Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192

Boissinot, Marjorie; Inman, Martyn; Hempshall, Aiden; James, Sally; Gill, Jason H.; Selby, Peter J.; Bowen, David; Grigg, R.; Cockerill, Peter N.

doi:10.1016/j.leukres.2012.07.002

Cited by 44 publications

(41 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We treated LPS‐induced cells with MS‐275 [which has reported selectivity for HDAC1 (Bradner, )], 500 nM apicidin or 1 μM MI‐192, [both of which have reported selectivity for HDAC2 and 3 (Khan et al . ; Boissinot et al ., )]. Treatment of BV‐2 cells with these inhibitors showed a rapid and stable increase in acetylated Histone H4 for apicidin but a gradual increase for MS‐275 and MI‐192 over a 24‐h period (Fig.…”

Section: Resultsmentioning

confidence: 92%

Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism

Durham

Grigg

Wood

2017

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies have shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study, we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV-2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is up-regulated and these increased levels are compensatory, suggesting that these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease.

show abstract

Section: Resultsmentioning

confidence: 92%

Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism

Durham

Grigg

Wood

2017

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…20, 25 We then attempted to determine whether HDAC3 was responsible for MI192-induced apoptosis. To elucidate the direct target of MI192, we used an in vitro deacetylation system (Figure 4c).…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

et al. 2017

View full text Add to dashboard Cite

Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochemistry showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.

show abstract

“…These HDACs 2 and 3 selective inhibitors display low nanomolar potency for HDAC2 and 3 (~20 nM) and high micromolar activity for HDACs 1, 4, 6, 7 and 8 (> 4 µM). No data were reported for HDACs 5, 9, 10 and 11 [52]. This report is the first to describe any small molecule structural motifs capable of imparting differential binding in favor of HDAC2 versus HDAC1.…”

Section: Development Of Hdac2 Selective Inhibitorsmentioning

confidence: 89%

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

et al. 2013

View full text Add to dashboard Cite

Increasing evidence supports a role for epigenetic involvement in some of the neurobiological alterations observed in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Additional data support the notion that small molecule inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms associated with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the associated biological effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.

show abstract

Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192

Cited by 44 publications

References 32 publications

Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism

Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

Contact Info

Product

Resources

About