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Genetic-to-epigenetic Therapy for Pancreatic Cancer

ABSTRACT: We utilized RNA-Seq to define molecular markers for the effect of chaetocin and MLN8237 combination. PDAC cells were treated with individual drugs or their combination and compared to vehicle. Treatment was limited to 24 hours to extract RNA before significant mitotic catastrophe occurred to capture the transcriptional effect.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97215 | GEO | 2017/09/01

SECONDARY ACCESSION(S): PRJNA380996

REPOSITORIES: GEO

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The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo

Project description:PURPOSE: Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluate the role of Aurora A, identified as an upregulated candidate molecule in bladder cancer, in regulating bladder tumor growth. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was evaluated using RNA microarray and reverse-transcriptase PCR. The specific Aurora kinase A inhibitor MLN8237 (Millennium) was used to determine effects on bladder cancer cell growth using in vitro and in vivo models using malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells. RESULTS: Urothelial carcinoma upregulates a set of 13 mitotic spindle associated transcripts, as compared to normal urothelium, including MAD2L1 (7.6-fold), BUB1B (8.8-fold), Aurora kinases A (5.6-fold) and Aurora kinase B (6.2-fold). Application of MLN8237 (10nM-1µM) to the human bladder tumor cell lines T24 and UM-UC-3 induced dose-dependent G2 cell cycle arrest, aneuploidy, mitotic spindle abnormalities, and apoptosis. MLN8237 arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model (p<0.05). Finally, in vitro combination of MLN8237 with either paclitaxel or gemcitabine produced schedule-dependent synergistic antiproliferative effects in T24 cells when administered sequentially. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma, and can be exploited with pharmacologic Aurora A inhibition. Future studies that explore the mechanisms of spindle checkpoint failure in bladder cancer and evaluate the therapeutic role of Aurora kinases for bladder cancer patients would be of value.

2013-05-01 | GSE42089 | GEO

The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo

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2015-09-20 | E-GEOD-64836 | biostudies-arrayexpress

Expression profiling tumor cells from MYCN-driven neuroblastoma upon BRD4 or AURKA inhibition

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Project description:This quinoline compound induces mitotic catastrophe in bladder cancer cells, disrupts spindle assembly and chromosome segregation, causes abnormal mitotic arrest and multinucleation, thereby inhibiting cell proliferation and triggering cell death to exert antitumor effects.

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Epigenetic inhibitors

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MYDGF Deficiency Exacerbates Mitotic Catastrophe of Podocytes in Glomerular Disease

Project description:MYDGF Deficiency Exacerbates Mitotic Catastrophe of Podocytes in Glomerular Disease

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Effect of calcipotriol treatment, chaetocin treatment and VDR knockdown on gene expression in BJ cells

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