Moscatilin Ameliorates Tau Phosphorylation and Cognitive Deficits in Alzheimer's Disease Models.

Alzheimer's disease (AD) is a neurodegenerative disease and a common cause of dementia, manifesting as progressive memory loss and cognitive decline. Moscatilin, which reportedly reduces fever and is anti-inflammatory, is the bibenzyl extract from Dendrobium loddigesii. This study aimed to examine whether moscatilin ameliorates tau phosphorylation and cognitive deficits in AD models. The first in vitro AD-like model was developed by cotransfection with the pCAX FLAG APP and pRK5-EGFP-Tau P301L plasmids, resulting in the neuronal overexpression of amyloid precursor protein (APP) and tau P301L, a tauopathy-associated tau. The second model was developed by using okadaic acid to induce tau protein phosphorylation. Spatial memory/cognition was assessed using water maze and elevated plus maze tests in a scopolamine-induced mouse model, and brain slices were evaluated further by immunohistochemistry (IHC). Moscatilin significantly reduced phospho-tau expression in a concentration-dependent manner, decreased tau aggregation, and reduced apoptosis. These results indicated that moscatilin reversed tauopathy through GSK3ß inactivation and inhibition of oxidative stress. Furthermore, in vivo data demonstrated that moscatilin ameliorated learning and memory impairments in mice, while IHC and Western blot results of the mouse brain confirmed that moscatilin decreased tau phosphorylation. Our novel findings suggest that moscatilin has neuroprotective effects against AD.

MPT0G413, A Novel HDAC6-Selective Inhibitor, and Bortezomib Synergistically Exert Anti-tumor Activity in Multiple Myeloma Cells.

In multiple myeloma (MM), homeostasis is largely maintained by misfolded protein clearance via the proteasomal and aggresomal pathways. Histone deacetylase 6 (HDAC6) binds polyubiquitinated proteins and dynein motors and transports this protein cargo to the aggresome for further degradation. Accordingly, a combination of an HDAC6 inhibitor and bortezomib (BTZ) could increase ubiquitinated protein accumulation, leading to further apoptosis. Here we evaluated the anti-MM activity of MPT0G413, a novel specific HDAC6 inhibitor, using in vitro and in vivo models. MPT0G413 treatment more significantly inhibited cell growth in MM cells than in normal bone marrow cells. Furthermore, the combination of MPT0G413 and BTZ enhanced polyubiquitinated protein accumulation and synergistically reduced MM viability, increased caspase-3, caspase-8, caspase-9 levels, and cleaved poly (ADP) ribosome polymerase and also inhibited adherence of MM cells to bone marrow stromal cells (BMSC) and reduced VEGF and IL-6 levels and cell growth in a co-culture system. The combination treatment disturbed the bone marrow microenvironment and induced synergic, caspase-dependent apoptosis. Xenograft tumor growth significantly decreased in combination-treated SCID mice. In conclusion, MPT0G413 and BTZ synergistically inhibit MM viability, providing a framework for the clinical evaluation of combined therapies for MM.

5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes.

This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.

The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.

Alzheimer's disease (AD) is a dreadful neurodegenerative disease that leads to severe impairment of cognitive function, leading to a drastic decline in the quality of life. The primary pathological features of AD include senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs), comprising aggregated amyloid ß (Aß) and hyperphosphorylated tau protein, respectively, in the hippocampus of AD patients. Histone deacetylase 6 (HDAC6) is a key enzyme in this neurodegenerative disease, in particular, as it relates to tau hyperphosphorylation. This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3ß (phospho-GSK3ß) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. In AD in vivo models, MPT0G211 appeared to ameliorate learning and memory impairment in animals. Furthermore, MPT0G211 treatment reduced the amount of phosphorylated tau in the hippocampal CA1 region. In summary, MPT0G211 treatment appears to be a promising strategy for improving the AD phenotypes, including tau hyperphosphorylation and aggregation, neurodegeneration, and learning and memory impairment, making it a valuable agent for further investigation.

(N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo.

A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.

Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis.

Histone deacetylases (HDACs) display multifaceted functions by coordinating the interaction of signal pathways with chromatin structure remodeling and the activation of non-histone proteins; these epigenetic regulations play an important role during malignancy progression. HDAC inhibition shows promise as a new strategy for cancer therapy; three HDAC inhibitors have been approved. We previously reported that N-hydroxy-3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (MPT0G157), a novel indole-3-ethylsulfamoylphenylacrylamide compound, demonstrated potent HDAC inhibition and anti-inflammatory effects. In this study, we evaluated its anti-cancer activity in vitro and in vivo. MPT0G157 treatment significantly inhibited different tumor growth at submicromolar concentration and was particularly potent in human colorectal cancer (HCT116) cells. Apoptosis and inhibited HDACs activity induced by MPT0G157 was more potent than that by the marketed drugs PXD101 (Belinostat) and SAHA (Vorinostat). In an in vivo model, MPT0G157 markedly inhibited HCT116 xenograft tumor volume and reduced matrigel-induced angiogenesis. The anti-angiogenetic effect of MPT0G157 was found to increase the hyperacetylation of heat shock protein 90 (Hsp90) and promote hypoxia-inducible factor-1α (HIF-1α) degradation followed by down-regulation of vascular endothelial growth factor (VEGF) expression. Our results demonstrate that MPT0G157 has potential as a new drug candidate for cancer therapy.

Expression of LEF1 is an independent prognostic factor for patients with oral squamous cell carcinoma.

BACKGROUND/PURPOSE: Lymphoid-enhancing factor 1 (LEF1) is a transcription factor mediating Wnt/ß-catenin signaling. In this study, we analyzed the clinicopathologic significance of LEF1 expression in oral squamous cell carcinoma (OSCC). METHODS: Expression levels of LEF1 in 135 cases of OSCC were determined by immunohistochemistry. The results were correlated with clinicopathologic parameters and patient outcome. RESULTS: LEF1 was only occasionally detected in basal and parabasal cells of nontumorous squamous epithelium. Overexpression of LEF1 was observed in 33 of 135 OSCCs (24%). LEF1 was more frequently expressed in moderately to poorly differentiated cancer (p = 0.0035) and was associated with lymphovascular invasion (p = 0.0252). Overexpression of LEF1 was significantly associated with poor prognosis (p = 0.0176, hazard ratio = 1.96, 95% CI = 1.02-3.75). Multivariate analysis revealed LEF1expression and margin status to be the significant independent predictors for overall survival. CONCLUSION: Our study suggests LEF1 expression in OSCC may play an important role in tumor progression and can be served as a predictor of poor prognosis for patients with OSCC.

Hepatocyte growth factor activates Wnt pathway by transcriptional activation of LEF1 to facilitate tumor invasion.

Hepatocyte growth factor (HGF) is a secretory protein that plays important roles in cancer growth and metastasis. Lymphoid-enhancing factor 1 (LEF1) is a transcription factor mediating Wnt/ß-catenin signaling. Using microarray analysis, we found HGF induced expression of LEF1 in liver and breast cancer cell lines. HGF induced expression of LEF1 through phosphatidylinositol 3-kinase/Akt and nuclear factor-kappa B (NF-κB) signaling. Multiple NF-κB-binding sites were mapped within 3 kb upstream of LEF1 transcription initiation site. NF-κB binding to a site 2 kb upstream of LEF1 transcription initiation site was confirmed by chromatin immunoprecipitation assay. Knockdown of LEF1 inhibited the expression of Slug and Zinc finger E-box-binding homeobox 2 (ZEB2) and markedly attenuated HGF-induced tumor migration and invasion. Using immunohistochemical staining, we found LEF1 was frequently expressed in multiple types of carcinoma but not in the non-tumorous epithelial cells. Our finding suggest that transcriptional activation of LEF1 is a mechanism of cross talk between HGF/c-Met and Wnt/ß-catenin pathways and is essential for HGF-induced tumor invasion.