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Man S, Li J, Li Y, Yan F, Wang Z, Huang J, Xia Y, Khan AJ, Wang L, Jia S, Wang J, Liu X, Zhang Y, Rahman FU, Li X. Elucidating the dual mechanistic action and synergism of platinum complexes bearing valproic acid as leaving ligand on NF-κB and inflammatory pathways in glioma. Eur J Med Chem 2025; 290:117522. [PMID: 40153933 DOI: 10.1016/j.ejmech.2025.117522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/27/2025] [Accepted: 03/16/2025] [Indexed: 04/01/2025]
Abstract
The valproic acid (VPA), an anti-epileptic drug, has demonstrated anticancer properties alone or in combination regimens in glioma. It has been shown synergistic activity with cisplatin in resistant cancer cells. In the current study, we synthesized Pt(II) complexes bearing VPA as ancillary/leaving ligand. All these complexes were obtained in good yields through simple reproducible synthetic procedures and characterized by multiple analytical techniques in both solution and solid state. In situ release of ancillary ligand (VPA) by these complexes was studied by 1H NMR in solution state that was catalysed by water in time dependent manner. The tumor preferential selective VPA-Pt actively controlling NF-kB signaling, culminating in the attenuation of IL-6 expression and the concomitant activation of p53 and caspase-3 pathways in gliomas. VPA-Pt exhibits potent cytotoxicity in human and mice glioma cancer cell lines, inducing apoptosis as evidenced by inhibition of cell proliferation and migration, disruption of mitochondrial membrane potential, and suppression of colony formation. An inhibitory effect of VPA-Pt4 on glioma was clearly evidenced through in vivo live bioluminescence imaging, histopathological examination, immunofluorescence evaluation, and protein expression analysis demonstrated that VPA-Pt4 significantly triggered apoptosis, with elevated levels of P53, caspase-3, cleaved caspase-3, along with a reduction in IL-6. Our discovery reveals a novel and efficient approach to glioma therapy.
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Affiliation(s)
- Shad Man
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China; Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Jiaqi Li
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Yimiao Li
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Fufu Yan
- Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Zerui Wang
- Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Jinxia Huang
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Yan Xia
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Abdul Jamil Khan
- Biomedical Nanocenter, School of Life Science, Inner Mongolia Agricultural University, Hohhot, 010018, People's Republic of China
| | - Liping Wang
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Shuang Jia
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Jie Wang
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Xing Liu
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China
| | - Yongmin Zhang
- Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France
| | - Faiz-Ur Rahman
- Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
| | - Xinyu Li
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
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Aebisher D, Woźnicki P, Czarnecka-Czapczyńska M, Dynarowicz K, Szliszka E, Kawczyk-Krupka A, Bartusik-Aebisher D. Molecular Determinants for Photodynamic Therapy Resistance and Improved Photosensitizer Delivery in Glioma. Int J Mol Sci 2024; 25:8708. [PMID: 39201395 PMCID: PMC11354549 DOI: 10.3390/ijms25168708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Gliomas account for 24% of all the primary brain and Central Nervous System (CNS) tumors. These tumors are diverse in cellular origin, genetic profile, and morphology but collectively have one of the most dismal prognoses of all cancers. Work is constantly underway to discover a new effective form of glioma therapy. Photodynamic therapy (PDT) may be one of them. It involves the local or systemic application of a photosensitive compound-a photosensitizer (PS)-which accumulates in the affected tissues. Photosensitizer molecules absorb light of the appropriate wavelength, initiating the activation processes leading to the formation of reactive oxygen species and the selective destruction of inappropriate cells. Research focusing on the effective use of PDT in glioma therapy is already underway with promising results. In our work, we provide detailed insights into the molecular changes in glioma after photodynamic therapy. We describe a number of molecules that may contribute to the resistance of glioma cells to PDT, such as the adenosine triphosphate (ATP)-binding cassette efflux transporter G2, glutathione, ferrochelatase, heme oxygenase, and hypoxia-inducible factor 1. We identify molecular targets that can be used to improve the photosensitizer delivery to glioma cells, such as the epithelial growth factor receptor, neuropilin-1, low-density lipoprotein receptor, and neuropeptide Y receptors. We note that PDT can increase the expression of some molecules that reduce the effectiveness of therapy, such as Vascular endothelial growth factor (VEGF), glutamate, and nitric oxide. However, the scientific literature lacks clear data on the effects of PDT on many of the molecules described, and the available reports are often contradictory. In our work, we highlight the gaps in this knowledge and point to directions for further research that may enhance the efficacy of PDT in the treatment of glioma.
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Affiliation(s)
- David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland
| | - Paweł Woźnicki
- English Division Science Club, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland;
| | - Magdalena Czarnecka-Czapczyńska
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego 15 Street, 41-902 Bytom, Poland;
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College of The University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Ewelina Szliszka
- Department of Microbiology and Immunology, Medical University of Silesia, Poniatowskiego 15, 40-055 Katowice, Poland;
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego 15 Street, 41-902 Bytom, Poland;
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland;
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Kartal B, Denizler-Ebiri FN, Güven M, Taşpınar F, Canpınar H, Çetin S, Karaduman T, Küççüktürk S, Castresana J, Taşpınar M. Exploring the combined anti-cancer effects of sodium butyrate and celastrol in glioblastoma cell lines: a novel therapeutic approach. Med Oncol 2024; 41:97. [PMID: 38532150 PMCID: PMC10965742 DOI: 10.1007/s12032-024-02340-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 02/21/2024] [Indexed: 03/28/2024]
Abstract
Glioblastoma, a highly aggressive and lethal brain cancer, lacks effective treatment options and has a poor prognosis. In our study, we explored the potential anti-cancer effects of sodium butyrate (SB) and celastrol (CEL) in two glioblastoma cell lines. SB, a histone deacetylase inhibitor, and CEL, derived from the tripterygium wilfordii plant, act as mTOR and proteasome inhibitors. Both can cross the blood-brain barrier, and they exhibit chemo- and radiosensitive properties in various cancer models. GB cell lines LN-405 and T98G were treated with SB and CEL. Cell viability was assessed by MTT assay and IC50 values were obtained. Gene expression of DNA repair, apoptosis, and autophagy-related genes was analyzed by RT-PCR. Cell cycle distribution was determined using flow cytometry. Viability assays using MTT assay revealed IC50 values of 26 mM and 22.7 mM for SB and 6.77 μM, and 9.11 μM for CEL in LN-405 and T98G cells, respectively. Furthermore, we examined the expression levels of DNA repair genes (MGMT, MLH-1, MSH-2, MSH-6), apoptosis genes (caspase-3, caspase-8, caspase-9), and an autophagy gene (ATG-6) using real-time polymerase chain reaction. Additionally, flow cytometry analysis revealed alterations in cell cycle distribution following treatment with SB, CEL and their combination. These findings indicate that SB and CEL may act through multiple mechanisms, including DNA repair inhibition, apoptosis induction, and autophagy modulation, to exert their anti-cancer effects in glioblastoma cells. This is the first study providing novel insights into the potential therapeutic effects of SB and CEL in glioblastoma.
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Affiliation(s)
- Bahar Kartal
- Department of Medical Biology, Faculty of Medicine, Yuzuncu Yıl University, Van, Turkey
| | | | - Mustafa Güven
- Faculty of Medicine, Yuzuncu Yıl University, Van, Turkey
| | - Filiz Taşpınar
- Department of Physiology, Faculty of Medicine, Aksaray University, Aksaray, Turkey
| | - Hande Canpınar
- Department of Basic Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Sedat Çetin
- Department of Biochemistry, Faculty of Veterinary Medicine, Yuzuncu Yıl University, Van, Turkey
| | - Tuğçe Karaduman
- Molecular Biology and Genetics, Faculty of Sciences and Letter, Aksaray University, Aksaray, Turkey
| | - Serkan Küççüktürk
- Department of Medical Biology, Faculty of Medicine, Karamanoğlu Mehmetbey University, Karaman, Turkey
| | - Javier Castresana
- Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain
| | - Mehmet Taşpınar
- Department of Medical Biology, Faculty of Medicine, Yuzuncu Yıl University, Van, Turkey.
- Department of Medical Biology, Faculty of Medicine, Aksaray University, Aksaray, Turkey.
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Chu H, Sun X, Wang J, Lei K, Shan Z, Zhao C, Ning Y, Gong R, Ren H, Cui Z. Synergistic effects of sodium butyrate and cisplatin against cervical carcinoma in vitro and in vivo. Front Oncol 2022; 12:999667. [PMID: 36338704 PMCID: PMC9633845 DOI: 10.3389/fonc.2022.999667] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/07/2022] [Indexed: 08/25/2023] Open
Abstract
BACKGROUNDS Cisplatin-based chemotherapy has been considered as the pivotal option for treating cervical cancer. However, some patients may present a poor prognosis due to resistance to chemotherapy. As a metabolite of natural products, sodium butyrate (NaB) could inhibit the proliferation of several malignant cells, but little is known about its combination with cisplatin in the treatment of cervical cancer. MATERIALS AND METHODS Flow cytometry, CCK-8 assay, and Transwell assay were utilized to analyze the cellular apoptosis, viability, cellular migration and invasion upon treating with NaB and/or cisplatin. The allograft mice model was established, followed by evaluating the tumor volume and necrotic area in mice treated with NaB and/or cisplatin. Western blot was performed for detecting protein expression involved in epithelial-mesenchymal transition (EMT) and the expression of MMPs. Immunohistochemical staining was conducted with the tumor sections. The transcription, expression, and cellular translocation of β-catenin were determined using luciferase reporter gene assay, Real-Time PCR, Western blot, and confocal laser scanning microscope, respectively. RESULTS NaB combined with cisplatin inhibited cell viability by promoting apoptosis of cervical cancer cells. In vivo experiments indicated that NaB combined with cisplatin could inhibit tumor growth and induce cancer cell necrosis. Single application of NaB activated the Wnt signaling pathway and induced partial EMT. NaB alone up-regulated MMP2, MMP7 and MMP9 expression, and promoted the migration and invasion of cervical cancer cells. The combination of cisplatin and NaB inhibited cellular migration and invasion by abrogating the nuclear transition of β-catenin, reverse EMT and down-regulate MMP2, MMP7 and MMP9. Immunohistochemical staining indicated that NaB combined with cisplatin up-regulated the expression of E-cadherin and reverse the EMT phenotype in the mice model. CONCLUSIONS NaB serves as a sensitizer for cisplatin, which may be a promising treatment regimen for cervical cancer when combined both. NaB alone should be utilized with caution for treating cervical cancer as it may promote the invasion and migration of cervical cancer cells.
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Affiliation(s)
- Huijun Chu
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoyuan Sun
- Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jia Wang
- Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ke Lei
- Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhengyi Shan
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chenyang Zhao
- Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ying Ning
- Graduate School, Medical College of Qingdao University, Qingdao, China
| | - Ruining Gong
- Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - He Ren
- Center for Gastrointestinal (GI) Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhumei Cui
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Quaas CE, Long DT. Targeting (de)acetylation: A Diversity of Mechanism and Disease. COMPREHENSIVE PHARMACOLOGY 2022:469-492. [DOI: 10.1016/b978-0-12-820472-6.00076-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Synergistic Anticancer Effect of Glycolysis and Histone Deacetylases Inhibitors in a Glioblastoma Model. Biomedicines 2021; 9:biomedicines9121749. [PMID: 34944565 PMCID: PMC8698815 DOI: 10.3390/biomedicines9121749] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/16/2021] [Accepted: 11/22/2021] [Indexed: 11/23/2022] Open
Abstract
Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy.
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Wei X, Xiao B, Wang L, Zang L, Che F. Potential new targets and drugs related to histone modifications in glioma treatment. Bioorg Chem 2021; 112:104942. [PMID: 33965781 DOI: 10.1016/j.bioorg.2021.104942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
Glioma accounts for 40-50% of craniocerebral tumors, whose outcome rarely improves after standard treatment. The development of new therapeutic targets for glioma treatment has important clinical significance. With the deepening of research on gliomas, recent researchers have found that the occurrence and development of gliomas is closely associated with histone modifications, including methylation, acetylation, phosphorylation, and ubiquitination. Additionally, evidence has confirmed the close relationship between histone modifications and temozolomide (TMZ) resistance. Therefore, histone modification-related proteins have been widely recognized as new therapeutic targets for glioma treatment. In this review, we summarize the potential histone modification-associated targets and related drugs for glioma treatment. We have further clarified how histone modifications regulate the pathogenesis of gliomas and the mechanism of drug action, providing novel insights for the current clinical glioma treatment. Herein, we have also highlighted the limitations of current clinical therapies and have suggested future research directions and expected advances in potential areas of disease prognosis. Due to the complicated glioma pathogenesis, in the present review, we have acknowledged the limitations of histone modification applications in the related clinical treatment.
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Affiliation(s)
- Xiuhong Wei
- Graduate School, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, China; Department of Neurology, Linyi People's Hospital, Shandong University, Linyi, Shandong, China
| | - Bolian Xiao
- Central Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China; Key Laboratory of Neurophysiology, Key Laboratory of Tumor Biology, Linyi, Shandong, China
| | - Liying Wang
- Department of Neurology, Linyi People's Hospital, Shandong University, Linyi, Shandong, China; Department of Neurology, the Clinical Medical College of Weifang Medical College, Weifang, Shandong, China
| | - Lanlan Zang
- Central Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China; Key Laboratory of Neurophysiology, Key Laboratory of Tumor Biology, Linyi, Shandong, China; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China.
| | - Fengyuan Che
- Graduate School, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, China; Department of Neurology, Linyi People's Hospital, Shandong University, Linyi, Shandong, China; Central Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China; Key Laboratory of Neurophysiology, Key Laboratory of Tumor Biology, Linyi, Shandong, China.
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Kunadis E, Lakiotaki E, Korkolopoulou P, Piperi C. Targeting post-translational histone modifying enzymes in glioblastoma. Pharmacol Ther 2020; 220:107721. [PMID: 33144118 DOI: 10.1016/j.pharmthera.2020.107721] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/08/2020] [Accepted: 10/27/2020] [Indexed: 12/30/2022]
Abstract
Glioblastoma (GBM) is the most common primary brain tumor in adults, and the most lethal form of glioma, characterized by variable histopathology, aggressiveness and poor clinical outcome and prognosis. GBMs constitute a challenge for oncologists because of their molecular heterogeneity, extensive invasion, and tendency to relapse. Glioma cells demonstrate a variety of deregulated genomic pathways and extensive interplay with epigenetic alterations. Epigenetic modifications have emerged as essential players in GBM research, with biomarker potential for tumor classification and prognosis and for drug targeting. Histone posttranslational modifications (PTMs) are crucial regulators of chromatin architecture and gene expression, playing a pivotal role in malignant transformation, tumor development and progression. Alteration in the expression of genes coding for lysine and arginine methyltransferases (G9a, SUV39H1 and SETDB1) and acetyltransferases and deacetylases (KAT6A, SIRT2, SIRT7, HDAC4, 6, 9) contribute to GBM pathogenesis. In addition, proteins of the sumoylation pathway are upregulated in GBM cell lines, including E1 (SAE1), E2 (Ubc9) components, and a SUMO-specific protease (SENP1). Preclinical and clinical studies are currently in progress targeting epigenetic enzymes in gliomas, including a new generation of histone deacetylase (HDAC), protein arginine methyltransferase (PRMT) and bromodomain (BRD) inhibitors. Herein, we provide an update on recent advances in glioma epigenetic research, focusing on the role of histone modifications and the use of epigenetic therapy as a valid treatment option for glioblastoma.
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Affiliation(s)
- Elena Kunadis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Eleftheria Lakiotaki
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Penelope Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
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Chen R, Zhang M, Zhou Y, Guo W, Yi M, Zhang Z, Ding Y, Wang Y. The application of histone deacetylases inhibitors in glioblastoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:138. [PMID: 32682428 PMCID: PMC7368699 DOI: 10.1186/s13046-020-01643-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/13/2020] [Indexed: 12/14/2022]
Abstract
The epigenetic abnormality is generally accepted as the key to cancer initiation. Epigenetics that ensure the somatic inheritance of differentiated state is defined as a crucial factor influencing malignant phenotype without altering genotype. Histone modification is one such alteration playing an essential role in tumor formation, progression, and resistance to treatment. Notably, changes in histone acetylation have been strongly linked to gene expression, cell cycle, and carcinogenesis. The balance of two types of enzyme, histone acetyltransferases (HATs) and histone deacetylases (HDACs), determines the stage of histone acetylation and then the architecture of chromatin. Changes in chromatin structure result in transcriptional dysregulation of genes that are involved in cell-cycle progression, differentiation, apoptosis, and so on. Recently, HDAC inhibitors (HDACis) are identified as novel agents to keep this balance, leading to numerous researches on it for more effective strategies against cancers, including glioblastoma (GBM). This review elaborated influences on gene expression and tumorigenesis by acetylation and the antitumor mechanism of HDACis. Besdes, we outlined the preclinical and clinical advancement of HDACis in GBM as monotherapies and combination therapies.
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Affiliation(s)
- Rui Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Mengxian Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Yangmei Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wenjing Guo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ziyan Zhang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, China
| | - Yanpeng Ding
- Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan, 430030, China
| | - Yali Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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Qin X, Xu Y, Peng S, Qian S, Zhang X, Shen S, Yang J, Ye J. Sodium butyrate opens mitochondrial permeability transition pore (MPTP) to induce a proton leak in induction of cell apoptosis. Biochem Biophys Res Commun 2020; 527:611-617. [PMID: 32423794 DOI: 10.1016/j.bbrc.2020.04.133] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 04/26/2020] [Indexed: 01/04/2023]
Abstract
Induction of apoptosis is a strategy in the treatment of glioma, a malignant tumor with the highest prevalence in the brain. Sodium butyrate (NaB) induces apoptosis in glioma cells at pharmacological dosages (>2.5 mM), but the mechanism remains largely unknown beyond the mitochondrial potential drop. In this study, NaB was found to open the mitochondrial permeability transient pore (MPTP) to induce a proton leak in the mechanism of apoptosis. The MPTP opening led to collapse of mitochondrial potential and suppression of ATP production in the NaB-treated cells. Proton leak was increased in the mitochondria under the coupling and uncoupling conditions from the MPTP opening. The proton leak was associated with an elevation in the protein abundance of adenine nucleotide translocator 2 (ANT2) and was blocked by an ANT-specific inhibitor of bongkrekic acid (BA). These data suggest that the proton leak is induced by NaB for the mitochondrial potential drop in the induction of apoptosis. The mechanism may be related to activation of ANT2 in the MPTP complex.
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Affiliation(s)
- Xiaojiao Qin
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China; Department of Neurology, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China
| | - Yanhong Xu
- Department of Neurology, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China; Central Laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China; Shanghai Diabetes Institute, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China
| | - Shiqiao Peng
- Central Laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China; Shanghai Diabetes Institute, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China
| | - Shengnan Qian
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China; Central Laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China
| | - Xiaoying Zhang
- Central Laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China
| | - Shuang Shen
- Central Laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China
| | - Jiajun Yang
- Department of Neurology, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China.
| | - Jianping Ye
- Central Laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China; Shanghai Diabetes Institute, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China.
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Zhang K, Hussain T, Wang J, Li M, Wang W, Ma X, Liao Y, Yao J, Song Y, Liang Z, Zhou X, Xu L. Sodium Butyrate Abrogates the Growth and Pathogenesis of Mycobacterium bovis via Regulation of Cathelicidin (LL37) Expression and NF-κB Signaling. Front Microbiol 2020; 11:433. [PMID: 32265874 PMCID: PMC7096352 DOI: 10.3389/fmicb.2020.00433] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 03/02/2020] [Indexed: 12/21/2022] Open
Abstract
Mycobacterium bovis is the causative agent of bovine tuberculosis, has been identified a serious threat to human population. It has been found that sodium butyrate (NaB), the inhibitor of histone deacetylase, can promote the expression of cathelicidin (LL37) and help the body to resist a variety of injuries. In the current study, we investigate the therapeutic effect of NaB on the regulation of host defense mechanism against M. bovis infection. We found an increased expression of LL37 in M. bovis infected THP-1 cells after NaB treatment. In contrast, NaB treatment significantly down-regulated the expression of Class I HDAC in THP-1 cells infected with M. bovis. Additionally, NaB reduced the expression of phosphorylated P65 (p-P65) and p-IκBα, indicating the inhibition of nuclear factor-κB (NF-κB) signaling. Furthermore, we found that NaB treatment reduced the production of inflammatory cytokines (IL-1β, TNF-α, and IL-10) and a key anti-apoptotic marker protein Bcl-2 in THP-1 cell infected with M. bovis. Notably, mice showed high resistance to M. bovis infection after NaB treatment. The reduction of viable M. bovis bacilli indicates that NaB-induced inhibition of M. bovis infection mediated by upregulation of LL37 and inhibition of NF-κB signaling pathway. These observations illustrate that NaB mediate protective immune responses against M. bovis infection. Overall, these results suggest that NaB can be exploited as a therapeutic strategy for the control of M. bovis in animals and human beings.
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Affiliation(s)
- Kai Zhang
- School of Agriculture, Ningxia University, Yinchuan, China
| | - Tariq Hussain
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.,College of Veterinary Sciences, The University of Agriculture Peshawar, Peshawar, Pakistan
| | - Jie Wang
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Mengying Li
- School of Agriculture, Ningxia University, Yinchuan, China
| | - Wenjia Wang
- School of Agriculture, Ningxia University, Yinchuan, China
| | - Xiaojing Ma
- School of Agriculture, Ningxia University, Yinchuan, China
| | - Yi Liao
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jiao Yao
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yinjuan Song
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Zhengmin Liang
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xiangmei Zhou
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Lihua Xu
- School of Agriculture, Ningxia University, Yinchuan, China
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Jose A, Chaitanya MVNL, Kannan E, Madhunapantula SV. Tricaproin Isolated From Simarouba glauca Inhibits the Growth of Human Colorectal Carcinoma Cell Lines by Targeting Class-1 Histone Deacetylases. Front Pharmacol 2018; 9:127. [PMID: 29593526 PMCID: PMC5857563 DOI: 10.3389/fphar.2018.00127] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/06/2018] [Indexed: 12/19/2022] Open
Abstract
While anticancer properties of Simarouba glauca (SG, commonly known as Paradise tree) are well documented in ancient literature, the underlying mechanisms leading to cancer cell death begin to emerge very recently. The leaves of SG have been used as potential source of anticancer agents in traditional medicine. Recently attempts have been made to isolate anticancer agents from the leaves of SG using solvent extraction, which identified quassinoids as the molecules with tumoricidal activity. However, it is not known whether the anti-cancer potential of SG leaves is just because of quassinoids alone or any other phytochemicals also contribute for the potency of SG leaf extracts. Therefore, SG leaves were first extracted with hexane, chloroform, ethyl acetate, 70% ethanol, water and anti-cancer potential (for inhibiting colorectal cancer (CRC) cells HCT-116 and HCT-15 proliferation) determined using Sulforhodamine-B (SRB) assay. The chloroform fraction with maximal anticancer activity was further fractionated by activity-guided isolation procedure and structure of the most potent compound determined using spectral analysis. Analysis of the structural characterization data showed the presence of tricaproin (TCN). TCN inhibited CRC cells growth in a time- and dose dependent manner but not the normal cell line BEAS-2B. Mechanistically, TCN reduced oncogenic Class-I Histone deacetylases (HDACs) activity, followed by inducing apoptosis in cells. In conclusion, the anti-cancer potential of SG is in part due to the presence of TCN in the leaves.
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Affiliation(s)
- Asha Jose
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Udhagamandalam, India
| | | | - Elango Kannan
- Department of Pharmacology, JSS College of Pharmacy, Udhagamandalam, India
| | - SubbaRao V Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
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Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine. Cell Oncol (Dordr) 2016; 40:21-32. [PMID: 27766591 DOI: 10.1007/s13402-016-0301-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2016] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Glioblastoma (GBM) ranks among the deadliest solid cancers worldwide and its prognosis has remained dismal, despite the use of aggressive chemo-irradiation treatment regimens. Limited drug delivery into the brain parenchyma and frequent resistance to currently available therapies are problems that call for a prompt development of novel therapeutic strategies. While only displaying modest efficacies as mono-therapy in pre-clinical settings, histone deacetylase inhibitors (HDACi) have shown promising sensitizing effects to a number of cytotoxic agents. Here, we sought to investigate the sensitizing effect of the HDACi trichostatin A (TSA) to the alkylating agent lomustine (CCNU), which is used in the clinic for the treatment of GBM. METHODS Twelve primary GBM cell cultures grown as neurospheres were used in this study, as well as one established GBM-derived cell line (U87 MG). Histone deacetylase (HDAC) expression levels were determined using quantitative real-time PCR and Western blotting. The efficacy of either CCNU alone or its combination with TSA was assessed using various assays, i.e., cell viability assays (MTT), cell cycle assays (flow cytometry, FACS), double-strand DNA break (DSB) quantification assays (microscopy/immunofluorescence) and expression profiling assays of proteins involved in apoptosis and cell stress (Western blotting and protein array). RESULTS We found that the HDAC1, 3 and 6 expression levels were significantly increased in GBM samples compared to non-neoplastic brain control samples. Additionally, we found that pre-treatment of GBM cells with TSA resulted in an enhancement of their sensitivity to CCNU, possibly via the accumulation of DSBs, decreased cell proliferation and viability rates, and an increased apoptotic rate. CONCLUSION From our data we conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM.
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Akbarzadeh L, Moini Zanjani T, Sabetkasaei M. Comparison of Anticancer Effects of Carbamazepine and Valproic Acid. IRANIAN RED CRESCENT MEDICAL JOURNAL 2016; 18:e37230. [PMID: 28184324 PMCID: PMC5291934 DOI: 10.5812/ircmj.37230] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 05/22/2016] [Accepted: 06/14/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Valproic acid (VPA) and carbamazepine (CBZ), two widely used antiepileptic drugs, have recently been found to inhibit histone deacetylases (HDAC). HDAC inhibitors (HDACIs) have various effects on cancer cells. OBJECTIVES The aim of this study was to compare the anticancer activity of these drugs on SW480 colon cancer cell lines. METHODS In the present experimental study, implemented during 2014 - 2015 in Iran, after incubation of cells into 96-well plates with 5,500 cells/well, the tested drugs were added, and cytotoxic effects were assessed by MTT. Moreover, after incubation of 8×106 cells in 75 cm² flasks to obtain β-catenin levels and 106 cells in a six-well plate to obtain vascular endothelial growth factor (VEGF) levels , these levels were estimated using enzyme-linked immunosorbent assay (ELISA) analysis. RESULTS Through MTT assay, we found that the inhibitory concentration of 50% (IC50) values for VPA and CBZ were 2.5 mM and 5 μM, respectively in comparison to controls in terms of total concentration and times evaluated (P < 0.0001). We also found that treatments with these drugs decreased levels of β-catenin (P < 0.0001) and VEGF (P < 0.0001) significantly more than controls. CONCLUSIONS VPA and CBZ treatments caused a decrease in β-Catenin and VEGF levels in SW480 colon cancer cell lines. These results suggest that CBZ can be considered a potential antitumor drug with potencies different from VPA.
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Affiliation(s)
- Ladan Akbarzadeh
- Department of Pharmacology, Shahid Beheshti University, Tehran, IR Iran
- Corresponding Author: Ladan Akbarzadeh, Department of Pharmacology, Shahid Beheshti University, Tehran, IR Iran. Tel: +98-9121034458, Fax: +98-2122439969, E-mail:
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15
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Koyuncuoglu T, Turkyilmaz M, Goren B, Cetinkaya M, Cansev M, Alkan T. Uridine protects against hypoxic-ischemic brain injury by reducing histone deacetylase activity in neonatal rats. Restor Neurol Neurosci 2015; 33:777-84. [DOI: 10.3233/rnn-150549] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Turkan Koyuncuoglu
- Uludag University Medical School Department of Physiology, Bursa, Turkey
| | - Mesut Turkyilmaz
- Uludag University Medical School Department of Pharmacology, Bursa, Turkey
| | - Bulent Goren
- Uludag University Medical School Department of Physiology, Bursa, Turkey
| | - Merih Cetinkaya
- Kanuni Sultan Suleyman Training and Research Hospital, Department of Pediatrics, Division of Neonatology, Istanbul, Turkey
| | - Mehmet Cansev
- Uludag University Medical School Department of Pharmacology, Bursa, Turkey
| | - Tulin Alkan
- Uludag University Medical School Department of Physiology, Bursa, Turkey
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Swierczynski S, Klieser E, Illig R, Alinger-Scharinger B, Kiesslich T, Neureiter D. Histone deacetylation meets miRNA: epigenetics and post-transcriptional regulation in cancer and chronic diseases. Expert Opin Biol Ther 2015; 15:651-64. [PMID: 25766312 DOI: 10.1517/14712598.2015.1025047] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Epigenetic regulation via DNA methylation, histone acetylation, as well as by microRNAs (miRNAs) is currently in the scientific focus due to its role in carcinogenesis and its involvement in initiation, progression and metastasis. While many target genes of DNA methylation, histone acetylation and miRNAs are known, even less information exists as to how these mechanisms cooperate and how they may regulate each other in a specific pathological context. For further development of therapeutic approaches, this review presents the current status of the crosstalk of histone acetylation and miRNAs in human carcinogenesis and chronic diseases. AREAS COVERED This article reviews information from comprehensive PubMed searches to evaluate relevant literature with a focus on possible association between histone acetylation, miRNAs and their targets. Our analysis identified specific miRNAs which collaborate with histone deacetylases (HDACs) and cooperatively regulate several relevant target genes. EXPERT OPINION Fourteen miRNAs could be linked to the expression of eight HDACs influencing the α-(1,6)-fucosyltransferase, polycystin-2 and the fibroblast-growth-factor 2 pathways. Focusing on the complex linkage of miRNA and HDAC expression could give deeper insights in new 'druggable' targets and might provide possible novel therapeutic approaches in future.
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Affiliation(s)
- Stefan Swierczynski
- Paracelsus Medical University, Salzburger Landeskliniken, Department of Surgery , Salzburg , Austria
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17
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Histone deacetylase inhibitors in hematological malignancies and solid tumors. Arch Pharm Res 2015; 38:933-49. [PMID: 25653088 DOI: 10.1007/s12272-015-0571-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/28/2015] [Indexed: 01/23/2023]
Abstract
Histone deacetylase (HDAC) inhibitors are emerging as promising anticancer drugs. Because aberrant activity and expression of HDACs have been implicated in various cancer types, a wide range of HDAC inhibitors are being investigated as anticancer agents. Furthermore, due to the demonstrable anticancer activity in both in vitro and in vivo studies, numerous HDAC inhibitors have undergone a rapid phase of clinical development in various cancer types, either as a monotherapy or in combination with other anticancer agents. Although preclinical trials show that HDAC inhibitors have a variety of biological effects across multiple pathways, including regulation of gene expression, inducing apoptosis and cell cycle arrest, inhibiting angiogenesis, and regulation of DNA damage and repair, the mechanism by which the clinical activity is mediated remains unclear. Understanding the mechanisms of anticancer activity of HDAC inhibitors is essential not only for rational drug design for targeted therapies, but for the design of optimized clinical protocols. This paper describes the links between HDACs and cancer, and the underlying mechanisms of action of HDAC inhibitors against hematological malignancies and solid tumors. Further, this review presents the clinical outcomes of vorinostat, romidepsin, and belinostat, which are approved by the United States Food and Drug Administration for the treatment of lymphomas.
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Abstract
In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca(2+) sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.
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Affiliation(s)
- Anne R. Bresnick
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
| | - David J. Weber
- Center for Biomolecular Therapeutics and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, Maryland 20102, USA
| | - Danna B. Zimmer
- Center for Biomolecular Therapeutics and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, Maryland 20102, USA
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Zohre S, Kazem NK, Abolfazl A, Mohammad RY, Aliakbar M, Effat A, Zahra D, Hassan D, Nosratollah Z. Trichostatin A-induced Apoptosis is Mediated by Krüppel-like Factor 4 in Ovarian and Lung Cancer. Asian Pac J Cancer Prev 2014; 15:6581-6. [DOI: 10.7314/apjcp.2014.15.16.6581] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Li Z, Zhu WG. Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int J Biol Sci 2014; 10:757-70. [PMID: 25013383 PMCID: PMC4081609 DOI: 10.7150/ijbs.9067] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/02/2014] [Indexed: 12/19/2022] Open
Abstract
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non-histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The primary purpose of this paper is to summarize recent studies of the links between HDACs and cancer, and further discuss the underlying mechanisms of anti-tumor activities of HDAC inhibitors and clinical implications.
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Affiliation(s)
- Zhiming Li
- 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100191, China. ; 2. Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China
| | - Wei-Guo Zhu
- 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100191, China. ; 2. Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China. ; 3. Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing 100871, China
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Marchion D, Münster P. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther 2014; 7:583-98. [PMID: 17428177 DOI: 10.1586/14737140.7.4.583] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Histone deacetylase (HDAC) inhibitors are an exciting new addition to the arsenal of cancer therapeutics. The inhibition of HDAC enzymes by HDAC inhibitors shifts the balance between the deacetylation activity of HDAC enzymes and the acetylation activity of histone acetyltransferases, resulting in hyperacetylation of core histones. Exposure of cancer cells to HDAC inhibitors has been associated with a multitude of molecular and biological effects, ranging from transcriptional control, chromatin plasticity, protein-DNA interaction to cellular differentiation, growth arrest and apoptosis. In addition to the antitumor effects seen with HDAC inhibitors alone, these compounds may also potentiate cytotoxic agents or synergize with other targeted anticancer agents. The exact mechanism by which HDAC inhibitors cause cell death is still unclear and the specific roles of individual HDAC enzymes as therapeutic targets has not been established. However, emerging evidence suggests that the effects of HDAC inhibitors on tumor cells may not only depend on the specificity and selectivity of the HDAC inhibitor, but also on the expression patterns of HDAC enzymes in the tumor tissue. In this review, the recent advances in the understanding and clinical development of HDAC inhibitors, as well as their current role in cancer therapy, will be discussed.
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Affiliation(s)
- Douglas Marchion
- H Lee Moffitt Cancer Center, Experimental Therapeutics Program, Department of Interdisciplinary Oncology, Tampa, FL 33612, USA
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Epigenetic modifications in cell lines of human astrocytoma differentially regulate expression of apoptotic genes. Childs Nerv Syst 2014; 30:123-9. [PMID: 23943192 DOI: 10.1007/s00381-013-2258-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 07/31/2013] [Indexed: 01/28/2023]
Abstract
OBJECTS Epigenetic alterations, known as epimutations, act by deregulating gene expression. These epimutations are reversible through the action of chromatin modifiers such as DNA methylation (DNA-met) and histone deacetylases (HDAC) inhibitors. The present study evaluated the effect of 5-azacitidine (5-aza) and sodium butyrate (NaBu) as inhibitors of DNA-met and HDAC, respectively, in the expression of genes involved in apoptosis. METHODS D54-MG, U373-MG, and T98G cell lines were exposed to 8 mM of NaBu and 12 μM of 5-aza, as well as a combination of both, for 24 h. The expression of the Bcl-2, Bak-1, Bax, Caspase-3, and Caspase-9 genes was assessed by RT-PCR. RESULTS They show that the Bcl-2, Caspase-3, and Caspase-9 genes were not expressed by the U373-MG and T98G lines, and that the D54-MG line did not express Bak-1. After treatment, however, these cell lines expressed all of the genes due to the effect of 5-aza on Bak-1 in D54-MG and Caspase-9 in T98G, which suggests repression by DNA-met. Meanwhile, Bcl-2, Caspase-3, and Caspase-9 were in the U373-MG and T98G lines expressed after NaBu treatment. The effect of 5-aza induced an increase in the expression of Bax and Bcl-2, while NaBu produced a similar effect on the Bak-1 and Bax genes. CONCLUSIONS Results reveal that histone deacetylation is the principle mechanism for repressing these genes and that their basal expression is regulated primarily by this form of histone modification.
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Matthews GM, Newbold A, Johnstone RW. Intrinsic and extrinsic apoptotic pathway signaling as determinants of histone deacetylase inhibitor antitumor activity. Adv Cancer Res 2013; 116:165-97. [PMID: 23088871 DOI: 10.1016/b978-0-12-394387-3.00005-7] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that impede the growth and/or survival of tumor cells. Depending on the physiological context, HDACi can induce apoptosis via two well-defined apoptotic pathways; the intrinsic/mitochondrial pathway and the death receptor (DR)/extrinsic pathway. A number of groups have demonstrated that overexpression of prosurvival Bcl-2 family members significantly reduces HDACi-mediated tumor cell death and therapeutic efficacy in preclinical models. In many cases, HDACi activate the intrinsic pathway via upregulation of a number of proapoptotic BH3-only Bcl-2 family genes including Bim, Bid, and Bmf. Additionally, HDACi can engage the extrinsic pathway through upregulation of DR expression, reductions in c-FLIP, and upregulation of ligands such as TRAIL. Overall, it appears that activation of the intrinsic apoptotic pathway is the predominant mechanism of HDACi-induced tumor cell death; however, the DR pathway may also be engaged, either to amplify the apoptotic signal through the intrinsic pathway or to directly induce cell death.
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Affiliation(s)
- Geoffrey M Matthews
- Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia
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Saito T, Nishida K, Furumatsu T, Yoshida A, Ozawa M, Ozaki T. Histone deacetylase inhibitors suppress mechanical stress-induced expression of RUNX-2 and ADAMTS-5 through the inhibition of the MAPK signaling pathway in cultured human chondrocytes. Osteoarthritis Cartilage 2013; 21:165-74. [PMID: 23017871 DOI: 10.1016/j.joca.2012.09.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 07/18/2012] [Accepted: 09/19/2012] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To investigate the inhibitory effects and the regulatory mechanisms of histone deacetylase (HDAC) inhibitors on mechanical stress-induced gene expression of runt-related transcription factor (RUNX)-2 and adisintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5 in human chondrocytes. METHODS Human chondrocytes were seeded in stretch chambers at a concentration of 5 × 10(4)cells/chamber. Cells were pre-incubated with or without HDAC inhibitors (MS-275 or trichostatin A; TSA) for 12h, followed by uniaxial cyclic tensile strain (CTS) (0.5Hz, 10% elongation), which was applied for 30 min using the ST-140-10 system (STREX, Osaka, Japan). Total RNA was extracted and the expression of RUNX-2, ADAMTS-5, matrix metalloproteinase (MMP)-3, and MMP-13 at the mRNA and protein levels were examined by real-time polymerase chain reaction (PCR) and immunocytochemistry, respectively. The activation of diverse mitogen-activated protein kinase (MAPK) pathways with or without HDAC inhibitors during CTS was examined by western blotting. RESULTS HDAC inhibitors (TSA: 10 nM, MS-275: 100 nM) suppressed CTS-induced expression of RUNX-2, ADAMTS-5, and MMP-3 at both the mRNA and protein levels within 1h. CTS-induced activation of p38 MAPK (p38), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) MAPKs was downregulated by both HDAC inhibitors. CONCLUSION The CTS-induced expression of RUNX-2 and ADAMTS-5 was suppressed by HDAC inhibitors via the inhibition of the MAPK pathway activation in human chondrocytes. The results of the current study suggested a novel therapeutic role for HDAC inhibitors against degenerative joint disease such as osteoarthritis.
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Affiliation(s)
- T Saito
- Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City, Okayama 700-8558, Japan
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Zhu S, Li Y, Zhao L, Hou P, Shangguan C, Yao R, Zhang W, Zhang Y, Tan J, Huang B, Lu J. TSA-induced JMJD2B downregulation is associated with cyclin B1-dependent survivin degradation and apoptosis in LNCap cells. J Cell Biochem 2012; 113:2375-82. [PMID: 22388778 DOI: 10.1002/jcb.24109] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Histone deacetylase (HDAC) inhibitors are emerging as a novel class of anti-tumor agents and have manifested the ability to induce apoptosis of cancer cells, and a significant number of genes have been identified as potential effectors responsible for HDAC inhibitor-induced apoptosis. However, the mechanistic actions of these HDAC inhibitors in this process remain largely undefined. We here report that the treatment of LNCap prostate cancer cells with HDAC inhibitor trichostatin A (TSA) resulted in downregulation of the Jumonji domain-containing protein 2B (JMJD2B). We also found that the TSA-mediated decrease in survivin expression in LNCap cells was partly attributable to downregulation of JMJD2B expression. This effect was attributable to the promoted degradation of survivin protein through inhibition of Cyclin B1/Cdc2 complex-mediated survivin Thr34 phosphorylation. Consequently, knockdown of JMJD2B enhanced TSA-induced apoptosis by regulating the Cyclin B1-dependent survivin degradation to potentiate the apoptosis pathways.
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Affiliation(s)
- Shan Zhu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
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Apoptosis of bladder cancer by sodium butyrate and cisplatin. J Infect Chemother 2012; 18:288-95. [DOI: 10.1007/s10156-011-0322-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Accepted: 09/27/2011] [Indexed: 12/22/2022]
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Xu J, Sampath D, Lang FF, Prabhu S, Rao G, Fuller GN, Liu Y, Puduvalli VK. Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures. J Neurooncol 2011; 105:241-51. [PMID: 21598070 DOI: 10.1007/s11060-011-0604-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 05/08/2011] [Indexed: 11/25/2022]
Abstract
Chromatin modification through histone deacetylase inhibition has shown evidence of activity against malignancies. The mechanism of action of such agents are pleiotropic and potentially tumor specific. In this study, we studied the mechanisms of vorinostat-induced cellular effects in gliomas. The effects of vorinostat on proliferation, induction of apoptosis and cell cycle effects were studied in vitro (D54, U87 and U373 glioma cell lines). To gain additional insights into its effects on human gliomas, vorinostat-induced changes were examined ex vivo using a novel organotypic human glioma slice model. Vorinostat treatment resulted in increased p21 levels in all glioma cells tested in a p53 independent manner. In addition, cyclin B1 levels were transcriptionally downregulated and resulted in reduced kinase activity of the cyclin B1/cdk1 complex causing a G2 arrest. These effects were associated with a dose- and time-dependent inhibition of cellular proliferation and anchorage-independent growth in association with hyperacetylation of core histones and induction of apoptosis. Of particular significance, we demonstrate histone hyperacetylation and increased p21 levels in freshly resected human glioma specimens maintained as organotypic slice cultures and exposed to vorinostat similar to cell lines suggesting that human glioma can be targeted by this agent. Our data suggest that the effects of vorinostat are associated with modulation of cell cycle related proteins and activation of a G2 checkpoint along with induction of apoptosis. These effects are mediated by both transcriptional and post-translational mechanisms which provide potential options that can be exploited to develop new therapeutic approaches against gliomas.
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Affiliation(s)
- Jihong Xu
- Department of Neuro-Oncology, The Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA
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Altmann A, Eisenhut M, Bauder-Wüst U, Markert A, Askoxylakis V, Hess-Stumpp H, Haberkorn U. Therapy of thyroid carcinoma with the histone deacetylase inhibitor MS-275. Eur J Nucl Med Mol Imaging 2010; 37:2286-97. [DOI: 10.1007/s00259-010-1573-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Accepted: 07/15/2010] [Indexed: 01/01/2023]
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Lin J, Yang Q, Wilder PT, Carrier F, Weber DJ. The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. J Biol Chem 2010; 285:27487-27498. [PMID: 20587415 DOI: 10.1074/jbc.m110.155382] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The S100B-p53 protein complex was discovered in C8146A malignant melanoma, but the consequences of this interaction required further study. When S100B expression was inhibited in C8146As by siRNA (siRNA(S100B)), wt p53 mRNA levels were unchanged, but p53 protein, phosphorylated p53, and p53 gene products (i.e. p21 and PIDD) were increased. siRNA(S100B) transfections also restored p53-dependent apoptosis in C8146As as judged by poly(ADP-ribose) polymerase cleavage, DNA ladder formation, caspase 3 and 8 activation, and aggregation of the Fas death receptor (+UV); whereas, siRNA(S100B) had no effect in SK-MEL-28 cells containing elevated S100B and inactive p53 (p53R145L mutant). siRNA(S100B)-mediated apoptosis was independent of the mitochondria, because no changes were observed in mitochondrial membrane potential, cytochrome c release, caspase 9 activation, or ratios of pro- and anti-apoptotic proteins (BAX, Bcl-2, and Bcl-X(L)). As expected, cells lacking S100B (LOX-IM VI) were not affected by siRNA(S100B), and introduction of S100B reduced their UV-induced apoptosis activity by 7-fold, further demonstrating that S100B inhibits apoptosis activities in p53-containing cells. In other wild-type p53 cells (i.e. C8146A, UACC-2571, and UACC-62), S100B was found to contribute to cell survival after UV treatment, and for C8146As, the decrease in survival after siRNA(S100B) transfection (+UV) could be reversed by the p53 inhibitor, pifithrin-alpha. In summary, reducing S100B expression with siRNA was sufficient to activate p53, its transcriptional activation activities, and p53-dependent apoptosis pathway(s) in melanoma involving the Fas death receptor and perhaps PIDD. Thus, a well known marker for malignant melanoma, S100B, likely contributes to cancer progression by down-regulating the tumor suppressor protein, p53.
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Affiliation(s)
- Jing Lin
- Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Maryland 21201
| | - Qingyuan Yang
- Department of Radiation Oncology, University of Maryland School of Medicine, Maryland 21201
| | - Paul T Wilder
- Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Maryland 21201; Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland 21201
| | - France Carrier
- Department of Radiation Oncology, University of Maryland School of Medicine, Maryland 21201; Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland 21201.
| | - David J Weber
- Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Maryland 21201; Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland 21201.
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Müller I, Wischnewski F, Pantel K, Schwarzenbach H. Promoter- and cell-specific epigenetic regulation of CD44, Cyclin D2, GLIPR1 and PTEN by methyl-CpG binding proteins and histone modifications. BMC Cancer 2010; 10:297. [PMID: 20565761 PMCID: PMC2912262 DOI: 10.1186/1471-2407-10-297] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2009] [Accepted: 06/17/2010] [Indexed: 12/14/2022] Open
Abstract
Background The aim of the current study was to analyze the involvement of methyl-CpG binding proteins (MBDs) and histone modifications on the regulation of CD44, Cyclin D2, GLIPR1 and PTEN in different cellular contexts such as the prostate cancer cells DU145 and LNCaP, and the breast cancer cells MCF-7. Since global chromatin changes have been shown to occur in tumours and regions of tumour-associated genes are affected by epigenetic modifications, these may constitute important regulatory mechanisms for the pathogenesis of malignant transformation. Methods In DU145, LNCaP and MCF-7 cells mRNA expression levels of CD44, Cyclin D2, GLIPR1 and PTEN were determined by quantitative RT-PCR at the basal status as well as after treatment with demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor Trichostatin A. Furthermore, genomic DNA was bisulfite-converted and sequenced. Chromatin immunoprecipitation was performed with the stimulated and unstimulated cells using antibodies for MBD1, MBD2 and MeCP2 as well as 17 different histone antibodies. Results Comparison of the different promoters showed that MeCP2 and MBD2a repressed promoter-specifically Cyclin D2 in all cell lines, whereas in MCF-7 cells MeCP2 repressed cell-specifically all methylated promoters. Chromatin immunoprecipitation showed that all methylated promoters associated with at least one MBD. Treatment of the cells by the demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) caused dissociation of the MBDs from the promoters. Only MBD1v1 bound and repressed methylation-independently all promoters. Real-time amplification of DNA immunoprecipitated by 17 different antibodies showed a preferential enrichment for methylated lysine of histone H3 (H3K4me1, H3K4me2 and H3K4me3) at the particular promoters. Notably, the silent promoters were associated with unmodified histones which were acetylated following treatment by 5-aza-CdR. Conclusions This study is one of the first to reveal the histone code and MBD profile at the promoters of CD44, Cyclin D2, GLIPR1 and PTEN in different tumour cells and associated changes after stimulation with methylation inhibitor 5-aza-CdR.
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Affiliation(s)
- Imke Müller
- Department of Tumour Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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Trichostatin A sensitizes cisplatin-resistant A549 cells to apoptosis by up-regulating death-associated protein kinase. Acta Pharmacol Sin 2010; 31:93-101. [PMID: 20048748 DOI: 10.1038/aps.2009.183] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
AIM To investigate the apoptosis-inducing effect of trichostatin A (TSA) in the human lung adenocarcinoma cisplatin-resistant cell line (A549/CDDP) and to examine whether TSA can enhance sensitivity to cisplatin treatment and the underlying molecular mechanisms of such an enhancement. METHODS Cell viability was evaluated using the Neutral Red assay. Apoptosis was assessed using Hoechst 33258 staining and flow cytometry analysis. Protein expression was detected by Western blotting. To determine the role of Death-associated protein kinase (DAPK) in TSA-induced apoptosis in the A549/CDDP cell line, cells were transfected with pcDNA3.1(+)-DAPK, which has a higher expression level of DAPK compared to endogenous expression, and DAPK activity was inhibited by both over-expression C-terminal fragment of DAPK which may competitive binding DAPK substrates to inhibit the function of DAPK and RNA interference. RESULTS TSA induced apoptosis in both A549 cells and A549/CDDP cells. TSA enhanced the sensitivity of A549/CDDP cells to cisplatin, along with concomitant DAPK up-regulation. When DAPK was over-expressed, A549/CDDP cells became sensitive to cisplatin and the cytotoxicity of TSA could be increased. Moreover, the cytotoxicity of TSA could be alleviated by inhibition of DAPK activity by the expression of a recombinant C-terminal fragment of DAPK or RNA interference. CONCLUSION TSA induced sensitivity to cisplatin treatment in cisplatin-resistant A549 cells. The up-regulation of DAPK is one of the mechanisms mediating sensitization to TSA-induced apoptosis in cisplatin-resistant cells.
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Horiuchi M, Morinobu A, Chin T, Sakai Y, Kurosaka M, Kumagai S. Expression and function of histone deacetylases in rheumatoid arthritis synovial fibroblasts. J Rheumatol 2009; 36:1580-9. [PMID: 19531758 DOI: 10.3899/jrheum.081115] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To explore the effects of histone deacetylases (HDAC) on rheumatoid arthritis synovial fibroblasts (RA-SF). METHODS The expression of mRNA encoding HDAC1 through HDAC11 in RA-SF and osteoarthritis-SF (OA-SF) was determined using real-time polymerase chain reactions. The functions of HDAC1 and HDAC2 in RA-SF were assessed using small interfering RNA (siRNA) technology. Cell counts and proliferation were examined by MTT assays and BrDU ELISA, respectively, and apoptosis was determined using the TUNEL assay and annexin V staining. Levels of cell cycle-related molecules and matrix metalloproteinases (MMP) were tested by Western blotting and ELISA, respectively. RESULTS Messenger RNA expression of HDAC1 was significantly higher in RA-SF than in OA-SF. Knockdown of HDAC1 and HDAC2 by siRNA resulted in decreased cell counts and cell proliferation, and increased apoptosis in RA-SF. Expression of p16, p21, and p53 was increased by knockdown of both HDAC1 and HDAC2. On the other hand, knockdown of HDAC1, but not of HDAC2, upregulated tumor necrosis factor-alpha-induced MMP-1 production by RA-SF. CONCLUSION HDAC1 is overexpressed in RA-SF compared to OA-SF. HDAC1 supports cell proliferation and survival of RA-SF, but suppresses MMP-1 production. HDAC2 also plays an important role in cell proliferation and apoptosis of RA-SF. Our study provides useful information to develop new HDAC inhibitors for the treatment of RA.
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Affiliation(s)
- Marika Horiuchi
- Department of Clinical Pathology and Immunology, Kobe University School of Medicine, Kobe, Japan
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Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. Blood 2008; 113:1982-91. [PMID: 19060243 DOI: 10.1182/blood-2008-05-156851] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpression of Bcl-2 or Bcl-X(L). Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of Emu-myc lymphomas overexpressing Bcl-2 or Bcl-X(L) to vorinostat and valproic acid (VPA). Combining low-dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis of these cells. ABT-737 was ineffective against Emu-myc/Mcl-1 and Emu-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, Emu-myc/Bcl-w lymphomas were insensitive to ABT-737 used alone or in combination with HDACi, indicating that the regulatory activity of ABT-737 is restricted to Bcl-2 and Bcl-X(L). Emu-myc lymphomas that expressed Bcl-2 throughout the tumorigenesis process were especially sensitive to ABT-737, while those forced to overexpress Mcl-1 were not. This supports the notion that tumor cells "addicted" to ABT-737 target proteins (ie, Bcl-2 or Bcl-X(L)) are likely to be the most sensitive target cell population. Our studies provide important preclinical data on the binding specificity of ABT-737 and its usefulness against primary hematologic malignancies when used as a single agent and in combination with HDACi.
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Makki MS, Heinzel T, Englert C. TSA downregulates Wilms tumor gene 1 (Wt1) expression at multiple levels. Nucleic Acids Res 2008; 36:4067-78. [PMID: 18535006 PMCID: PMC2475629 DOI: 10.1093/nar/gkn356] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The Wilms tumor gene WT1 encodes a zinc-finger transcription factor that is inactivated in a subset of pediatric kidney cancers. During embryogenesis, WT1 is expressed in a time- and tissue-specific manner in various organs including gonads and kidney but also in the hematopoietic system. Although widely regarded as a tumor suppressor gene, wild-type WT1 is overexpressed in a variety of hematologic malignancies, most notably in acute lymphoblastic leukemia as well as myelodysplastic syndromes. Reduction of WT1 expression levels leads to decrease of proliferation and apoptosis of leukemic cells, suggesting that in certain contexts WT1 might act as an oncogene. We show here that histone deacetylase inhibitors like Trichostatin A (TSA) can promptly and dramatically downregulate Wt1 expression levels in different cell lines. This effect was mostly due to the cessation of transcription and was mediated by sequences located in intron 3 of Wt1. In addition, TSA also caused enhanced degradation of the Wt1 protein by the proteasome. This was at least in part due to induction of the ubiquitin-conjugating enzyme UBCH8. Thus, downregulation of Wt1 expression might contribute to the beneficial effects of histone deacetylase inhibitors that are currently used in clinical trials as cancer therapeutics.
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Affiliation(s)
- Mohammad Shahidul Makki
- Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany
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Warren KE, McCully C, Dvinge H, Tjørnelund J, Sehested M, Lichenstein HS, Balis FM. Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates. Cancer Chemother Pharmacol 2007; 62:433-7. [DOI: 10.1007/s00280-007-0622-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Accepted: 09/30/2007] [Indexed: 10/22/2022]
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Buckley MT, Yoon J, Yee H, Chiriboga L, Liebes L, Ara G, Qian X, Bajorin DF, Sun TT, Wu XR, Osman I. The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med 2007; 5:49. [PMID: 17935615 PMCID: PMC2100044 DOI: 10.1186/1479-5876-5-49] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2007] [Accepted: 10/12/2007] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Treatment options for patients with recurrent superficial bladder cancer are limited, necessitating aggressive exploration of new treatment strategies that effectively prevent recurrence and progression to invasive disease. We assessed the effects of belinostat (previously PXD101), a novel histone deacetylase inhibitor, on a panel of human bladder cancer cell lines representing superficial and invasive disease, and on a transgenic mouse model of superficial bladder cancer. METHODS Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed. Ha-ras transgenic mice with established superficial bladder cancer were randomized to receive either belinostat or vehicle alone, and assessed for bladder weight, hematuria, gene expression profiling, and immunohistochemistry (IHC). RESULTS Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM). The 5637 cell line, which was derived from a superficial papillary tumor, was the most sensitive to treatment. Belinostat (100 mg/kg, intraperitoneal, 5 days each week for 3 weeks) treated mice had less bladder weight (p < 0.05), and no hematuria compared with 6/10 control mice that developed at least one episode. IHC of bladder tumors showed less cell proliferation and a higher expression of p21WAF1 in the belinostat-treated mice. Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes. CONCLUSION Our data demonstrate that belinostat inhibits bladder cancer and supports the clinical evaluation of belinostat for the treatment of patients with superficial bladder cancer.
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Baradari V, Höpfner M, Huether A, Schuppan D, Scherübl H. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol 2007; 13:4458-66. [PMID: 17724801 PMCID: PMC4611578 DOI: 10.3748/wjg.v13.i33.4458] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib.
METHODS: Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry.
RESULTS: MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1. Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects.
CONCLUSION: The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.
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Affiliation(s)
- Viola Baradari
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
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Mohana Kumar B, Song HJ, Cho SK, Balasubramanian S, Choe SY, Rho GJ. Effect of histone acetylation modification with sodium butyrate, a histone deacetylase inhibitor, on cell cycle, apoptosis, ploidy and gene expression in porcine fetal fibroblasts. J Reprod Dev 2007; 53:903-13. [PMID: 17558190 DOI: 10.1262/jrd.18180] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The present study evaluated the effective dose of sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor, for determination of the level of enhancement of histone acetylation in porcine fetal fibroblasts (PFFs) based on their morphology, growth, apoptosis and cell cycle status. Cells were analyzed for their histone acetylation levels at H3, H4 and H2A and expression of genes related to histone deacetylation (HDAC1, HDAC2 and HDAC3), pro-apoptosis (Bax and Bak) and anti-apoptosis (Bcl-2). PFFs at passage 3-4 were cultured with 0, 0.5, 1.0, 2.0 and 3.0 mM NaB for 96 h. NaB inhibited cell proliferation at all tested concentrations in a dose-dependent manner. However, there was slow cell growth for PFFs treated with 2.0 and 3.0 mM NaB compared with those of untreated PFFs and those treated with other lower concentrations (0.5 and 1.0 mM). More than 85% of the cells that were untreated or treated with 0.5 or 1.0 mM NaB had intact membranes, whereas, approximately 30% of the cells treated with 2.0 or 3.0 mM NaB had increased cell sizes and a more flattened and elongated appearance. NaB induced apoptosis in a dose-dependent manner; the rates of apoptosis were 2.5 +/- 0.4% for 1.0 mM NaB, 7.6 +/- 1.1% for 2.0 mM NaB and 11.2 +/- 1.4% for 3.0 mM NaB. The chromosomal sets of PFFs treated with 0.5 and 1.0 mM NaB were normal, whereas a lower proportion of PFFs treated with 2.0 and 3.0 mM were classified as normal. NaB at 0.5 and 1.0 mM showed little effect on cell cycle. However, 2.0 and 3.0 mM resulted in an increased cell population at the G(0)/G(1) phase. Increased NaB concentrations led to elevated acetylation of H3, H4 and H2A. NaB altered the expression of histone deacetylation and apoptosis-related genes. In conclusion, 1.0 mM NaB induced histone hyperacetylation in the PFFs and produced less deleterious effects than other concentrations; these PFFs might serve as suitable donors for porcine somatic cell nuclear transfer (SCNT).
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Affiliation(s)
- Basavarajappa Mohana Kumar
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea
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Donadelli M, Costanzo C, Beghelli S, Scupoli MT, Dandrea M, Bonora A, Piacentini P, Budillon A, Caraglia M, Scarpa A, Palmieri M. Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin A and gemcitabine. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2007; 1773:1095-106. [PMID: 17555830 DOI: 10.1016/j.bbamcr.2007.05.002] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Revised: 04/24/2007] [Accepted: 05/03/2007] [Indexed: 12/17/2022]
Abstract
We investigated the ability of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to interact with gemcitabine (GEM) in inducing pancreatic cancer cell death. The combined treatment with TSA and GEM synergistically inhibited growth of four pancreatic adenocarcinoma cell lines and induced apoptosis. This effect was associated with the induction of reactive oxygen species (ROS) by GEM, increased expression of the pro-apoptotic BIM gene by both TSA and GEM and downregulation of the 5'-nucleotidase UMPH type II gene by TSA. The expression of other genes critical for GEM resistance (nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ribonucleotide reductase genes) was not affected by TSA. The functional role of ROS in cell growth inhibition by GEM was supported by (i) a significantly reduced GEM-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine, and (ii) a positive correlation between the basal level of ROS and sensitivity to GEM in 10 pancreatic cancer cell lines. The functional role of both Bim and 5'-nucleotidase UMPH type II in cell growth inhibition by TSA and GEM was assessed by RNA interference assays. In vivo studies on xenografts of pancreatic adenocarcinoma cells in nude mice showed that the association of TSA and GEM reduced to 50% the tumour mass and did not cause any apparent form of toxicity, while treatments with TSA or GEM alone were ineffective. In conclusion, the present study demonstrates a potent anti-tumour activity of TSA/GEM combination against pancreatic cancer cells in vitro and in vivo, strongly supporting the use of GEM in combination with an HDAC inhibitor for pancreatic cancer therapy.
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Affiliation(s)
- Massimo Donadelli
- Department of Morphological and Biomedical Sciences, Section of Biochemistry, University of Verona, Verona, Italy
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Li GC, Zhang X, Pan TJ, Chen Z, Ye ZQ. Histone deacetylase inhibitor trichostatin A inhibits the growth of bladder cancer cells through induction of p21WAF1 and G1 cell cycle arrest. Int J Urol 2006; 13:581-6. [PMID: 16771729 DOI: 10.1111/j.1442-2042.2006.01344.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE To investigate whether Trichostatin A (TSA) possesses antitumor activity against human bladder cancer cells, and if any, its mechanism. MATERIALS AND METHODS A human bladder cancer cell line, BIU-87, was treated with different concentrations of TSA. After treatment, cell growth was measured by MTT assay. Cell apoptosis and cell cycle changes were examined by means of flow cytometry (FCM). Apoptosis was confirmed by apoptotic ladder formation assay. mRNA expression of p21WAF1 and p53 was assessed by differential reverse transcription-polymerase chain reaction. RESULTS Trichostatin A significantly inhibited the proliferation of bladder cancer cell at nanomolar concentrations in a time- and dose-dependent fashion. TSA treatment caused cell cycle arrest at the G1 phase and increased apoptotic cell death as shown by FCM and DNA fragmentation analysis, accompanied by increased p21WAF1 mRNA expression. In addition, TSA treatment did not alter p53 mRNA expression. CONCLUSION Our results indicate that TSA is able to inhibit bladder cancer cell growth in vitro, possibly through p21WAF1 mediated cell cycle arrest and apoptotic cell death. This study suggests that TSA may be a potential therapeutic agent for the treatment of bladder cancer.
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Affiliation(s)
- Gong-Cheng Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Eyüpoglu IY, Hahnen E, Tränkle C, Savaskan NE, Siebzehnrübl FA, Buslei R, Lemke D, Wick W, Fahlbusch R, Blümcke I. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Mol Cancer Ther 2006; 5:1248-55. [PMID: 16731757 DOI: 10.1158/1535-7163.mct-05-0533] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC(90), 3.75 micromol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G(0)-G(1) cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein-transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 micromol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas.
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Affiliation(s)
- Ilker Y Eyüpoglu
- Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.
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Piacentini P, Donadelli M, Costanzo C, Moore PS, Palmieri M, Scarpa A. Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation. Virchows Arch 2006; 448:797-804. [PMID: 16568310 DOI: 10.1007/s00428-006-0173-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Accepted: 02/08/2006] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is an aggressive neoplasia, and standard chemotherapies are by and large ineffective. The purpose of this work was to get a comprehensive preclinical study on the ability of anticancer drug combinations that best inhibit growth of pancreatic adenocarcinoma cells. We evaluated the in vitro growth inhibition of ten pancreatic cancer cell lines to gemcitabine and 5-fluorouracil, newer generation cytotoxic agents (oxaliplatin, irinotecan), targeted therapy (gefitinib) and a histone deacetylase (HDAC) inhibitor (trichostatin A). Cells were treated with the single drug alone and all pairwise drug association. Our results demonstrate that TSA can effectively increase the drug sensitivity of all the cell lines studied. The association of TSA and irinotecan determines an increase in growth inhibition on the highest percentage of cell lines (80%). Our findings may represent an experimental basis for potential clinical application of HDAC inhibitors, in particular in association with drugs used in cancer clinical treatment, supporting the idea that HDAC inhibitors could act as sensitizers for chemotherapy.
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Affiliation(s)
- Paolo Piacentini
- Department of Pathology, Section of Anatomic Pathology, University of Verona, Verona, Italy
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43
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Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, Ismail S, Stevens C, Meyn RE. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 2005; 11:4912-22. [PMID: 16000590 DOI: 10.1158/1078-0432.ccr-04-2088] [Citation(s) in RCA: 261] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Histone deacetylase (HDAC) inhibitors have emerged recently as promising anticancer agents. They arrest cells in the cell cycle and induce differentiation and cell death. The antitumor activity of HDAC inhibitors has been linked to their ability to induce gene expression through acetylation of histone and nonhistone proteins. However, it has recently been suggested that HDAC inhibitors may also enhance the activity of other cancer therapeutics, including radiotherapy. The purpose of this study was to evaluate the ability of HDAC inhibitors to radiosensitize human melanoma cells in vitro. EXPERIMENTAL DESIGN A panel of HDAC inhibitors that included sodium butyrate (NaB), phenylbutyrate, tributyrin, and trichostatin A were tested for their ability to radiosensitize two human melanoma cell lines (A375 and MeWo) using clonogenic cell survival assays. Apoptosis and DNA repair were measured by standard assays. RESULTS NaB induced hyperacetylation of histone H4 in the two melanoma cell lines and the normal human fibroblasts. NaB radiosensitized both the A375 and MeWo melanoma cell lines, substantially reducing the surviving fraction at 2 Gy (SF2), whereas it had no effect on the normal human fibroblasts. The other HDAC inhibitors, phenylbutyrate, tributyrin, and trichostatin A had significant radiosensitizing effects on both melanoma cell lines tested. NaB modestly enhanced radiation-induced apoptosis that did not correlate with survival but did correlate with functional impairment of DNA repair as determined based on the host cell reactivation assay. Moreover, NaB significantly reduced the expression of the repair-related genes Ku70 and Ku86 and DNA-dependent protein kinase catalytic subunit in melanoma cells at the protein and mRNA levels. Normal human fibroblasts showed no change in DNA repair capacity or levels of DNA repair proteins following NaB treatment. We also examined gamma-H2AX phosphorylation as a marker of radiation response to NaB and observed that compared with controls, gamma-H2AX foci persisted long after ionizing exposure in the NaB-treated cells. CONCLUSIONS HDAC inhibitors radiosensitize human tumor cells by affecting their ability to repair the DNA damage induced by ionizing radiation and that gamma-H2AX phosphorylation can be used as a predictive marker of radioresponse.
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Affiliation(s)
- Anupama Munshi
- Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Duan H, Heckman CA, Boxer LM. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol 2005; 25:1608-19. [PMID: 15713621 PMCID: PMC549348 DOI: 10.1128/mcb.25.5.1608-1619.2005] [Citation(s) in RCA: 204] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPalpha and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBPalpha binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas.
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MESH Headings
- Acetylation/drug effects
- Apoptosis
- Barbiturates/pharmacology
- Binding Sites/genetics
- CCAAT-Enhancer-Binding Proteins/metabolism
- Cell Cycle/drug effects
- Cell Line, Tumor
- Chromosomes, Human, Pair 14
- Chromosomes, Human, Pair 18
- Down-Regulation
- Enzyme Inhibitors/pharmacology
- Histone Deacetylase 2
- Histone Deacetylase Inhibitors
- Histone Deacetylases/metabolism
- Histone Deacetylases/physiology
- Histones/metabolism
- Humans
- Hydroxamic Acids/pharmacology
- Lymphoma, B-Cell/enzymology
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/metabolism
- Mutation/genetics
- Promoter Regions, Genetic/drug effects
- Promoter Regions, Genetic/genetics
- Protein Kinases/metabolism
- Proto-Oncogene Proteins c-bcl-2/genetics
- Proto-Oncogene Proteins c-bcl-2/metabolism
- RNA, Messenger/analysis
- RNA, Messenger/metabolism
- Repressor Proteins/antagonists & inhibitors
- Repressor Proteins/metabolism
- Repressor Proteins/physiology
- Translocation, Genetic
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Affiliation(s)
- Hong Duan
- Center for Molecular Biology in Medicine, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA, USA
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45
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Abstract
In addition to a variety of other novel agents, interest in histone deacetylase inhibitors (HDACIs) as antineoplastic drugs has recently accelerated and increasing numbers of these compounds have entered clinical trials in humans. HDACIs represent a prototype of molecularly targeted agents that perturb signal transduction, cell cycle-regulatory and survival-related pathways. Newer generation HDACIs have been introduced into the clinical arena that are considerably more potent on a molar basis than their predecessors and are beginning to show early evidence of activity, particularly in hematopoietic malignancies. In addition, there is an increasing appreciation of the fact that HDACIs may act through mechanisms other than induction of histone acetylation and, as in the case of other molecularly-targeted agents, it is conceivable that the ultimate role of HDACIs in cancer therapy will be as modulators of apoptosis induced by other cytotoxic agents. One particularly promising strategy involves attempts to combine HDACIs with other novel agents to promote tumour cell differentiation or apoptosis. The present review focuses on recent insights into the mechanisms by which HDACIs exert their anticancer effects, either alone or in combination with other compounds, as well as attempts to translate these findings into the clinic.
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Affiliation(s)
- Roberto R Rosato
- Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
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46
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Klass CM, Krug LT, Pozharskaya VP, Offermann MK. The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production. Blood 2005; 105:4028-34. [PMID: 15687238 PMCID: PMC1895088 DOI: 10.1182/blood-2004-09-3569] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Primary effusion lymphoma (PEL) is a B-cell lymphoma in which human herpesvirus-8 (HHV-8) is found within all tumor cells and represents a target for selectively destroying tumor cells. HHV-8 is latent in most PEL cells and, hence, resistant to antiviral agents that inhibit lytic replication. We demonstrate that PEL cell lines containing HHV-8 without and with coinfection with Epstein-Barr virus responded to the antiseizure medication valproate with entry into the lytic cascade and production of infectious virus. Minimal cell death occurred when noninfected BL-41 cells were incubated with valproate, whereas apoptosis occurred in response to valproate in PELs that supported lytic replication of HHV-8. The anti-viral agents ganciclovir and phosphonoformic acid (PFA) blocked valproate-induced production of infectious virus without blocking entry into the lytic cascade, and apoptosis occurred at levels that were as high as when virus production was not blocked. Ganciclovir and PFA also prevented most valproate-induced expression of the late lytic viral transcript open reading frame 26 (ORF-26), but they did not block the induction of either viral interleukin-6 (vIL-6) or viral G protein-coupled receptor (vGPCR). These studies provide evidence that incubation of PELs with valproate in the presence of ganciclovir or PFA can selectively target tumor cells for apoptosis without increasing viral load.
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Affiliation(s)
- Carmen M Klass
- Winship Cancer Institute, Emory University, 1365-B Clifton Rd NE, Atlanta, GA 30322, USA
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47
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Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005; 45:495-528. [PMID: 15822187 DOI: 10.1146/annurev.pharmtox.45.120403.095825] [Citation(s) in RCA: 450] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.
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Affiliation(s)
- Daryl C Drummond
- Hermes Biosciences, Inc., South San Francisco, California 94080, USA
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48
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Li H, Wu X. Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells. Biochem Biophys Res Commun 2004; 324:860-7. [PMID: 15474507 DOI: 10.1016/j.bbrc.2004.09.130] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2004] [Indexed: 12/23/2022]
Abstract
Histone deacetylase (HDAC) inhibitors have shown promise in clinical cancer therapy and to consistently induce p21WAF1/CIP1 expression in a p53-independent manner and via increased acetylation of the chromatin at the Sp1 sites in the p21WAF1/CIP1 promoter region. However, the exact mechanism by which HDAC inhibitors induce p21WAF1/CIP1 remains unclear. In this study, we observed that Trichostatin A (TSA), a HDAC inhibitor, induced strikingly p21WAF1/CIP1 expression in human cervical cancer (HeLa) cells, and this induction correlated with downregulation of c-myc expression. Coincident with this observation, knock down of c-myc with a c-myc specific small interfering RNA dramatically induced expression of p21WAF1/CIP1 in these cancer cells. These data suggest that c-myc may play a critical role in repression of p21WAF1/CIP1 expression in HeLa cells. More importantly, using chromatin immunoprecipitation assay, we observed for the first time that c-myc bound to the endogenous p21WAF1/CIP1 promoter in untreated HeLa cells, but not in TSA-treated cells. Taken together, TSA induced c-myc downregulation and release from the endogenous p21WAF1/CIP1 promoter contributes, at least partially, to transcriptional activation of the p21WAF1/CIP1 in HeLa cells.
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Affiliation(s)
- Hui Li
- Institute of Medical Virology, Wuhan University School of Medicine, Wuhan, Hubei 430071, PR China.
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Bandyopadhyay D, Mishra A, Medrano EE. Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53-mediated pathway. Cancer Res 2004; 64:7706-10. [PMID: 15520174 DOI: 10.1158/0008-5472.can-03-3897] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Melanoma cells typically express wild-type p53, yet they are notoriously resistant to DNA-damaging agents. Here, we show that sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor, induced apoptosis in human melanoma cells in a dose- and time-dependent manner. Apoptosis was associated with HDAC1-dependent induction of Bax and acetylation of p53. Down-regulation of HDAC1 by an antisense vector sensitized the cells to NaB-induced apoptosis, whereas its overexpression conferred resistance to this agent. Increased HDAC1 levels and activity impaired NaB-mediated activation of Bax promoter and Bax protein levels. Finally, using p53-null melanoma cell line and RNA interference in cells expressing wild-type p53 protein, we show that Bax induction and NaB-mediated apoptosis is p53 dependent.
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Affiliation(s)
- Debdutta Bandyopadhyay
- Huffington Center on Aging and Department of Dermatology, Baylor College of Medicine, Houston, Texas 77030, USA.
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50
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Nishida K, Komiyama T, Miyazawa SI, Shen ZN, Furumatsu T, Doi H, Yoshida A, Yamana J, Yamamura M, Ninomiya Y, Inoue H, Asahara H. Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. ACTA ACUST UNITED AC 2004; 50:3365-76. [PMID: 15476220 DOI: 10.1002/art.20709] [Citation(s) in RCA: 172] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To examine whether depsipeptide (FK228), a histone deacetylase (HDA) inhibitor, has inhibitory effects on the proliferation of synovial fibroblasts from rheumatoid arthritis (RA) patients, and to examine the effects of systemic administration of FK228 in an animal model of arthritis. METHODS Autoantibody-mediated arthritis (AMA) was induced in 19 male DBA/1 mice (6-7 weeks old); 10 of them were treated by intravenous administration of FK228 (2.5 mg/kg), and 9 were used as controls. The effects of FK228 were examined by radiographic, histologic, and immunohistochemical analyses and arthritis scores. RA synovial fibroblasts (RASFs) were obtained at the time of joint replacement surgery. In vitro effects of FK228 on cell proliferation were assessed by MTT assay. Cell morphology was examined by light and transmission electron microscopy. The effects on the expression of the cell cycle regulators p16INK4a and p21(WAF1/Cip1) were examined by real-time polymerase chain reaction and Western blot analysis. The acetylation status of the promoter regions of p16INK4a and p21(WAF1/Cip1) were determined by chromatin immunoprecipitation assay. RESULTS A single intravenous injection of FK228 (2.5 mg/ml) successfully inhibited joint swelling, synovial inflammation, and subsequent bone and cartilage destruction in mice with AMA. FK228 treatment induced histone hyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor alpha and interleukin-1beta in the synovial tissues of mice with AMA. FK228 inhibited the in vitro proliferation of RASFs in a dose-dependent manner. Treatment of cells with FK228 induced the expression of p16INK4a and up-regulated the expression of p21(WAF1/Cip1). These effects of FK228 on p16INK4a and p21(WAF1/Cip1) were related to the acetylation of the promoter region of the genes. CONCLUSION Our findings strongly suggest that systemic administration of HDA inhibitors may represent a novel therapeutic target in RA by means of cell cycle arrest in RASFs via induction of p16INK4a expression and increase in p21(WAF1/Cip1) expression.
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Affiliation(s)
- Keiichiro Nishida
- Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
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