Aurora B: A new promising therapeutic target in cancer

Chieffi, Paolo

doi:10.5582/irdr.2018.01018

Cited by 37 publications

(32 citation statements)

References 33 publications

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“…Inhibition of Aurora B activity has been found to inhibit proliferation and induce tumor regression in animal model systems. Several small molecule inhibitors of Aurora B are currently under phase I/II evaluation or preclinical testing [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

A simple and robust cell-based assay for the discovery of novel cytokinesis inhibitors

et al. 2020

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Cytokinesis is the last step of mitotic cell division that separates the cytoplasm of dividing cells. Small molecule inhibitors targeting either the elements of the regulatory pathways controlling cytokinesis, or the terminal effectors have been of interest as potential drug candidates for the treatment of various diseases. Here we present a detailed protocol for a cell-based cytokinesis assay that can be used for the discovery of novel cytokinesis inhibitors. The assay is performed in a 96-well plate format in 48 h. Living cells, nuclei and nuclei of dead cells are identified by a single staining step using three fluorescent dyes, followed by rapid live cell imaging. The primary signal is the nuclei-to-cell ratio (NCR). In the presence of cytokinesis inhibitors, this ratio increases over time, as the ratio of multinucleated cells increases in the population. The ratio of dead nuclei to total nuclei provides a simultaneous measure of cytotoxicity. A screening window coefficient ( Z `) of 0.65 indicates that the assay is suitable for screening purposes, as the positive and negative controls are well-separated. EC 50 values can be reliably determined in a single 96-well plate by using only six different compound concentrations, enabling the testing of 4 compounds per plate. An excellent test-retest reliability ( R 2 = 0.998) was found for EC 50 values covering a ~1500-fold range of potencies. Established small molecule inhibitors of cytokinesis operating via direct action on actin dynamics or nonmuscle myosin II are used to demonstrate the robustness, simplicity and flexibility of the assay.

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Section: Introductionmentioning

confidence: 99%

A simple and robust cell-based assay for the discovery of novel cytokinesis inhibitors

et al. 2020

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“…The presence of AURKB overexpression in ALL patients described in this study, proves to be an important target to inhibition by specific target molecules, as GW806742X. It was shown, that AURKB inhibitors interferes with normal chromosome alignment during mitosis and induces endoreduplication, leading cells to death through catastrophic mitosis, becoming a suitable anticancer strategy 37,46,47 . In specific cases, inhibitors of disease-related aurora-kinases have been used experimentally with some success and mark a major advance in the treatment of patients with ALL 6,48 .…”

Section: Discussionmentioning

confidence: 59%

Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia

Moreira-Nunes

Mesquita

Portilho

et al. 2020

Sci Rep

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Aurora kinases (AURKA and AURKB) are mitotic kinases with an important role in the regulation of several mitotic events, and in hematological malignancies, AURKA and AURKB hyperexpression are found in patients with cytogenetic abnormalities presenting a unfavorable prognosis. The aim of this study was evaluated the mRNA expression profile of pediatric Acute Lymphoblastic Leukaemia (ALL) patients and the efficacy of two AURKA and AURKB designed inhibitors (GW809897X and GW806742X) in a leukemia cell line as a potential novel therapy for ALL patients. Cellular experiments demonstrated that both inhibitors induced cell death with caspase activation and cell cycle arrest, however only the GW806742X inhibitor decreased with more efficacy AURKA and AURKB expression in K-562 leukemia cells. In ALL patients both AURKA and AURKB showed a significant overexpression, when compared to health controls. Moreover, AURKB expression level was significant higher than AURKA in patients, and predicted a poorer prognosis with significantly lower survival rates. No differences were found in AURKA and AURKB expression between gene fusions, immunophenotypic groups, white blood cells count, gender or age. In summary, the results in this study indicates that the AURKA and AURKB overexpression are important findings in pediatric ALL, and designed inhibitor, GW806742X tested in vitro were able to effectively inhibit the gene expression of both aurora kinases and induce apoptosis in K-562 cells, however our data clearly shown that AURKB proves to be a singular finding and potential prognostic biomarker that may be used as a promising therapeutic target to those patients.

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“…Interestingly, the 5 hub nodes RRM2, AURKB, DTL, CCNB1, CCNB2 identified from the PPI network constructed by148 shared DEGs were all associated with cell cycle and mitosis, and down-regulated in the ectopic lesions in our analysis while always up-regulated in cancer tissues (Wang et al, 1997;Kolesar et al, 2009;Takashima et al, 2014;Kobayashi et al, 2015;Chieffi, 2018), thus promoting excessive proliferation, which suggested limited and controlled proliferative activity in EMs endometriotic lesions, distinct from cancerous proliferation feature. For example, RRM2, one of the subunits of ribonucleotide reductase complex providing precursors indispensable for DNA synthesis (Engström et al, 1985), was reported lowly expressed in EC compared to the EU in another genome-wide microarray study (Zafrakas et al, 2008), while its overexpression would enhance tumor angiogenesis and growth in multiple cancers (Zhang et al, 2009;Rahman et al, 2013).…”

Section: The Individual Pe Dataset E-mtab-694mentioning

confidence: 72%

Common and specific gene signatures among three different endometriosis subtypes

Jiang

Zhang

Wang

et al. 2020

PeerJ

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Aims To identify the common and specific molecular mechanisms of three well-defined subtypes of endometriosis (EMs): ovarian endometriosis (OE), peritoneal endometriosis (PE), and deep infiltrating endometriosis (DIE). Methods Four microarray datasets: GSE7305 and GSE7307 for OE, E-MTAB-694 for PE, and GSE25628 for DIE were downloaded from public databases and conducted to compare ectopic lesions (EC) with eutopic endometrium (EU) from EMs patients. Differentially expressed genes (DEGs) identified by limma package were divided into two parts: common DEGs among three subtypes and specific DEGs in each subtype, both of which were subsequently performed with the Kyoto Encyclopedia of Genes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed by common DEGs and five hub genes were screened out from the PPI network. Besides, these five hub genes together with selected interested pathway-related genes were further validated in an independent OE RNA-sequencing dataset GSE105764. Results A total of 54 EC samples from three EMs subtypes (OE, PE, DIE) and 58 EU samples were analyzed, from which we obtained 148 common DEGs among three subtypes, and 729 specific DEGs in OE, 777 specific DEGs in PE and 36 specific DEGs in DIE. The most enriched pathway of 148 shared DEGs was arachidonic acid (AA) metabolism, in which most genes were up-regulated in EC, indicating inflammation was the most common pathogenesis of three subtypes. Besides, five hub genes AURKB, RRM2, DTL, CCNB1, CCNB2 identified from the PPI network constructed by 148 shared DEGs were all associated with cell cycle and mitosis, and down-regulated in EC, suggesting a slow and controlled proliferation in ectopic lesions. The KEGG pathway analysis of specific DEGs in each subtype revealed that abnormal ovarian steroidogenesis was a prominent feature in OE; OE and DIE seems to be at more risk of malignant development since both of their specific DEGs were enriched in the pathways in cancer, though enriched genes were different, while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment. Conclusion By integrated bioinformatic analysis, we explored common and specific molecular signatures among different subtypes of endometriosis: activated arachidonic acid (AA) metabolism-related inflammatory process and a slow and controlled proliferation in ectopic lesions were common features in OE, PE and DIE; OE and DIE seemed to be at more risk of malignant development while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment, all of which could deepen our perception of endometriosis.

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Aurora B: A new promising therapeutic target in cancer

Cited by 37 publications

References 33 publications

A simple and robust cell-based assay for the discovery of novel cytokinesis inhibitors

A simple and robust cell-based assay for the discovery of novel cytokinesis inhibitors

Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia

Common and specific gene signatures among three different endometriosis subtypes

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