The effects of conventional treatment for myelodysplastic syndrome (MDS) are not remarkable to date, while only a minority of patients was eligible for allogeneic stem cell transplantation. As epigenetics plays a significant role during the occurrence and development of MDS, and histone deacetylase inhibitors (HDACI), a class of gene expression modulating drugs, are currently being developed for therapy of several types of solid tumor, more attention is paying to HDACI as potential therapy of MDS. This review summarizes briefly the rationale for HDACI use in MDS, the common mechanism of HDACI, the present state of the clinical efficiency, and future development in this field.
Epigenesis, Genetic ; Histone Deacetylase Inhibitors ; therapeutic use ; Humans ; Myelodysplastic Syndromes ; drug therapy ; genetics

Histone modification is an important mechanism in oncogenesis and development of hematologic malignancies. Acetylation of lysine residues on histones and opening chromatin are correlated with activation of genes, whereas lysine residues methylation can result in either activation or repression on expressions of chromatin. The main point of all is deacetylation of histone mediated by histone deacetylases (HDACs). HDAC inhibitors are divided into 4 categories: short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides and benzamides, owning different mechanisms in HDAC inhibition. Many kinds of I/II phase clinical tests showed that all these HDAC inhibitors have obviously therapeutic efficacies in treatment of hematologic malignancies with low poisons. Combination of HDAC inhibitors with DNA demethylation drugs can decrease DNA methylation, increase histone acetylation and recover antioncogene expression. As important parts of epigenetics, histone acetylation and HDAC inhibitors possess positive prospects in treatment of hematologic malignancies. In this review the advances of study on mechanisms of histone modification, HDAC inhibitors and their use in treatment of hematologic malignancies are summarized.
Acetylation ; Hematologic Neoplasms ; drug therapy ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; genetics ; Histones ; chemistry ; genetics ; metabolism

During the past few years, gene expression studies have shown that the perturbation of transcription frequently results in neuronal dysfunction in polyglutamine (PolyQ) diseases such as Huntington's disease (HD). Histone deacetylases (HDACs) act as repressors of transcription through interaction with co-repressor complexes, leading to chromatin remodelling. Aberrant interaction between PolyQ proteins and regulators of transcription could be one mechanism by which transcriptional dysregulation occurs. Here, the authors discuss the possible mechanism of transcriptional dysfunction in PolyQ disease, including the effect of histone acetyltransferases (HATs) and HDACs on pathogenesis, and the potential therapeutic pathways through which histone deacetylase inhibitors (HDACIs) might act to correct the aberrant transcription observed in HD and other PolyQ diseases.
Animals ; Histone Acetyltransferases ; genetics ; metabolism ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; genetics ; metabolism ; Humans ; Huntington Disease ; drug therapy ; enzymology ; metabolism ; Peptides ; metabolism

OBJECTIVES: Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms. METHODS: Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubA_L group (giving 25 mg/kg TubA), and a SAH+TubA_H group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery. RESULTS: The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubA_H group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubA_L group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) . CONCLUSIONS HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.
Rats ; Male ; Animals ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage/drug therapy* ; Vasospasm, Intracranial/metabolism* ; Histone Deacetylase Inhibitors/therapeutic use* ; Neuroprotective Agents/therapeutic use* ; Histone Deacetylase 6/pharmacology* ; Apoptosis ; Brain Injuries/drug therapy*

OBJECTIVE: To explore the impact on cerebral protection of Trichostatin A (TSA) preconditioning in rats with middle cerebral artery occlusion (MCAO); the relationship between cerebral protection of TSA and interleukin-1 beta (IL-1β); and the impact of age on the mechanism of cerebral protection of TSA. METHODS: The modified suture method was used to create stable a MCAO model. A total of 96 male SD rats were assigned randomly to four groups: a control group, a dimethyl sulfoxide (DMSO) preconditioned group, a low-dose (0.03 mg/kg) TSA-preconditioned group, and a high-dose (0.1 mg/kg) TSA-preconditioned group. Each group included four sub-groups for reperfusion for 6, 12, 24 and 48 hours, respectively, 6 rats per sub-group. An additional, eighteen healthy, male Sprague Dawley (SD) rats that received TSA preconditioning (0.1 mg/kg) were divided into three groups based on their age: young, mid-age, and old, One-way analysis of variance was used to compare the differences between groups, and the Spearman rank correlation was used to examine relationships between IL-1β concentrations in blood and cerebrospinal fluid and cerebral infarction volume. RESULTS: The cerebral infarction volume of rats in the high-dose TSA group was less than that of the other 3 groups (P<0.05). The IL-1β in blood and the cerebrospinal fluid of rats in the highdose TSA group was lower than that in control and DMSO groups (P<0.05); for the low-dose TSA group IL-1β levels were statistically the same as in controls. The Spearman rank coefficients were 0.841 and 0.618 for cerebral infarction volume correlate to blood IL-1β and to cerebrospinal fluid IL-1β, respectively (P<0.05). No statistical differences were found in cerebral infarction volume and IL-1β levels in blood or cerebrospinal fluid (P>0.05). CONCLUSION High-dose TSA preconditioning reduces cerebral infarction volume and decreases IL- 1β levels in blood and cerebrospinal fluid; age does not affect these parameters.
Animals ; Histone Deacetylase Inhibitors ; therapeutic use ; Hydroxamic Acids ; therapeutic use ; Infarction, Middle Cerebral Artery ; physiopathology ; Interleukin-1beta ; metabolism ; Ischemic Preconditioning ; methods ; Male ; Rats ; Reperfusion Injury ; prevention & control

The global burden of advanced stage cervical cancer remains significant, particular in resource poor countries where effective screening programs are absent. Unfortunately, a proportion of patients will be diagnosed with advanced stage disease, and may suffer from persistent or recurrent disease despite treatment with combination chemotherapy and radiation. Patients with recurrent disease have a poor salvage rate, with an expected 5-year survival of less than 10%. Recently, significant gains have been made in the antiangiogenic arena; nonetheless the need to develop effective alternate targeted strategies is implicit. As such, a review of molecular targeted therapy in the treatment of this disease is warranted. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, represents an exciting arena yet to be fully explored.
Angiogenesis Inhibitors/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Female ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Molecular Targeted Therapy/*methods ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Salvage Therapy/methods ; Uterine Cervical Neoplasms/*drug therapy

Aminopyridines ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Benzamides ; therapeutic use ; Clinical Trials as Topic ; Depsipeptides ; therapeutic use ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; therapeutic use ; Indoles ; therapeutic use ; Neoplasms ; drug therapy ; enzymology ; Sulfonamides ; therapeutic use

Alzheimer's disease (AD) is a neurodegenerative disorder characteristic of neurons reducing, senile plaques, neurofibrillary tangles and so on, and the most common cause of dementia among the elderly. Many efforts have been made to understand the epigenetic mechanisms involved in the development of AD, such as gene methylation and histone acetylation, although the exact mechanisms are not yet entirely clear. Here, we provide a review of the epigenetic mechanisms and related research in AD, which may provide a new direction for the research as well as the development of the epigenetic drugs.
Acetylation ; Alzheimer Disease ; drug therapy ; genetics ; Animals ; DNA Methylation ; genetics ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors ; therapeutic use ; Histones ; genetics ; metabolism ; Humans ; MicroRNAs ; metabolism

CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin's lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.
Humans ; Antineoplastic Agents/therapeutic use* ; Apoptosis ; Bortezomib/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; ErbB Receptors/antagonists & inhibitors* ; G2 Phase Cell Cycle Checkpoints ; Histone Deacetylase Inhibitors/pharmacology* ; Histone Deacetylases/metabolism* ; M Cells ; Multiple Myeloma/drug therapy*

OBJECTIVEThe roots of Chlorophytum borivilanum are used in traditional medicine for the treatment of arthritis and inflammation. The aim of the work was to evaluate the anti-inflammatory activity of isolated saponins from Chlorophytum borivilianum (ISCB).

METHODSThe ISCB was screened using the carrageenan-induced paw edema, histamine-induced paw edema, cotton pellet-induced granuloma, and Freund's adjuvant-induced arthritis in rats at orally administered doses of 3, 10, and 30 mg/kg. Effect of ISCB on histone deacetylase (HDAC) level was measured by the HDAC assay at the highest dose (30 mg/kg).

RESULTSThe results showed that the ISCB significantly reduced carrageenan-induced inflammation, histamine-induced inflammation, cotton pellet-induced granuloma and Freund's adjuvant-induced arthritis in rats. The ISCB at a dose of 30 mg/kg significantly inhibited HDAC level in rat paw tissue.

CONCLUSIONIt is concluded that saponins isolated from roots of C. borivilianum possess anti-inflammatory and anti-arthritic properties. ISCB may act by inhibiting histamine, prostaglandin and HDAC. This suggests that ISCBs have potential for therapeutic use in the treatment of inflammation and arthritis.

Animals ; Anti-Inflammatory Agents ; pharmacology ; Arthritis, Experimental ; drug therapy ; Female ; Histone Deacetylase Inhibitors ; pharmacology ; Histone Deacetylases ; metabolism ; Liliaceae ; chemistry ; Male ; Plant Roots ; chemistry ; Rats ; Rats, Wistar ; Saponins ; pharmacology ; therapeutic use ; toxicity