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HDAC Activity (hdac + activity)

Distribution by Scientific Domains

Chemistry	50%

Selected Abstracts

Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide

CANCER SCIENCE, Issue 10 2010
Hideki Mizutani
Romidepsin (FK228) is a potent histone deacetylase (HDAC) inhibitor, which has a potent anticancer activity, but its molecular mechanism is unknown. We investigated the mechanism of FK228-induced apoptosis in the human leukemia cell line HL-60 and its hydrogen peroxide (H2O2)-resistant sub-clone, HP100, and the human colon cancer cell line Caco-2. Cytotoxicity and DNA ladder formation induced by FK228 could be detected in HL-60 cells after a 24-h incubation, whereas they could not be detected in HP100 cells. Trichostatin A (TSA), an HDAC inhibitor, induced DNA ladder formation in both HL-60 and HP100 cells. In contrast, FK228 inhibited HDAC activity in both HL-60 and HP100 cells to a similar extent. These findings suggest that FK228-induced apoptosis involves H2O2 -mediated pathways and that TSA-induced apoptosis does not. Flow cytometry revealed H2O2 formation and a change in mitochondrial membrane potential (,,m) in FK228-treated cells. FK228 also induced apoptosis in Caco-2 cells, which was prevented by N -acetyl-cysteine, suggesting that reactive oxygen species participate in apoptosis in various types of tumor cells. Interestingly, in a cell-free system, FK228 generated superoxide (O2,) in the presence of glutathione, suggesting that H2O2 is derived from dismutation of O2, produced through redox-cycle of FK228. Therefore, in addition to HDAC inhibition, H2O2 generated from FK228 may participate in its apoptotic effect. (Cancer Sci 2010;) [source]

Inhibition of NF-,B activation by the histone deacetylase inhibitor 4-Me2N-BAVAH induces an early G1 cell cycle arrest in primary hepatocytes

CELL PROLIFERATION, Issue 5 2007
P. Papeleu
4-Me2N-BAVAH has been shown to induce histone hyperacetylation and to inhibit proliferation in Friend erythroleukaemia cells in vitro. However, the molecular mechanisms have remained unidentified. Materials and Methods:,In this study, we evaluated the effects of 4-Me2N-BAVAH on proliferation in non-malignant cells, namely epidermal growth factor-stimulated primary rat hepatocytes. Results and Conclusion:,We have found that 4-Me2N-BAVAH inhibits HDAC activity at non-cytotoxic concentrations and prevents cells from responding to the mitogenic stimuli of epidermal growth factor. This results in an early G1 cell cycle arrest that is independent of p21 activity, but instead can be attributed to inhibition of cyclin D1 transcription through a mechanism involving inhibition of nuclear factor-kappaB activation. In addition, 4-Me2N-BAVAH delays the onset of spontaneous apoptosis in primary rat hepatocyte cultures as evidenced by down-regulation of the pro-apoptotic proteins Bid and Bax, and inhibition of caspase-3 activation. [source]

The Transcriptional Coactivator p300 Plays a Critical Role in the Hypertrophic and Protective Pathways Induced by Phenylephrine in Cardiac Cells but Is Specific to the Hypertrophic Effect of Urocortin

CHEMBIOCHEM, Issue 1 2005
Sean M. Davidson Dr.
Abstract Anacardic acid is an alkylsalicylic acid obtained from cashew-nut-shell liquid, and is a potent inhibitor of p300 histone acetyl-transferase (HAT) activity. We have used anacardic acid to prevent the induction of hypertrophy in isolated neonatal rat cardiomyocytes. Hypertrophy was detected as an increase in cell size, the rearrangement of sarcomeres into a striated pattern, and the induction of embryonic genes ,-MHC and ANF. p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the ,1-adrenergic agonist, phenylephrine, or by treatment with urocortin, a member of the corticotrophin-releasing-factor family, which stimulates specific G protein-coupled receptors. Spiruchostatin A is a natural-product inhibitor of histone deacetylases (HDAC) similar to the depsipeptide FK228 molecule. We have recently synthesized spiruchostatin A and now show that, although HDACs act in opposition to HATs, spiruchostatin A has the same effect as anacardic acid, that is, it prevents the induction of hypertrophy in response to phenylephrine or urocortin. Pretreatment with either phenylephrine or urocortin reduced the extent of death observed after the exposure of isolated cardiomyocytes to simulated ischaemia and reoxygenation. Inhibition of p300 or HDAC activity eliminated the protection conferred by phenylephrine; however, it did not affect the protection conferred by urocortin. Therefore, it might eventually be possible to use chemical inhibitors such as these in a therapeutic setting to dissociate the protective effect and hypertrophic effect of urocortin, enhancing the survival of cardiomyocytes exposed to transient ischemia, while inhibiting the hypertrophic pathway that would otherwise be induced concurrently. [source]

Searching for Disease Modifiers,PKC Activation and HDAC Inhibition,A Dual Drug Approach to Alzheimer's Disease that Decreases A, Production while Blocking Oxidative Stress

CHEMMEDCHEM, Issue 7 2009

Abstract A series of benzolactam compounds were synthesized, some of which caused a concentration-dependent increase in sAPP, and decrease in A, production in the concentration range of 0.1,10,,M. Moreover, some compounds showed neuroprotective effects in the 10,20,,M range in the HCA cortical neuron model of oxidative stress and no toxicity in measurements of neuron viability by MTT assay, even at the highest concentrations tested (20,,M). Alzheimer's disease (AD) is a well-studied neurodegenerative process characterized by the presence of amyloid plaques and neurofibrillary tangles. In this study, a series of protein kinase,C (PKC) activators were investigated, some of which also exhibit histone deacetylase (HDAC) inhibitory activity, under the hypothesis that such compounds might provide a new path forward in the discovery of drugs for the treatment of AD. The PKC-activating properties of these drugs were expected to enhance the ,-secretase pathway in the processing of amyloid precursor protein (APP), while their HDAC inhibition was anticipated to confer neuroprotective activity. We found that benzolactams 9 and 11,14 caused a concentration-dependent increase in sAPP, and decrease in ,-amyloid (A,) production in the concentration range of 0.1,10,,M, consistent with a shift of APP metabolism toward the ,-secretase-processing pathway. Moreover, compounds 9,14 showed neuroprotective effects in the 10,20,,M range in the homocysteate (HCA) cortical neuron model of oxidative stress. In parallel, we found that the most neuroprotective compounds caused increased levels of histone acetylation (H4), thus indicating their likely ability to inhibit HDAC activity. As the majority of the compounds studied also show nanomolar binding affinities for PKC, we conclude that it is possible to design, de,novo, agents that combine both PKC-activating properties along with HDAC inhibitory properties. Such agents would be capable of modulating amyloid processing while showing neuroprotection. These findings may offer a new approach to therapies that exhibit disease-modifying effects, as opposed to symptomatic relief, in the treatment of AD. [source]