Computer program for the expression of the kinetic equations of enzyme reactions as functions of the rate constants and the initial concentrations.
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ABSTRACT:
SUBMITTER: Varon R
PROVIDER: S-EPMC1131808 | biostudies-other | 1990 Sep
REPOSITORIES: biostudies-other
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Project description:Histone deacetylases (HDACs) are critical in the control of gene expression and dysregulation of their activity has been implicated in a broad range of diseases including cancer, cardiovascular and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. While it has also been suggested that HDACi with increased isozyme-selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi SAHA and TSA. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histoneacetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that the evaluation of different classes of HDACi compounds using recombinant HDACs or histone acetylation is insufficient to predict their functional impact on cell activity. Control, SAHA 6hr, SAHA 24hr, SAHA 24hr (pulsed), C1 6hr, C1, 24hr, C1 24hr (pulsed)
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