• Bulletin of the Korean Chemical Society
• /
• v.33 no.2
• /
• pp.535-540
• /
• 2012

A series of benzamide-based histone deacetylases (HDACs) inhibitors possessing N-(aminopyridine) residue as the zinc binding site of HDAC were synthesized and evaluated. Among these derivatives, compounds with N-(2-amino-4-pyridine) benzamide moiety have been found as the most potent ones. Moreover, introduction of appropriate substituents on the terminal aryl group acting as the surface-recognition domain could significantly improve the antiproliferative activity. In particular, the compound 4k possessed favorable pharmacokinetic characteristics and exhibited potent antitumor activity on xenograft model in mice at well tolerated doses, thus suggesting a good therapeutic index.

• Proceedings of the Korea Environmental Mutagen Society Conference
• /
• 2004.05a
• /
• pp.114-114
• /
• 2004

• Biomolecules & Therapeutics
• /
• v.23 no.5
• /
• pp.434-441
• /
• 2015

Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP ($IC_{50}=0.67{\mu}M$) than in DU145 cells ($IC_{50}=1.10{\mu}M$) and PC3 cells ($IC_{50}=5.60{\mu}M$) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.

• Environmental Mutagens and Carcinogens
• /
• v.24 no.3
• /
• pp.128-136
• /
• 2004

CYP1A1 is known to be inducible by xenobiotic compouds such as polyciclic aromatic hydrocarbons(PAHs) and 2,3,7,8-tetrachloro-dibenzo-p-dioxin(TCDD). These chemicals have been identified worldwide and can have a significant impact on the human health and well being of human and wildlife. Given these issues, the detection and quantification of these chemicals in biological, environmental and food samples is important. First, we investigated the effect of on CYP1A1 promoter activity, 7-ethoxyresorufin-O-deethylase(EROD) activity and CYP1A1 mRNA expression induced by benzo(k)fluoranthene(B(k)F) in MCF-7 cells. We found that B(k)F significantly up-regulates the level of CYP1A1 prompter activity, EROD and CYP1A1 mRNA. When cells were treated with genistein, it was not changed that EROD and CYP1A1 mRNA, compared to that of control. However, genistein inhibited the B(k)F-induced CYP1A1 promoter activity and mRNA level at high concentration. Furthermore, in this study, effects of HDAC(histone deacetvlase) inhibitors on human prostate cancer cells proliferation were examined. HC-toxin, SAHA and TSA inhibited cell proliferation in PC3 cells. A novel HDAC inhibitor, IN2001 also suppressed the growth of PC3 cells. And IN2001 and SAHA increased S phase and G2/M phase at 12 hrs treatment but cells were arrested G0/G1 phase at 45 hrs treatment. The HC-toxin treatment for 24 hrs and 48 hrs increased G0/G1 at low concentration ($0.1\mu\textrm{m}$) but increased G2/M at more than concentration of $1\mu\textrm{m}$. TSA increased G2/M phase. These findings height the possbility of developing HDAC inhibitors as potential anticancer therapeutic agents for the treatment of prostate cancer.

• Biomolecules & Therapeutics
• /
• v.20 no.3
• /
• pp.280-285
• /
• 2012

The developing embryo naturally experiences relatively low oxygen conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$). Previously, we demonstrated that histone deacetylase (HDAC) is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-$1{\alpha}$ in many human cancer cells. Furthermore HDAC1 and 3 mediate the differentiation of mECSs and hematopoietic stem cells. However, the role of HDACs and their inhibitors in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we examined the effects of several histone deacetylase inhibitors (HDACIs) on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC under hypoxia effectively decreased the HIF-$1{\alpha}$ protein levels and substantially improved the expression of the LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. In particular, valproic acid (VPA), a pan HDACI, showed dramatic changes in HIF-$1{\alpha}$ protein levels and LIFR protein expression levels compared to other HDACIs, including sodium butyrate (SB), trichostatin A (TSA), and apicidin (AP). Importantly, our RT-PCR data and alkaline phosphatase assays indicate that VPA helps to maintain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that VPA may block the early differentiation of mESCs under hypoxia via the destabilization of HIF-$1{\alpha}$.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
• /
• v.36 no.4
• /
• pp.243-249
• /
• 2010

Tissue engineered bone (TEB) can replace an autogenous bone graft requiring an secondary operation site as well as avoid complications like inflammation or infection from xenogenic or synthetic bone graft. Adult mesenchymal stem cells (MSC) for TEB are considered to have various ranges of differentiation capacity or multipotency by the donor site and age. This study examined the effect of age on proliferation capacity, differentiation capacity and bone morphogenetic protein-2 (BMP-2) responsiveness of human bone marrow stromal cells (hBMSC) according to the age. In addition, to evaluate the effect on enhancement for osteoblast differentiation, the hBMSC were treated with Trichostatin A (TSA) and 5-Azacitidine (5-AZC) which was HDAC inhibitors and methyltransferase inhibitors respectively affecting chromatin remodeling temporarily and reversibly. The young and old group of hBMSC obtained from the iliac crest from total 9 healthy patients, showed similar proliferation capacity. Cell surface markers such as CD34, CD45, CD90 and CD105 showed uniform expression regardless of age. However, the young group showed more prominent transdifferentiation capacity with adipogenic differentiation. The osteoblast differentiation capacity or BMP responsiveness was low and similar between young and old group. TSA and 5-AZC showed potential for enhancing the BMP effect on osteoblast differentiation by increasing the expression level of osteogenic master gene, such as DLX5, ALP. More study will be needed to determine the positive effect of the reversible function of HDAC inhibitors or methyltransferase inhibitors on enhancing the low osteoblast differentiation capacity of hBMSC.

• Journal of Life Science
• /
• v.17 no.4 s.84
• /
• pp.552-560
• /
• 2007

Histone deacetylase (HDAC) is overexpressed in a variety of cancers and is closely correlated with oncogenic factors. HDAC inhibitors such as trichostatin A(TSA) and sodium butyrate (Na-B) have been shown to induce apoptosis in vitro and in vivo in many cancer cells. The anti-apoptotic Bcl-2 protein has the remarkable ability to prevent cell death and Bcl-2 overexpression has been reported to protect against cell death. We previously reported that the apoptotic cell death of human leukemic U937 cells by TSA and Na-B treatment was associated with the down-regulation of Bcl-2 expression and activation of caspases. In the present study, we investigated the effects of Bcl-2 overexpression on the growth inhibition, cell cycle arrest and apoptosis induced by TSA and Na-B in U937 cells. TSA-induced growth inhibition, cell cycle arrest and apoptosis were significantly attenuated in Bcl-2 overexpressing U937/Bcl-2 cells however Na-B did not affected. Induction of apoptosis by TSA was accompanied by down-regulation of Bcl-2 expression, activation of caspase-3, -8 and -9, and degradation of DNA fragmentation factor/inhibitor of caspase-activated DNase, which was blocked by the overexpression of Bcl-2. Collectively, these findings suggest that ectopic expression of Bcl-2 appeared to inhibit TSA-induced apoptosis by interfering with inhibition of Bcl-2 and caspase activation.

• Archives of Pharmacal Research
• /
• v.27 no.4
• /
• pp.407-414
• /
• 2004

The expression of CYP3A4 gene is induced by a variety of structurally unrelated xenobiotics including the antibiotic rifampicin, pregnenolone 16-carbonitrile (PCN), and endogenous hormones, that might mediate through steroid and xenobiotic receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. In order to gain the insight of the molecular mechanism of CYP3A4 gene expression, study has been undertaken to investigate if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter in human hepatoma HepG2 cells. Also we have investigated to see if SXR is involved in the regulation of CYP3A4 proximal promoter activity in human hepatoma HepG2 cells. HepG2 cells were transfected with a plasmid PCYP3A4-Luc containing ${\~}1kb$ of the CYP3A4 proximal promoter region (-863 to +64 bp) in front of a reporter gene, luciferase, in the presence or absence of pSAP-SXR. In HepG2 cells, CYP3A4 inducers, such as rifampicin, PCN and RU486 showed minimal stimulation of CYP3A4 proximal promoter activity in the absence of SXR and histone deacetylase (HDAC) inhibitors. 4-Dimethylamino-H-[4-(2-hydroxycarbamoylvinyl)benzyl]benzamide (IN2001), a new class HDAC inhibitor significantly increased CYP3A4 proximal promoter activity over untreated control cells and rifampicin concomitant treatment with IN2001 increased further CYP3A4 proximal promoter activity that was stimulated by IN2001 The results of this study demon-strated that both HDAC inhibitors and SXR are essential to increase of CYP3A4 proximal promoter activity by CYP3A4 inducers such as PCN, rifampicin, and RU486. Especially SXR seems to be important for the dose dependent response of CYP3A4 inducing chemicals to stimulate CYP3A4 proximal promoter activity. Also this data suggested that HDAC inhibitors seemed to facilitate the CYP3A4 proximal promoter to be activated by chemicals.

• Proceedings of the Korean Society of Veterinary Pathology Conference
• /
• 2003.10a
• /
• pp.10-10
• /
• 2003

Histone deacetylase (HDAC) inhibition has been demonstrated to change the expressions of a restricted set of cellular genes, T cells have an essential role in the pathogenesis of allergen-induced airway inflammation [1]. In recent studies, it has been demonstrated that treatment with HDAC inhibitors induces a T cell-suppressive effect [2]. The purpose of this study was to determine whether treatment with trichostatin A (TSA), a representative HDAC inhibitor, would reduce the allergen-induced airway inflammation in a mouse asthma model. (omitted)

• Molecules and Cells
• /
• v.45 no.4
• /
• pp.231-242
• /
• 2022

The neuromuscular junction (NMJ), which is a synapse for signal transmission from motor neurons to muscle cells, has emerged as an important region because of its association with several peripheral neuropathies. In particular, mutations in GARS that affect the formation of NMJ result in Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. These disorders are mainly considered to be caused by neuronal axon abnormalities; however, no treatment is currently available. Therefore, in order to determine whether the NMJ could be targeted to treat neurodegenerative disorders, we investigated the NMJ recovery effect of HDAC6 inhibitors, which have been used in the treatment of several peripheral neuropathies. In the present study, we demonstrated that HDAC6 inhibition was sufficient to enhance movement by restoring NMJ impairments observed in a zebrafish disease model. We found that CKD-504, a novel HDAC6 inhibitor, was effective in repairing NMJ defects, suggesting that treatment of neurodegenerative diseases via NMJ targeting is possible.