Dataset Information

The Existing Drug Vorinostat as a New Lead Against Cryptosporidiosis by Targeting the Parasite Histone Deacetylases.

ABSTRACT: Cryptosporidiosis affects all human populations, but can be much more severe or life-threatening in children and individuals with weak or weakened immune systems. However, current options to treat cryptosporidiosis are limited.An in vitro phenotypic screening assay was employed to screen 1200 existing drugs for their anticryptosporidial activity and to determine the inhibitory kinetics of top hits. Selected top hits were further evaluated in mice. The action of the lead compound vorinostat on the parasite histone deacetylase (HDAC) was biochemically validated.Fifteen compounds exhibited anticryptosporidial activity at nanomolar level in vitro. Among them, the histone deacetylase (HDAC) inhibitor vorinostat retained outstanding efficacy in vitro (half maximal effective concentration, EC50 = 203 nM) and in an interleukin 12 knockout mouse model (50% inhibition dose = 7.5 mg/kg). Vorinostat was effective on various parasite developmental stages and could irreversibly kill the parasite. Vorinostat was highly effective against the parasite native HDAC enzymes (half maximal inhibitory concentration, IC50 = 90.0 nM) and a recombinant Cryptosporidium parvum HDAC (the inhibitor constant, Ki = 123.0 nM).These findings suggest the potential for repurposing of vorinostat to treat cryptosporidiosis, and imply that the parasite HDAC can be explored for developing more selective anticryptosporidial therapeutics.

SUBMITTER: Guo F

PROVIDER: S-EPMC5939870 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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The Existing Drug Vorinostat as a New Lead Against Cryptosporidiosis by Targeting the Parasite Histone Deacetylases.

Guo Fengguang F Zhang Haili H McNair Nina N NN Mead Jan R JR Zhu Guan G

The Journal of infectious diseases 20180301 7

<h4>Background</h4>Cryptosporidiosis affects all human populations, but can be much more severe or life-threatening in children and individuals with weak or weakened immune systems. However, current options to treat cryptosporidiosis are limited.<h4>Methods</h4>An in vitro phenotypic screening assay was employed to screen 1200 existing drugs for their anticryptosporidial activity and to determine the inhibitory kinetics of top hits. Selected top hits were further evaluated in mice. The action of ...[more]

PMID: 29300993

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Project description:Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is unknown. Class I histone deacetylases (including HDAC1, 2, 3, and 8) are one of the major classes of the HDAC family and catalyze the removal of acetyl groups from lysine residues in histones and cellular proteins. Class I HDACs exhibit distinct cellular and subcellular expression patterns and are involved in many biological processes and diseases through diverse signaling pathways. However, the link between class I HDACs and uLMS is still being determined. In this study, we assessed the expression panel of Class I HDACs in uLMS and characterized the role and mechanism of class I HDACs in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that HDAC1, 2, and 3 are aberrantly upregulated in uLMS tissues compared to adjacent myometrium. Immunoblot analysis demonstrated that the expression levels of HDAC 1, 2, and 3 exhibited a graded increase from normal and benign to malignant uterine tumor cells. Furthermore, inhibition of HDACs with Class I HDACs inhibitor (Tucidinostat) decreased the uLMS proliferation in a dose-dependent manner. Notably, gene set enrichment analysis of differentially expressed genes (DEGs) revealed that inhibition of HDACs with Tucidinostat altered several critical pathways. Moreover, multiple epigenetic analyses suggested that Tucidinostat may alter the transcriptome via reprogramming the oncogenic epigenome and inducing the changes in microRNA-target interaction in uLMS cells. In the parallel study, we also determined the effect of DL-sulforaphane on the uLMS. Our study demonstrated the relevance of class I HDACs proteins in the pathogenesis of malignant uLMS. Further understanding the role and mechanism of HDACs in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer.

Dataset Information

The Existing Drug Vorinostat as a New Lead Against Cryptosporidiosis by Targeting the Parasite Histone Deacetylases.

Publications

The Existing Drug Vorinostat as a New Lead Against Cryptosporidiosis by Targeting the Parasite Histone Deacetylases.

Similar Datasets

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