results: CCT137690 was determined to have a cytotoxic and apoptotic effect in MCSCs and melanoma. It caused polyploidy and cell cycle arrest at the G2/M phase in MCSCs and melanoma cells. The significant decrease in the expression of MMP2, MMP7, MMP10, CCNB1, IRAK1, PLK2 genes, and the increase in the expression of PTEN, CASP7, p53 genes were detected. Conclusion: Aurora kinases inhibitor CCT137690 displays promising anticancer activity in melanoma and especially melanoma cancer stem cells. The effect of CCT137690 on melanoma and MCSC may provide a new approach to treatment protocols.

Download Full-text

P32 The Aurora kinase inhibitor AZD1152 inhibits cell proliferation, modifies the cell cycle and enhances chemotherapeutic activity in in vitro models

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)70037-5 ◽

2007 ◽

Vol 5 (8) ◽

pp. 19

Author(s):

A. Azzariti ◽

L. Porcelli ◽

G.M. Simone ◽

A. Paradiso

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

In Vitro Models ◽

Aurora Kinase Inhibitor ◽

Chemotherapeutic Activity

Download Full-text

Improving Generation of Cardiac Organoids from Human Pluripotent Stem Cells Using the Aurora Kinase Inhibitor ZM447439

Biomedicines ◽

10.3390/biomedicines9121952 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1952

Author(s):

Su-Jin Lee ◽

Hyeon-A Kim ◽

Sung-Joon Kim ◽

Hyang-Ae Lee

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Pluripotent Stem Cells ◽

Drug Testing ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Gene Profiling ◽

Success Rates ◽

Aurora Kinase Inhibitor ◽

Drug Induced

Drug-induced cardiotoxicity reduces the success rates of drug development. Thus, the limitations of current evaluation methods must be addressed. Human cardiac organoids (hCOs) derived from induced pluripotent stem cells (hiPSCs) are useful as an advanced drug-testing model; they demonstrate similar electrophysiological functionality and drug reactivity as the heart. How-ever, similar to other organoid models, they have immature characteristics compared to adult hearts, and exhibit batch-to-batch variation. As the cell cycle is important for the mesodermal differentiation of stem cells, we examined the effect of ZM447439, an aurora kinase inhibitor that regulates the cell cycle, on cardiogenic differentiation. We determined the optimal concentration and timing of ZM447439 for the differentiation of hCOs from hiPSCs and developed a novel protocol for efficiently and reproducibly generating beating hCOs with improved electrophysiological functionality, contractility, and yield. We validated their maturity through electro-physiological- and image-based functional assays and gene profiling with next-generation sequencing, and then applied these cells to multi-electrode array platforms to monitor the cardio-toxicity of drugs related to cardiac arrhythmia; the results confirmed the drug reactivity of hCOs. These findings may enable determination of the regulatory mechanism of cell cycles underlying the generation of iPSC-derived hCOs, providing a valuable drug testing platform.

Download Full-text

Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor “BI-847325” on anaplastic thyroid carcinoma

DARU Journal of Pharmaceutical Sciences ◽

10.1007/s40199-018-0231-3 ◽

2019 ◽

Vol 27 (1) ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Hilda Samimi ◽

Vahid Haghpanah ◽

Shiva Irani ◽

Ehsan Arefian ◽

Alireza Naderi Sohi ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Carcinoma ◽

Kinase Inhibitor ◽

Transcript Level ◽

Aurora Kinase ◽

Anaplastic Thyroid Carcinoma ◽

Aurora Kinase Inhibitor

Download Full-text

Effect of miR-184 on Proliferation and Apoptosis of Pancreatic Ductal Adenocarcinoma and Its Mechanism

Technology in Cancer Research & Treatment ◽

10.1177/1533033820943237 ◽

2020 ◽

Vol 19 ◽

pp. 153303382094323

Author(s):

Shentao Li ◽

He Li ◽

Weiwei Ge ◽

Kai Song ◽

Chunyu Yuan ◽

...

Keyword(s):

Cell Cycle ◽

Pancreatic Ductal Adenocarcinoma ◽

Caspase 3 ◽

Survival Curve ◽

Ductal Adenocarcinoma ◽

Control Group ◽

Caspase 9 ◽

Tumor Tissues ◽

Adenocarcinoma Cells

Objective: Previous studies have shown that abnormal expression of microRNA-184 leads to a variety of cancers, including pancreatic ductal adenocarcinoma, suggesting microRNA-184 as a new treatment target for pancreatic ductal adenocarcinoma. However, the molecular mechanism of microRNA-184 in pancreatic ductal adenocarcinoma remains unclear. It is important to investigate the effect and role of microRNA-184 in pancreatic ductal adenocarcinoma. Methods: The clinical and laboratory inspection data of 120 patients with pancreatic cancer admitted to the First Affiliated Hospital of Anhui Medical University were compared. MicroRNA-184 expression in tumor tissues and cells was evaluated using reverse transcription polymerase chain reaction. Flow cytometry and Annexin V/propidium iodide staining were performed to examine cell cycle and apoptosis. Western blotting analysis was conducted to measure the protein expression of p-PI3K, p-AKT, JNK1, C-Myc, C-Jun, caspase-9, and caspase-3. Results: MicroRNA-184 expression was low in patients with pancreatic ductal adenocarcinoma. Survival curve showed that patients with lower expression of microRNA-184 in tumor tissues had a worse prognosis and shorter survival time ( P < .05), and the multivariate analysis identified that microRNA-184 was an independent prognostic indicator ( P < .05). In vitro studies showed that microRNA-184 overexpression induced apoptosis and suppressed cell cycle transition from G1 to S and G2 phases in pancreatic ductal adenocarcinoma cells. Furthermore, molecular studies revealed that inhibition of microRNA-184 promoted the gene expression of p-PI3K, p-AKT, JNK1, C-Myc, and C-Jun compared with the control group. Overexpression of microRNA-184 led to significantly increased expression of caspase-9 and caspase-3 and significantly decreased expression of Bcl-2. Conclusion: This study suggests that microRNA-184 inhibits the proliferation and promotes the apoptosis of pancreatic ductal adenocarcinoma cells by downregulating the expression of C-Myc, C-Jun, and Bcl-2. Our verification of the role of microRNA-184 may provide a novel biomarker for the diagnosis, therapy, and prognosis of pancreatic ductal adenocarcinoma.

Download Full-text