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Epigenetic therapies in acute myeloid leukemia: the role of hypomethylating agents, histone deacetylase inhibitors and the combination of hypomethylating agents with histone deacetylase inhibitors

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Chinese Medical Journal 2020年第6期133卷 699-715页

作者： Qing-Yu Xu Li Yu Department of Hematology-Oncology International Cancer CenterShenzhen University General HospitalShenzhen University Health Science CenterShenzhenGuangdong 518000China Department of Hematology and Oncology Medical Faculty MannheimHeidelberg UniversityMannheim 68169Germany

Epigenetic regulation includes changes of DNA methylation and modifications of histone proteins and is essential for normal physiologic functions,especially for controlling gene expression.Epigenetic dysregulation plays a key role in disease pathogenesis and progression of some malignancies,including acute myeloid leukemia(AML).Epigenetic therapies,including hypomethylating agents(HMAs)and histone deacetylase(HDAC)inhibitors,were developed to reprogram the epigenetic abnormalities in AML.However,the molecular mechanisms and therapeutic effects of the two agents alone or their combination remain unknown.An overview of these epigenetic therapies is given here.A literature search was conducted through PubMed database,looking for important biological or clinical studies related to the epigenetic regimens in the treatment of AML until October 15th,2019.Various types of articles,including original research and reviews,were assessed,identified,and eventually summarized as a collection of data pertaining the mechanisms and clinical effects of HMAs and HDAC inhibitors in AML patients.We provided here an overview of the current understanding of the mechanisms and clinical therapeutic effects involved in the treatment with HMAs and HDAC inhibitors alone,the combination of epigenetic therapies with intensive chemotherapy,and the combination of both types of epigenetic therapies.Relevant clinical trials were also discussed.Generally speaking,the large number of studies and their varied outcomes demonstrate that effects of epigenetic therapies are heterogeneous,and that HMAs combination regimens probably contribute to significant response rates.However,more research is needed to explore therapeutic effects of HDAC inhibitors and various combinations of HMAs and HDAC inhibitors.

关键词： Acute myeloid leukemia Decitabine 5-azacytidine Histone deacetylase inhibitors Intensive chemotherapy

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Neuroprotective mechanism of TMP269, a selective class ⅡA histone deacetylase inhibitor, after cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2020年第2期15卷 277-284页

作者： Lu Su Dan Liang Shen-Yi Kuang Qiang Dong Xiang Han Zheng Wang Department of Neurology Huashan HospitalFudan UniversityShanghaiChina Department of Rehabilitation Medicine Huashan HospitalFudan UniversityShanghaiChina

TMP269 is a selective class ⅡA histone deacetylase inhibitor that has a protective effect on the central nervous system, whose specific mechanism of action is unclear. We aimed to reveal the optimal concentration of TMP269 for protecting against cerebral ischemia/reperfusion injury and its neuroprotective mechanism. Male Sprague-Dawley rats were randomly divided into sham, ischemia/reperfusion, and 1, 4, 10 and 16 mg/kg TMP269 groups. Cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. TMP269 was intraperitoneally administered at different doses 0.5 hours before ischemia induction. Western blot assay and immunohistochemistry were used to detect effects of TMP269 on histone 2 acetylation. The results showed that the level of histone 2 acetylation was increased 24 hours after TMP269 injection. 2,3,5-Triphenyltetrazolium chloride staining was utilized to examine effect of TMP269 on infarct volume. The results found that different doses of TMP269 could reduce the infarct volume. Western blot assay, immunohistochemistry and Evans blue staining were employed to measure the effect of TMP269 on blood-brain barrier. The results showed that TMP269 counteracted the abnormal endothelial cell permeability changes caused by cerebral ischemia/reperfusion. Western blot assay and immunohistochemistry were used to determine the effect of TMP269 on tissue kallikrein. The results found that TMP269 up-regulated the expression of tissue kallikrein. Western blot assay further determined the optimal concentration to be 4 mg/kg. In conclusion, TMP269 plays a neuroprotective role by up-regulating the level of histone 2 acetylation, alleviating endothelial cell injury after cerebral ischemia/reperfusion, and up-regulating the expression of tissue kallikrein. The experimental protocol was approved in 2014 by the Department of Laboratory Animal Science, Fudan University, China(approval No. 20140143 C001).

关键词： blood-brain barrier drug treatment endothelial cell permeability histone deacetylase inhibitor neuroprotection stroke tissue kallikrein TMP269

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Class Ⅰ histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells

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Acta Pharmaceutica Sinica B 2020年第4期10卷 615-627页

作者： Baoyuan Zhang Junfang Lyu Eun Ju Yang Yifan Liu Changjie Wu Lakhansing Pardeshi Kaeling Tan Qiang Chen Xiaoling Xu Chu-Xia Deng Joong Sup Shim Cancer Centre Faculty of Health SciencesUniversity of MacaoMacao SARChina Institute of Translational Medicine Faculty of Health SciencesUniversity of MacaoMacao SARChina

Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its deficiency to act as a therapeutic target of DNA damaging agents.In this study,we found that inhibition of the classⅠhistone deacetylases(HDAC)exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells.Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein(TXNIP),causing reactive oxygen species(ROS)-mediated DNA damage.This effect induced preferential apoptosis in BRCA1-/-breast cancer cells where DNA repair system is compromised.Two animal experiments and gene expression-associated patients’survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC.Finally,the combination of inhibitors of HDAC and bromodomain and extra-terminal motif(BET),another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage,showed a strong anticancer effect in BRCA1-/-breast cancer cells.Together,this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries,HDAC and BET.

关键词： BRCA1 Histone deacetylase HDAC Synthetic lethality Reactive oxygen species DNA damage Breast cancer

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lncRNA-SNHG15 accelerates the development of hepatocellular carcinoma by targeting mi R-490-3p/histone deacetylase 2 axis

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World Journal of Gastroenterology 2019年第38期25卷 5789-5799页

作者： Wei Dai Jia-Liang Dai Mao-Hua Tang Mu-Shi Ye Shuo Fang Department of Hepatobiliary Surgery the Affiliated Hospital of Guangdong Medical UniversityZhanjiang 524001Guangdong ProvinceChina Department of Infectious Disease the Second Affiliated Hospital of Guangdong Medical UniversityZhanjiang 524003Guangdong ProvinceChina Department of Surgery the Affiliated Hospital of Guangdong Medical UniversityZhanjiang 524001Guangdong ProvinceChina The Seventh Affiliated Hospital Sun Yat-sen UniversityShenzhen 518107Guangdong ProvinceChina Li KaShing Faculty of Medicine the University of Hong KongHong KongChina

BACKGROUND Hepatocellular carcinoma(HCC)has become a great threat for people’s health.Many long noncoding RNAs are involved in the pathogenesis of HCC.SNHG15,as a tissue specific long noncoding RNAs,has been studied in many human cancers,except HCC.AIM To explore the regulatory mechanism of SNHG15 in HCC.METHODS In the present research,101 HCC patient samples,two HCC cell lines and one normal liver cell line were used.RT-qPCR and Western blot analysis were applied to detect SNHG15,miR-490-3p and histone deacetylase 2(HDAC2)expression.The regulatory mechanism of SNHG15 was investigated using CCK-8,Transwell and luciferase reporter assays.RESULTS Our research showed that up-regulation of SNHG15 was found in HCC and was related to aggressive behaviors in HCC patients.Moreover,knockdown of SNHG15 restrained HCC cell proliferation,migration and invasion.In addition,SNHG15 served as a molecular sponge for miR-490-3p.Further,miR-490-3p directly targets HDAC2.HDAC2 was involved in HCC progression by interacting with the SNHG15/miR-490-3p axis.CONCLUSION In conclusion,long noncoding RNA SNHG15 promotes HCC progression by mediating the miR-490-3p/HDAC2 axis in HCC.

关键词： SNHG15 miR-490-3p Hepatocellular carcinoma Histone deacetylase 2 Pathogenesis Regulatory mechanism

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deacetylase inhibitors-focus on non-histone targets and effects

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World Journal of Biological Chemistry 2010年第5期1卷 55-61页

作者： Matthias Ocker Institute for Surgical Research Philipps University Marburg

Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.

关键词： Epigenetics Histone deacetylase inhibitors Histone code Posttranslational modifications Unfolded protein response

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Histone deacetylase 6 mediated NALP3 inflammasome activation contributes to dopaminergic injury in experimental models of Parkinson disease

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中国药理学与毒理学杂志 2018年第9期32卷 686-687页

作者： YAN Shao-qi WEI Xin-bing JIAN Wen-cheng QIN Yue JIANG Fan LOU Hai-yan ZHANG Bin Department of Pharmacology School of Basic Medical SciencesShandong University Jinan 250012China Department of Radiology Qilu HospitalShandong University Jinan 250012China Department of Pathophysiology School of Basic Medical SciencesShandong University Jinan 250012China

OBJECTIVE To investigate the mechanisms of histone deacetylase 6(HDAC6)deacetylation activity on NALP3 inflammasome activation and explore the protective effect s of pharmacological inhibition of HDAC6 on dopaminergic injury.METHODS In vitro and in vivo6-OHDA induced Parkinson disease(PD) model was used.To distinguish the effect of deacetylase catalytic domains of HDAC6,we used a specific HDAC6 inhibitor tubastatin A(TBA),siRNAHDAC6,and pcDNA-HDAC6-FLAG plasmid.First,the role of pharmacological inhibition or siRNA or overexpression of HDAC6 on NALP3 inflammasome and cell death was explored by using Western blotting,TUNEL,and flow cytometric analysis.Then,the acetylation level of peroxiredoxin 2(Prx2) and the production of reactive oxygen species(ROS) in cells under different treatments was examined by using immunoprecipitation and DCFH-DA fluorescence assay.The effects of TBA on neuroinflammation and nigrostriatal dopaminergic system in vivo was further investigated by using Western blotting,immunohistochemistry and HPLC analysis.RESULTS TBA remarkably inhibited 6-OHDA induced NALP3 inflammasome activation,reduced dopaminergic neurodegeneration and neuroinflammation as demonstrated by increased TH-positive neurons,striatal levels of DA and its metabolites,and decreased gliocyte proliferation.TBA recovered acetylation of Prx2,and reduced ROS production,which was associated with decreased NALP3 inflammasome activation.CONCLUSION HDAC6 may medicate deacetylation of Prx2 contributes to NALP3 inflammasome activation in PD pathology,suggesting that the development of specific pharmacological inhibitors of HDAC6 be required for this kind of disease.

关键词： histone deacetylase 6 NALP3 peroxiredoxin 2 reactive oxygen species

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Current evidence for histone deacetylase inhibitors in pancreatic cancer

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World Journal of Gastroenterology 2013年第6期19卷 813-828页

作者： Ioannis Koutsounas Constantinos Giaginis Efstratios Patsouris Stamatios Theocharis First Department of Pathology Medical SchoolNational and Kapodistrian University of AthensGR-11527 AthensGreece Department of Food Science and Nutrition University of the AegeanGR-81400 LemnosGreece

Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have only slightly improved patient outcomes.More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm.Among new agents,histone deacetylase inhibitors (HDACIs) are now being tested.HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression,apoptosis,cell cycle progression and angiogenesis.HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines.In the present review,the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro,as well as their antiproliferative effects in animal models are presented.HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor ef-fects,at well-tolerated doses.

关键词： Pancreatic cancer Histone deacetylases Histone deacetylase inhibitors Experimental studies

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Histone deacetylase inhibitors and pancreatic cancer:Are there any promising clinical trials?

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World Journal of Gastroenterology 2013年第8期19卷 1173-1181页

作者： Ioannis Koutsounas Constantinos Giaginis Stamatios Theocharis Department of Forensic Medicine and Toxicology Medical SchoolUniversity of AthensGR-11527 AthensGreece Department of Food Science and Nutrition University of the AegeanGR-81400 LemnosGreece

Pancreatic cancer,although not very frequent,has an exceptionally high mortality rate,making it one of the most common causes of cancer mortality in developed countries.Pancreatic cancer is difficult to diagnose,allowing few patients to have the necessary treatment at a relatively early stage.Despite a marginal benefit in survival,the overall response of pancreatic cancer to current systemic therapy continues to be poor,and new therapies are desperately needed.Histone deacetylase(HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors(HDACIs) have been shown to induce differentiation and cell cycle arrest,activate the extrinsic or intrinsic pathways of apoptosis,and inhibit invasion,migration and angiogenesis in different cancer cell lines.As a result of promising preclinical data,various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies.Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma.The use of HDACIs in clinical trials,in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed.Unfortunately,clinical data for HDACIs in patients with pancreatic cancer are inadequate,because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase Ⅱ/Ⅲ trials,among others with advanced solid tumors,is very limited.More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.

关键词： Pancreatic cancer Histone deacetylases Histone deacetylase inhibitors Clinical trials

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Biophysical Mechanism of the SAHA Inhibition of Zn^（2+）-Histone deacetylase-Like Protein(FB188 HDAH)Assessed via Crystal Structure Analysis

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Computational Molecular Bioscience 2018年第2期8卷 91-114页

作者： Cynthia Raquel Trejo-Munoz Ricardo Vázquez-Ramírez Luis Mendoza Carlos Kubli-Garfias Escuela Superior de Medicina Instituto Politécnico NacionalCiudad de MéxicoMéxico Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de MéxicoCiudad de MéxicoMéxico

The zinc-containing enzyme HDAC-like amidohydrolase (FB188 HDAH), identified in the Bordetella alcaligenes bacteria, is similar to enzymes that participate in epigenetic mechanisms such as histone modifications. The X-ray crystal structure of FB188 HDAH complexed with the antagonist SAHA (suberoylanilide hydroxamic acid) has been solved (PDB ID: 1ZZ1). Notably, the complex crystallizes as a tetramer in the asymmetric unit cell of the crystal. The crystal yielded a suitable structure to analyze the dynamics of the inhibitory mechanism of SAHA on this histone deacetylase. Applying computational chemistry techniques and quantum mechanics theory, several physicochemical properties were calculated to compare the active site of the enzyme of the four monomers. Significant differences were observed in the areas and volumes of the binding pocket, as well as hydrophobic interactions, dipole moments, atomic charges and electrostatic potential, among other properties. Remarkably, a free-energy curve resulting from the evaluation of the energies of SAHA and the interacting amino acids of the four crystal monomers unveiled the biophysical mechanism of the FB188 HDAH inhibition exerted by SAHA to a greater extent. The biophysical mechanism of SAHA inhibition on FB188 deacetylase was clearly observed as a dynamic process. It is possible to define the physicochemical dynamics of the molecular complex by the application of computational chemistry techniques and quantum mechanics theory by studying the crystal structures of the interacting molecules.

关键词： SAHA deacetylase FB188 HDAH Free-Energy Crystal-Analysis

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Determination of Fragmentation Schemes and Metabolites of Fluorinated Histone deacetylase Inhibitors for Use as Positron Emission Tomography Imaging Agents Using HPLC-MS/MS

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International Journal of Analytical Mass Spectrometry and Chromatography 2018年第1期6卷 1-19页

作者： Wei-Hsi Chen Yu-Chieh Hsiao Ming-Hsin Li Mu-Chen Tsai Chun-Fang Feng Han-Chih Chang Hung-Wen Yu Chyng-Yann Shiue Chemistry Division Institute of Nuclear Energy Research Taiwan Isotope Application Division Institute of Nuclear Energy Research Taiwan PET Center Department of Nuclear Medicine National Taiwan University Hospital Taiwan PET Center Department of Nuclear Medicine Tri-Service General Hospital Taiwan

High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.

关键词： Histone deacetylase Inhibitors Positron Emission Tomography Imaging Agent Dementia LC-Tandem MS Fragmentation Mechanism Metabolism Pathways Epigenetics

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