Histone deacetylase inhibitors attenuate P-aIgA1-induced cell proliferation and extracellular matrix synthesis in human renal mesangial cells in vitro

(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 μM ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells; Furthermore, ergosterol markedly improved transforming growth factor-β1 (TGF-β1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-β1/Smad2 signaling pathway.

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Anti-tumoral efficiacy of four different histone deacetylase inhibitors on hepatoma cells in vitro

Journal of Hepatology ◽

10.1016/s0168-8278(03)80384-7 ◽

2003 ◽

Vol 38 ◽

pp. 95

Author(s):

M. Ganslmayer ◽

C. Herold ◽

M. Ocker ◽

S. Zopf ◽

S. Kareth ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Hepatoma Cells

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Cyclosporin A affects extracellular matrix synthesis and degradation by mouse MC3T3‐E1 osteoblasts in vitro

Nephrology Dialysis Transplantation ◽

10.1093/ndt/16.3.500 ◽

2001 ◽

Vol 16 (3) ◽

pp. 500-505 ◽

Cited By ~ 30

Author(s):

Alessia Fornoni ◽

Flavia Cornacchia ◽

Guy A. Howard ◽

Bernard A. Roos ◽

Gary E. Striker ◽

...

Keyword(s):

Extracellular Matrix ◽

Cyclosporin A ◽

Matrix Synthesis ◽

Synthesis And Degradation

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Inhibitory Effects of Cancer Cell Proliferation by Novel Histone Deacetylase Inhibitors Involve p21/WAF1 Induction and G2/M Arrest

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.28.849 ◽

2005 ◽

Vol 28 (5) ◽

pp. 849-853 ◽

Cited By ~ 12

Author(s):

Taishi Maeda ◽

Yasuo Nagaoka ◽

Yuki Kawai ◽

Nobumasa Takagaki ◽

Chikako Yasuda ◽

...

Keyword(s):

Cell Proliferation ◽

Histone Deacetylase ◽

Cancer Cell ◽

Histone Deacetylase Inhibitors ◽

Cancer Cell Proliferation ◽

Inhibitory Effects ◽

P21 Waf1

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Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2016.01.013 ◽

2016 ◽

Vol 109 ◽

pp. 350-359 ◽

Cited By ~ 19

Author(s):

Jiachen Wen ◽

Yu Bao ◽

Qun Niu ◽

Jinyu Yang ◽

Yinbo Fan ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors

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Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis

10.1101/296384 ◽

2018 ◽

Cited By ~ 1

Author(s):

Soo-Hyun Kim ◽

Richard P. Redvers ◽

Lap Hing Chi ◽

Xiawei Ling ◽

Andrew J. Lucke ◽

...

Keyword(s):

Breast Cancer ◽

Mammary Gland ◽

Brain Metastasis ◽

Histone Deacetylase ◽

Clinical Relevance ◽

Histone Deacetylase Inhibitors ◽

Novel Therapies ◽

Breast Cancer Brain Metastasis ◽

The Brain

ABSTRACTBreast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.SUMMARY STATEMENTWe introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis and test novel therapies.

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