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

Among those enzymes that regulate gene expression, histone deacetylases (HDACs) play important roles in cell cycles. Extensive studies were carried out in the field of HDACs and the applications of HDAC inhibitors (HDACIs) as chemotherapeutic interventions for diverse diseases. HDACIs have moved from laboratories to clinic uses. Huge bodies of related research results were well documented and dispersed in literature. According to our understanding, HDACIs can be broadly classified as hydroxamic acids, cyclic tetrapeptides, short chain fatty acids, benzamides and electrophilic ketones. Herein, we are going to review the design and their structure-activity relationships of HDACIs and according to their structural catalogs.
Antineoplastic Agents ; chemistry ; pharmacology ; Benzamides ; chemistry ; Fatty Acids ; chemistry ; Histone Acetyltransferases ; metabolism ; Histone Deacetylase Inhibitors ; chemistry ; pharmacology ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; chemistry ; Molecular Structure ; Peptides, Cyclic ; chemistry ; Structure-Activity Relationship

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.
Animals ; Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Biphenyl Compounds ; chemical synthesis ; chemistry ; pharmacology ; Histone Deacetylase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Histone Deacetylases ; metabolism ; Mice ; Molecular Structure ; Phenylpropionates ; chemical synthesis ; chemistry ; pharmacology

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, on the basis of preliminary studies, sixteen N-(2-amino-4-pyridine) benzamide derivaties (class A) and sixteen N-(2-amino-3-pyridine) benzamide derivaties (class B) were designed and prepared, and their structures were confirmed by 1H NMR and HR-MS individually. The results showed that 30 target compounds except V-20 and V-21 had HDACs inhibitory activity and V -13, V -14, V -16 were equal to CI-994 at 200 micromol x L(-1) in vitro. Compounds V-30, V-31 and V-32 exhibited potent inhibitory activities on Hut78, Jurkat E6-1, A549, K562 and MDA-MB-435s.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Benzamides ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Histone Deacetylase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Histone Deacetylases ; metabolism ; Humans

Acetylation ; Animals ; Child ; DNA Methylation ; Epigenesis, Genetic ; Heart ; physiology ; Heart Defects, Congenital ; etiology ; genetics ; metabolism ; Histone Acetyltransferases ; metabolism ; Histone Deacetylases ; metabolism ; Histones ; chemistry ; genetics ; physiology ; Humans ; Protein Processing, Post-Translational ; Transcription Factors ; metabolism

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

Histone deacetylase (HDAC) has been highlighted as one of key players in tumorigenesis and angiogenesis. Recently, several derivatives of psammaplin (Psams) from a marine sponge have been known to inhibit the HDAC activity, but the molecular mechanism for the inhibition has not fully understood. Here, we explored the mode of action of Psams for the inhibition of HDAC activity in the molecular and cellular level. Among the derivatives, psammaplin A (Psam A) showed the potent inhibitory activity in enzyme assay and anti-proliferation assay with IC50 value of 0.003 and 1 microM, respectively. Psam A selectively induced hyperacetylation of histones in the cells, resulting in the upregulation of gelsolin, a well-known HDAC target gene, in a transcriptional level. In addition, reduced Psam A showed a stronger inhibitory activity than that of non-reduced one. Notably, glutathione-depleted cells were not sensitive to Psam A, implying that cellular reduction of the compound is responsible for the HDAC inhibition of Psam A after uptake into the cells. Together, these data demonstrate that Psam A could exhibit its activity under the reduced condition in the cells and be a new natural prodrug targeting HDAC.
Tyrosine/*analogs & derivatives/chemistry/pharmacology ; Prodrugs/chemistry/*pharmacology ; Oxidation-Reduction ; Molecular Structure ; Humans ; Histones/metabolism ; Histone Deacetylases/*antagonists & inhibitors/*classification/genetics/metabolism ; Hela Cells ; Enzyme Inhibitors/chemistry/*pharmacology ; Disulfides/chemistry/*pharmacology ; Cell Proliferation ; Biological Products/chemistry/*pharmacology ; Acetylation

Ascorbic Acid ; chemistry ; pharmacology ; Cellular Reprogramming ; Genetic Vectors ; genetics ; metabolism ; Histone Deacetylases ; genetics ; metabolism ; Humans ; Induced Pluripotent Stem Cells ; cytology ; drug effects ; Protein Kinase Inhibitors ; chemistry ; pharmacology ; RNA, Small Interfering ; metabolism

Histone deacetylases (HDACs) inhibition causes hyperacetylation of histones leading to growth arrest, differentiation and apoptosis of tumor cells, representing a new strategy in cancer therapy. Many of previously reported HDACs inhibitors are hydroxamic acid derivatives, which could chelate the zinc ion in the active site in a bidentate fashion. However, hydroxamic acids occasionally have produced problems such as poor pharmacokinetics, severe toxicity and low selectivity. Herein we describe the identification of a new series of non-hydroxamate HDACs inhibitors bearing diketo ester moieties as zinc binding group. HDACs inhibition assay and antiproliferation assays in vitro against multiple cancer cell lines were used for evaluation. These compounds displayed low antiproliferative activity against solid tumor cells, while good antiproliferative activity against human leukemic monocyte lymphoma cell line U937. Compound CPUYS707 is the best with GI50 value of 0.31 micromol x L(-1) against U937 cells, which is more potent than SAHA and MS-275. HDACs inhibition activity of these compounds is lower than that expected, further evaluation is needed.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Benzamides ; pharmacology ; Biphenyl Compounds ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Design ; Esters ; chemistry ; Histone Deacetylase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Molecular Structure ; Pyridines ; pharmacology ; U937 Cells ; drug effects ; Zinc ; chemistry

Acetylation ; Animals ; Apoptosis ; drug effects ; Benzamides ; pharmacology ; Drug Delivery Systems ; Enzyme Inhibitors ; pharmacology ; Histone Acetyltransferases ; drug effects ; metabolism ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; chemistry ; physiology ; Histones ; drug effects ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Neoplasms ; pathology ; Peptides ; pharmacology ; Pyridines ; pharmacology ; Valproic Acid ; pharmacology