Histone deacetylase inhibitors suppress ACE2 and ABO simultaneously, suggesting a preventive potential against COVID-19

Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.

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Histone deacetylase inhibitors suppress ACE2 and ABO simultaneously, suggesting a preventive potential against COVID-19

Scientific Reports ◽

10.1038/s41598-021-82970-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yoichiro Takahashi ◽

Akira Hayakawa ◽

Rie Sano ◽

Haruki Fukuda ◽

Megumi Harada ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Abo Blood Group ◽

Blood Group System ◽

Cell Surfaces ◽

Angiotensin Converting Enzyme 2 ◽

Increased Risk ◽

Epithelial Cell Lines ◽

Preventive Drug

AbstractCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.

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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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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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Histone Deacetylase Inhibitors: Assays to Assess Effectiveness In Vitro and In Vivo

Chromatin and Chromatin Remodeling Enzymes, Part B - Methods in Enzymology ◽

10.1016/s0076-6879(03)76013-3 ◽

2003 ◽

pp. 199-205 ◽

Cited By ~ 14

Author(s):

Victoria M Richon ◽

Xianbo Zhou ◽

J.Paul Secrist ◽

Carlos Cordon-Cardo ◽

W.Kevin Kelly ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors

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Histone deacetylase inhibitors induce invasion of human melanoma cells in vitro via differential regulation of N-cadherin expression and RhoA activity

BMC Cancer ◽

10.1186/s12885-016-2693-3 ◽

2016 ◽

Vol 16 (1) ◽

Cited By ~ 8

Author(s):

María Díaz-Núñez ◽

Alejandro Díez-Torre ◽

Olivier De Wever ◽

Ricardo Andrade ◽

Jon Arluzea ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Melanoma Cells ◽

Differential Regulation ◽

Human Melanoma ◽

Rhoa Activity ◽

Human Melanoma Cells

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Design, synthesis and evaluation of belinostat analogs as histone deacetylase inhibitors

Future Medicinal Chemistry ◽

10.4155/fmc-2018-0587 ◽

2019 ◽

Vol 11 (21) ◽

pp. 2765-2778

Author(s):

Jie-Huan Zhang ◽

Madhusoodanan Mottamal ◽

Hai-Shan Jin ◽

Shanchun Guo ◽

Yan Gu ◽

...

Keyword(s):

Histone Deacetylase ◽

Active Compound ◽

Histone Deacetylase Inhibitors ◽

Hdac Inhibitors ◽

Antitumor Therapy ◽

Design Synthesis ◽

Inhibitory Activities ◽

Antiproliferative Activities

Aim: Histone deacetylase (HDAC) is an attractive target for antitumor therapy. Therefore, the development of novel HDAC inhibitors is warranted. Materials & methods: A series of HDAC inhibitors based on N-hydroxycinnamamide fragment was designed as the clinically used belinostat analog using amide as the connecting unit. All target compounds were evaluated for their in vitro HDAC inhibitory activities and some selected compounds were tested for their antiproliferative activities. Conclusion: Among them, compound 7e showed an IC50 value of 11.5 nM in inhibiting the HDAC in a pan-HDAC assay, being the most active compound of the series.

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