Sensitivity of MiaPaCa2 cells to E2F inhibitor Ly101-4B.
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ABSTRACT:
PROVIDER: PRJNA432326 | ENA |
REPOSITORIES: ENA
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Project description:MiaPaCa2 cells where screened with a set of original compounds with anticancer activity available at our laboratory. From these compounds we identified the nucleoside analogue ly101-4B as a strong inhibitor of the E2F activity. We confirmed its activity by studying its effect on MiaPaCa2's cell viability , caspase 3/7 activity and LDH release, to measure cell growth, apoptosis and necrosis after treatment with LY101-4B 25 µM. Then, to investigate the mechanism of action of ly101-4B we performed a transcriptomic analysis by using an Affymetrix approach (Genechip® Human Gene 1.0 ST Arrays).
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Project description:To assess the effects of histone deacetylase (HDAC) inhibitor, HDACi 4b, treatment on muscle function on a molecular level, we performed microarray analysis on skeletal muscle (gastrocnemius) samples from wt and N17182Q mice treated with the HDAC inhibitor 4b for 3 months (50 mg/kg; s.c. injection 3x weekly; n=4 per group). The transcriptome pattern in N17182Q mice compared to wt controls consisted of deficits in the expression of genes related to mitochondrial function and oxidative metabolism. In addition, we noted that numerous genes associated with basal contractile function were altered in HD N17182Q mice. These include genes related to the muscle contractile complex, Tnnt3 and Myh8, as well as several additional myosin genes: myosin heavy chain genes, Myh10 and Myh4, and myosin light chain genes, Myl1, Mylc2 and Mylk. These findings implicate deficits in the underlying contractile function in skeletal muscle from HD mice. Further, we found robust effects of 4b treatment on the expression of genes in skeletal muscle, with 556 genes showing significantly altered expression, at p<0.005, in 4b-treated N17182Q muscle compared to vehicle-treated control mice. n=4 vehicle-treated WT mice, n=5 HDACi 4b-treated WT mice, n=4 vehicle-treated N17182Q transgenic mice, and n=3 HDACi 4b-treated N17182Q transgenic mice.
2014-11-01 | E-GEOD-56963 | biostudies-arrayexpress
Project description:To assess the effects of histone deacetylase (HDAC) inhibitor, HDACi 4b, treatment on muscle function on a molecular level, we performed microarray analysis on skeletal muscle (gastrocnemius) samples from wt and N17182Q mice treated with the HDAC inhibitor 4b for 3 months (50 mg/kg; s.c. injection 3x weekly; n=4 per group). The transcriptome pattern in N17182Q mice compared to wt controls consisted of deficits in the expression of genes related to mitochondrial function and oxidative metabolism. In addition, we noted that numerous genes associated with basal contractile function were altered in HD N17182Q mice. These include genes related to the muscle contractile complex, Tnnt3 and Myh8, as well as several additional myosin genes: myosin heavy chain genes, Myh10 and Myh4, and myosin light chain genes, Myl1, Mylc2 and Mylk. These findings implicate deficits in the underlying contractile function in skeletal muscle from HD mice. Further, we found robust effects of 4b treatment on the expression of genes in skeletal muscle, with 556 genes showing significantly altered expression, at p<0.005, in 4b-treated N17182Q muscle compared to vehicle-treated control mice.
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Project description:Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2(300Q) transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2(300Q) transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.
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