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1
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Luo T, Li C, Zhou L, Sun H, Yang MM. Protein Acetylation in Age-Related Macular Degeneration: Mechanisms, Roles, and Therapeutic Perspectives. Invest Ophthalmol Vis Sci 2025; 66:30. [PMID: 40402519 DOI: 10.1167/iovs.66.5.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Age-related macular degeneration (AMD) is a top cause of severe vision loss and blindness in older adults globally. This multifactorial disease arises from genetic, environmental, and age-related factors. Protein acetylation modification plays a key role in AMD progression through both epigenetic and non-epigenetic pathways. This review comprehensively discusses the multidimensional impacts of protein acetylation in AMD, particularly its dynamic regulation of angiogenesis, oxidative stress, inflammatory responses, and cellular senescence. Recent evidence shows that histone acetylation modification inhibits choroidal neovascularization (CNV) formation by regulating vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1α) expression, while upregulating the complement inhibitor clusterin to maintain Bruch's membrane integrity. Additionally, the NAD+-dependent deacetylase SIRT1 modulates the deacetylation of transcription factors such as PGC-1α, NF-κB, and FOXO3, enhancing mitochondrial antioxidant function and suppressing inflammatory cascades to disrupt the vicious cycle of oxidative stress and chronic inflammation. In terms of cellular senescence, histone hypoacetylation and hyperacetylation of non-histone proteins (e.g., p53, E2F1) jointly cause retinal pigment epithelial (RPE) cell-cycle arrest and autophagy imbalance, accelerating AMD progression. Genetic evidence further reveals subtype-specific expression changes and epigenetic regulatory mechanisms of histone deacetylases (HDACs), such as HDAC11 and HDAC1/3, in AMD. This article explores the clinical significance of these findings and proposes a novel combined therapeutic strategy. It involves synergistically targeting acetylation homeostasis with HDAC inhibitors (e.g., TSA, AN7) and SIRT1 activators while inhibiting abnormal angiogenesis, repairing metabolic disorders, and restoring autophagy function. This dual-targeting approach may overcome current anti-VEGF therapy limitations and open new precision management avenues for AMD.
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Affiliation(s)
- Tianyi Luo
- The Second Clinical Medical College of Jinan University, Department of Ophthalmology, Shenzhen People's Hospital, Shenzhen, China
| | - Cunzi Li
- The Second Clinical Medical College of Jinan University, Department of Ophthalmology, Shenzhen People's Hospital, Shenzhen, China
| | - Lan Zhou
- Department of Ophthalmology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, China
- Post-doctoral Scientific Research Station of Basic Medicine, Jinan University, Guangzhou, China
| | - Hongyan Sun
- Department of Ophthalmology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, China
| | - Ming Ming Yang
- Department of Ophthalmology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, China
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2
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Yao W, Hu X, Wang X. Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases. Signal Transduct Target Ther 2024; 9:232. [PMID: 39278916 PMCID: PMC11403012 DOI: 10.1038/s41392-024-01918-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/11/2024] [Accepted: 06/30/2024] [Indexed: 09/18/2024] Open
Abstract
Histone post-translational modifications (HPTMs), as one of the core mechanisms of epigenetic regulation, are garnering increasing attention due to their close association with the onset and progression of diseases and their potential as targeted therapeutic agents. Advances in high-throughput molecular tools and the abundance of bioinformatics data have led to the discovery of novel HPTMs which similarly affect gene expression, metabolism, and chromatin structure. Furthermore, a growing body of research has demonstrated that novel histone modifications also play crucial roles in the development and progression of various diseases, including various cancers, cardiovascular diseases, infectious diseases, psychiatric disorders, and reproductive system diseases. This review defines nine novel histone modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation. It comprehensively introduces the modification processes of these nine novel HPTMs, their roles in transcription, replication, DNA repair and recombination, metabolism, and chromatin structure, as well as their involvement in promoting the occurrence and development of various diseases and their clinical applications as therapeutic targets and potential biomarkers. Moreover, this review provides a detailed overview of novel HPTM inhibitors targeting various targets and their emerging strategies in the treatment of multiple diseases while offering insights into their future development prospects and challenges. Additionally, we briefly introduce novel epigenetic research techniques and their applications in the field of novel HPTM research.
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Affiliation(s)
- Weiyi Yao
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Xinting Hu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
- Taishan Scholars Program of Shandong Province, Jinan, Shandong, 250021, China.
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3
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Lian B, Chen X, Shen K. Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer. Front Immunol 2023; 14:1164514. [PMID: 36969235 PMCID: PMC10034161 DOI: 10.3389/fimmu.2023.1164514] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs via mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.
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Affiliation(s)
| | | | - Kunwei Shen
- *Correspondence: Xiaosong Chen, ; Kunwei Shen,
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4
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Watanabe E, Yokoi A, Yoshida K, Sugiyama M, Kitagawa M, Nishino K, Yamamoto E, Niimi K, Yamamoto Y, Kajiyama H. Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma. Cancer Med 2023; 12:4543-4556. [PMID: 36106577 PMCID: PMC9972027 DOI: 10.1002/cam4.5243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/20/2022] [Accepted: 08/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. METHODS Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. RESULTS Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model. CONCLUSION Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.
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Affiliation(s)
- Eri Watanabe
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Kosuke Yoshida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Mai Sugiyama
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masami Kitagawa
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kimihiro Nishino
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Eiko Yamamoto
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kaoru Niimi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Yamamoto
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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5
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Effect of histone deacetylase 8 gene deletion on breast cancer cellular mechanism in vitro and in vivo study. Life Sci 2022; 311:121156. [DOI: 10.1016/j.lfs.2022.121156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 10/06/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022]
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6
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Desantis V, Solimando AG, Ribatti D. Epigenetic regulation of angiogenesis in tumor progression. ADVANCES IN GENETICS 2022; 110:31-54. [PMID: 39492151 DOI: 10.1016/bs.adgen.2022.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
Epigenetic is the study of those alterations regulating gene expression without altering DNA sequence and inherited by transmission through cell division. DNA hypomethylation, hypermethylation of tumor suppressor genes, aberrant histone modifications and/or specific microRNAs expression profiles contribute to tumor initiation and progression. In this review, we will discuss the role of epigenetic changes in the regulation of tumor angiogenesis.
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Affiliation(s)
- Vanessa Desantis
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Antonio G Solimando
- Department of Biomedical Sciences and Human Oncology (DIMO), Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
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Zhang Y, Lim D, Cai Z, Peng J, Jia B, Chu G, Zhang F, Dong C, Feng Z. Valproic acid counteracts polycyclic aromatic hydrocarbons (PAHs)-induced tumorigenic effects by regulating the polarization of macrophages. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 241:113779. [PMID: 35751934 DOI: 10.1016/j.ecoenv.2022.113779] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 05/31/2022] [Accepted: 06/14/2022] [Indexed: 06/15/2023]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are common persistent organic pollutants that are carcinogenic, teratogenic and mutagenic, causing a variety of harm to human health. In this study, we investigated the mechanism of how valproic acid (VPA) interferes with the carcinogenesis of PAHs protect normal tissues via the regulation of macrophages' function. Using the established model of transformed malignant breast cancer by 7,12-dimethylbenz[a]anthracene (DMBA), a representative PAH carcinogen, we discovered VPA induces the polarization of macrophages toward the M1 phenotype in the tumor tissues, facilitates the expression of pro-inflammatory cytokines such as IFN-γ, IL-12 and TNF-α, activates CD8+ T cells to secret Granzyme B thus to promote the apoptosis of tumor cells and suppresses the viability of vascular endothelial cells in tissue stroma of tumor. Surprisingly, VPA selectively induces macrophages to polarize towards the M2 phenotype in normal tissues and promotes the expression of anti-inflammatory cytokines such as IL-10 to enhance cell proliferation. Additionally, at the cellular level, VPA can directly regulate the polarization of macrophages to affect the growth of vascular endothelial cells by simulating the living conditions of tumor and normal cells. Collectively, VPA exerts an interventional effect on tumor growth and a protective effect on normal tissues by regulation of selective macrophages' polarization in their microenvironment.
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Affiliation(s)
- Yisha Zhang
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - David Lim
- Translational Health Research Institute, School of Health Sciences, Western Sydney University, Campbelltown, New South Wales, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
| | - Zuchao Cai
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Junxuan Peng
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Beidi Jia
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Guoliang Chu
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Fengmei Zhang
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Chao Dong
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
| | - Zhihui Feng
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
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8
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Abstract
Hypoxia is defined as a cellular stress condition caused by a decrease in oxygen below physiologically normal levels. Cells in the core of a rapidly growing solid tumor are faced with the challenge of inadequate supply of oxygen through the blood, owing to improper vasculature inside the tumor. This hypoxic microenvironment inside the tumor initiates a gene expression program that alters numerous signaling pathways, allowing the cancer cell to eventually evade adverse conditions and attain a more aggressive phenotype. A multitude of studies covering diverse aspects of gene regulation has tried to uncover the mechanisms involved in hypoxia-induced tumorigenesis. The role of epigenetics in executing widespread and dynamic changes in gene expression under hypoxia has been gaining an increasing amount of support in recent years. This chapter discusses, in detail, various epigenetic mechanisms driving the cellular response to hypoxia in cancer.
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Affiliation(s)
- Deepak Pant
- Epigenetics and RNA Processing Lab (ERPL), Indian Institute of Science Education and Research Bhopal, Bhopal, India
| | - Srinivas Abhishek Mutnuru
- Epigenetics and RNA Processing Lab (ERPL), Indian Institute of Science Education and Research Bhopal, Bhopal, India
| | - Sanjeev Shukla
- Epigenetics and RNA Processing Lab (ERPL), Indian Institute of Science Education and Research Bhopal, Bhopal, India.
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9
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Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, C S R. Multi-target weapons: diaryl-pyrazoline thiazolidinediones simultaneously targeting VEGFR-2 and HDAC cancer hallmarks. RSC Med Chem 2021; 12:1540-1554. [PMID: 34671737 PMCID: PMC8459325 DOI: 10.1039/d1md00125f] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
In anticancer drug discovery, multi-targeting compounds have been beneficial due to their advantages over single-targeting compounds. For instance, VEGFR-2 has a crucial role in angiogenesis and cancer management, whereas HDACs are well-known regulators of epigenetics and have been known to contribute significantly to angiogenesis and carcinogenesis. Herein, we have reported nineteen novel VEGFR-2 and HDAC dual-targeting analogs containing diaryl-pyrazoline thiazolidinediones and their in vitro and in vivo biological evaluation. In particular, the most promising compound 14c has emerged as a dual inhibitor of VEGFR-2 and HDAC. It demonstrated anti-angiogenic activity by inhibiting in vitro HUVEC proliferation, migration, and tube formation. Moreover, an in vivo CAM assay showed that 14c repressed new capillary formation in CAMs. In particular, 14c exhibited cytotoxicity potential on different cancer cell lines such as MCF-7, K562, A549, and HT-29. Additionally, 14c demonstrated significant potency and selectivity against HDAC4 in the sub-micromolar range. To materialize the hypothesis, we also performed molecular docking on the crystal structures of both VEGFR-2 (PDB ID: 1YWN) and HDAC4 (PDB-ID: 4CBY), which corroborated the designing and biological activity. The results indicated that compound 14c could be a potential lead to develop more optimized multi-target analogs with enhanced potency and selectivity.
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Affiliation(s)
- Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy Navi Mumbai India
| | - Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy Navi Mumbai India
| | - Sabreena Safuan
- Universiti Sains Malaysia School of Health Sciences Health Campus Universiti Sains Malaysia 16150 Kubang Kerian Kelantan Malaysia
| | - Alan P Kumar
- Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore
| | - Markus Schweipert
- Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt Germany
| | - Franz-Josef Meyer-Almes
- Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt Germany
| | - Ramaa C S
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy Navi Mumbai India
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10
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Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, Ramaa CS. Double-edged Swords: Diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis. Bioorg Chem 2021; 116:105350. [PMID: 34547645 DOI: 10.1016/j.bioorg.2021.105350] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/13/2021] [Accepted: 09/07/2021] [Indexed: 12/20/2022]
Abstract
In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.
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Affiliation(s)
- Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India
| | - Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India
| | - Sabreena Safuan
- School of Health Sciences, Health Campus Universiti Sains 16150 Kubang Kerian, Kelantan, Malaysia
| | - Alan P Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Markus Schweipert
- Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany
| | - Franz-Josef Meyer-Almes
- Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany.
| | - C S Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India.
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11
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Zhang B, Xu Z, Zhou W, Liu Z, Zhao J, Gou S. A light-controlled multi-step drug release nanosystem targeting tumor hypoxia for synergistic cancer therapy. Chem Sci 2021; 12:11810-11820. [PMID: 34659720 PMCID: PMC8442699 DOI: 10.1039/d1sc01888d] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 07/25/2021] [Indexed: 12/25/2022] Open
Abstract
Hypoxia is a major obstacle for cancer therapy due to its association with cell proliferation, tumor distant metastasis, and treatment resistance. In this study, a hypoxia-activated bifunctional prodrug (CC5) was designed, synthesized and encapsulated by a photo-responsive ruthenium complex-derived polymer to yield a light-controlled multi-step drug release system (CC5-RuCa) for synergistic therapy against tumor hypoxia. Under NIR irradiation, CC5-RuCa not only generated ROS to kill the cancer cells in the exterior of the tumor but also released the prodrug CC5 with enhanced intratumoral penetration in the severe hypoxia region inside the tumor tissue. In vivo studies on MDA-MB-231 xenograft models revealed that CC5-RuCa with preferential accumulation in the tumor exhibited highly efficient tumor regression through the synergistic effect of photodynamic therapy and hypoxia-activated chemotherapy.
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Affiliation(s)
- Bin Zhang
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University Nanjing 211189 China
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University Nanjing 211189 China
| | - Zichen Xu
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University Nanjing 211189 China
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University Nanjing 211189 China
| | - Wen Zhou
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University Nanjing 211189 China
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University Nanjing 211189 China
| | - Zhikun Liu
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University Nanjing 211189 China
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University Nanjing 211189 China
| | - Jian Zhao
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University Nanjing 211189 China
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University Nanjing 211189 China
| | - Shaohua Gou
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University Nanjing 211189 China
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University Nanjing 211189 China
- Nanjing Junruo Institute of Biomedicine Nanjing 211100 China
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12
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Munro SK, Balakrishnan B, Lissaman AC, Gujral P, Ponnampalam AP. Cytokines and pregnancy: Potential regulation by histone deacetylases. Mol Reprod Dev 2021; 88:321-337. [PMID: 33904218 DOI: 10.1002/mrd.23430] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 10/04/2020] [Accepted: 10/12/2020] [Indexed: 12/26/2022]
Abstract
Cytokines are important regulators of pregnancy and parturition. Aberrant expression of proinflammatory cytokines during pregnancy contributes towards preterm labor, pre-eclampsia, and gestational diabetes mellitus. The regulation of cytokine expression in human cells is highly complex, involving interactions between environment, transcription factors, and feedback mechanisms. Recent developments in epigenetic research have made tremendous advancements in exploring histone modifications as a key epigenetic regulator of cytokine expression and the effect of their signaling molecules on various organ systems in the human body. Histone acetylation and subsequent deacetylation by histone deacetylases (HDACs) are major epigenetic regulators of protein expression in the human body. The expression of various proinflammatory cytokines, their role in normal and abnormal pregnancy, and their epigenetic regulation via HDACs will be discussed in this review.
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Affiliation(s)
- Sheryl K Munro
- Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Biju Balakrishnan
- Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Abbey C Lissaman
- Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Palak Gujral
- Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Anna P Ponnampalam
- Liggins Institute, The University of Auckland, Auckland, New Zealand.,Department of Physiology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand.,Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand
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13
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Anticancer properties of chimeric HDAC and kinase inhibitors. Semin Cancer Biol 2020; 83:472-486. [PMID: 33189849 DOI: 10.1016/j.semcancer.2020.11.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/04/2020] [Accepted: 11/04/2020] [Indexed: 12/11/2022]
Abstract
Histone deacetylases (HDACs) are epigenetic regulators of chromatin condensation and decondensation and exert effects on the proliferation and spread of cancer. Thus, HDAC enzymes are promising drug targets for the treatment of cancer. Some HDAC inhibitors such as the hydroxamic acid derivatives vorinostat or panobinostat were already approved for the treatment of hematologic cancer diseases, and are under intensive investigation for their use in solid tumors. But there are also drawbacks of the clinical application of HDAC inhibitors like intrinsic or acquired drug resistance and, thus, new HDAC inhibitors with improved activities are sought for. Kinase inhibitors are very promising anticancer drugs and often showed synergistic anticancer effects in combination with HDAC inhibitors. Several hybrid molecules with HDAC and kinase inhibitory structural motifs were disclosed with even improved anticancer activities when compared with co-application of HDAC and receptor tyrosine kinase inhibitors. Chimeric inhibitors with HDAC inhibitory activities exert a rapidly growing field of research and only in this year several new dual HDAC/kinase inhibitors were disclosed. This review briefly summarizes the status and future perspective of the most advanced and promising dual HDAC/kinase inhibitors and their potential as anticancer drug candidates.
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14
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Ribatti D, Tamma R. Epigenetic control of tumor angiogenesis. Microcirculation 2020; 27:e12602. [PMID: 31863494 DOI: 10.1111/micc.12602] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/22/2019] [Accepted: 12/16/2019] [Indexed: 12/17/2022]
Abstract
The term "epigenetic" is used to refer to heritable alterations in chromatin that are not due to changes in DNA sequence. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of genes. The aim of this article is to analyze the role of epigenetic mechanisms in the control and regulation of tumor angiogenetic processes. The reversibility of epigenetic events in contrast to genetic aberrations makes them potentially suitable for therapeutic intervention. In this context, DNA methyltransferase (DNMT) and HDAC inhibitors indirectly-via the tumor cells-exhibit angiostatic effects in vivo, and inhibition of miRNAs can contribute to the development of novel anti-angiogenesis therapies.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
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15
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Zhang S, Gong Z, Oladimeji PO, Currier DG, Deng Q, Liu M, Chen T, Li Y. A high-throughput screening identifies histone deacetylase inhibitors as therapeutic agents against medulloblastoma. Exp Hematol Oncol 2019; 8:30. [PMID: 31788346 PMCID: PMC6858705 DOI: 10.1186/s40164-019-0153-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/04/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Medulloblastoma is the most frequently occurring malignant brain tumor in children. Current treatment strategies for medulloblastoma include aggressive surgery, cranio-spinal irradiation and adjuvant chemotherapy. Because current treatments can cause severe long-term side effects and are not curative, successful treatment remains a challenge. METHODS In this study, we employed a high-throughput cell viability assay to screen 12,800 compounds and to identify drug candidates with anti-proliferative properties for medulloblastoma cells. We also tested these compounds for attenuating medulloblastoma tumor development using mouse xenografts. RESULTS We identified two histone deacetylase inhibitors (dacinostat and quisinostat) with anti-proliferative properties for medulloblastoma cells. We showed that both compounds induce cytotoxicity, trigger cell apoptosis, and block cell cycle progression at the G2/M phase. In addition, dacinostat and quisinostat attenuated xenograft medulloblastoma growth in mice. CONCLUSIONS Our findings suggest that histone deacetylase inhibitors are potent therapeutic agents against medulloblastoma.
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Affiliation(s)
- Shanshan Zhang
- Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaojian Gong
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Peter O. Oladimeji
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Duane G. Currier
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Qipan Deng
- Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
| | - Ming Liu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Yong Li
- Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
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16
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Steinemann G, Dittmer A, Schmidt J, Josuttis D, Fähling M, Biersack B, Beindorff N, Jolante Koziolek E, Schobert R, Brenner W, Müller T, Nitzsche B, Höpfner M. Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer. Mol Oncol 2019; 13:2679-2696. [PMID: 31583820 PMCID: PMC6887589 DOI: 10.1002/1878-0261.12582] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/12/2019] [Accepted: 10/01/2019] [Indexed: 12/16/2022] Open
Abstract
Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton‐interfering pharmacophores, in testicular germ cell tumors (TGCT). The effectiveness of animacroxam was compared to that of the commonly applied chemotherapeutic cisplatin as well as the clinically approved HDAC inhibitor vorinostat. The antineoplastic and antiangiogenic effects of animacroxam on TGCT in vivo were assessed through exploratory animal studies and a modified chorioallantoic membrane assay, revealing that animacroxam has significant antitumor activity in TGCT. A novel positron emission tomography/MR‐imaging approach was applied to determine tumor volume and glucose [2‐fluoro‐2‐deoxy‐d‐glucose (18F‐FDG)] uptake in TGCT tumors, revealing reduced glucose uptake in animacroxam‐treated TGCTs and showing a dose‐dependent suppression of glycolytic enzymes, which led to a breakdown in glycolytic energy production. Furthermore, the observed antiangiogenic effects of animacroxam were related to its ability to inhibit endothelial cell–cell communication, as the expression of gap junction‐forming connexin 43 was strongly suppressed, and gap‐junctional intercellular mass transport was reduced. Our data suggest that the chimeric HDAC inhibitor animacroxam may become a promising candidate for the treatment of solid cancers and may serve as an interesting alternative to platinum‐based therapies.
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Affiliation(s)
- Gustav Steinemann
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | - Alexandra Dittmer
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | - Jacob Schmidt
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | - David Josuttis
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | - Michael Fähling
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Vegetative Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | | | - Nicola Beindorff
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Berlin Experimental Radionuclide Imaging Center (BERIC), Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | - Eva Jolante Koziolek
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Berlin Experimental Radionuclide Imaging Center (BERIC), Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Berlin, Germany
| | - Rainer Schobert
- Department of Organic Chemistry, University of Bayreuth, Germany
| | - Winfried Brenner
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Berlin Experimental Radionuclide Imaging Center (BERIC), Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany.,German Cancer Consortium (DKTK), Berlin, Germany
| | - Thomas Müller
- Clinic of Internal Medicine IV - Hematology and Oncology Division, Universitätsklinikum Halle (Saale), Germany
| | - Bianca Nitzsche
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
| | - Michael Höpfner
- Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Institute of Physiology, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Germany
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17
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Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise. Nat Rev Clin Oncol 2019; 17:91-107. [PMID: 31570827 DOI: 10.1038/s41571-019-0267-4] [Citation(s) in RCA: 297] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2019] [Indexed: 12/16/2022]
Abstract
Epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and tumour maintenance that can influence all of the recognized hallmarks of cancer. Despite regulatory approvals for the treatment of certain haematological malignancies, the efficacy of the first generation of epigenetic drugs (epi-drugs) in patients with solid tumours has been disappointing; however, successes have now been achieved in selected solid tumour subtypes, thanks to the development of novel compounds and a better understanding of cancer biology that have enabled precision medicine approaches. Several lines of evidence support that, beyond their potential as monotherapies, epigenetic drugs could have important roles in synergy with other anticancer therapies or in reversing acquired therapy resistance. Herein, we review the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other forms of anticancer therapy, including chemotherapy, radiation therapy, hormone therapy, molecularly targeted therapy and immunotherapy. We provide a critical appraisal of the preclinical rationale, completed clinical studies and ongoing clinical trials relating to combination therapies incorporating epi-drugs. Finally, we propose and discuss rational clinical trial designs and drug development strategies, considering key factors including patient selection, tumour biomarker evaluation, drug scheduling and response assessment and study end points, with the aim of optimizing the development of such combinations.
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Affiliation(s)
- Daphné Morel
- ATIP-Avenir Group, UMR981, INSERM (French National Institute of Health and Medical Research), Gustave Roussy Cancer Campus, Villejuif, France
| | - Daniel Jeffery
- Nuclear Dynamics Unit - UMR3664, National Centre for Scientific Research, Institut Curie, Paris, France
| | | | - Geneviève Almouzni
- Nuclear Dynamics Unit - UMR3664, National Centre for Scientific Research, Institut Curie, Paris, France.
| | - Sophie Postel-Vinay
- ATIP-Avenir Group, UMR981, INSERM (French National Institute of Health and Medical Research), Gustave Roussy Cancer Campus, Villejuif, France. .,Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France.
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18
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Camuzi D, de Amorim ÍSS, Ribeiro Pinto LF, Oliveira Trivilin L, Mencalha AL, Soares Lima SC. Regulation Is in the Air: The Relationship between Hypoxia and Epigenetics in Cancer. Cells 2019; 8:cells8040300. [PMID: 30939818 PMCID: PMC6523720 DOI: 10.3390/cells8040300] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022] Open
Abstract
Hypoxia is an inherent condition of tumors and contributes to cancer development and progression. Hypoxia-inducible factors (HIFs) are the major transcription factors involved in response to low O2 levels, orchestrating the expression of hundreds of genes involved in cancer hallmarks’ acquisition and modulation of epigenetic mechanisms. Epigenetics refers to inheritable mechanisms responsible for regulating gene expression, including genes involved in the hypoxia response, without altering the sequence of DNA bases. The main epigenetic mechanisms are DNA methylation, non-coding RNAs, and histone modifications. These mechanisms are highly influenced by cell microenvironment, such as O2 levels. The balance and interaction between these pathways is essential for homeostasis and is directly linked to cellular metabolism. Some of the major players in the regulation of HIFs, such as prolyl hydroxylases, DNA methylation regulators, and histone modifiers require oxygen as a substrate, or have metabolic intermediates as cofactors, whose levels are altered during hypoxia. Furthermore, during pathological hypoxia, HIFs’ targets as well as alterations in epigenetic patterns impact several pathways linked to tumorigenesis, such as proliferation and apoptosis, among other hallmarks. Therefore, this review aims to elucidate the intricate relationship between hypoxia and epigenetic mechanisms, and its crucial impact on the acquisition of cancer hallmarks.
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Affiliation(s)
- Diego Camuzi
- Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro CEP 20231-050, Brazil.
| | - Ísis Salviano Soares de Amorim
- Laboratório de Biologia do Câncer (LABICAN), Departamento de Biofisica e Biometria (DBB), Instituto de Biologia Roberto Alcântara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro CEP 20511-010, Brazil.
| | - Luis Felipe Ribeiro Pinto
- Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro CEP 20231-050, Brazil.
| | - Leonardo Oliveira Trivilin
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Federal do Espírito Santo (UFES), Espírito Santo CEP 29500-000, Brazil.
| | - André Luiz Mencalha
- Laboratório de Biologia do Câncer (LABICAN), Departamento de Biofisica e Biometria (DBB), Instituto de Biologia Roberto Alcântara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro CEP 20511-010, Brazil.
| | - Sheila Coelho Soares Lima
- Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro CEP 20231-050, Brazil.
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19
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Li Y, Xiao J, Zhang Q, Yu W, Liu M, Guo Y, He J, Liu Y. The association between anti-tumor potency and structure-activity of protein-kinases inhibitors based on quinazoline molecular skeleton. Bioorg Med Chem 2019; 27:568-577. [DOI: 10.1016/j.bmc.2018.12.032] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/19/2018] [Accepted: 12/22/2018] [Indexed: 02/03/2023]
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20
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Murad HY, Yu H, Luo D, Bortz EP, Halliburton GM, Sholl AB, Khismatullin DB. Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis. Mol Cancer Res 2019; 17:1087-1101. [PMID: 30617107 DOI: 10.1158/1541-7786.mcr-18-0782] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/22/2018] [Accepted: 01/03/2019] [Indexed: 12/30/2022]
Abstract
Chemical-based medicine that targets specific oncogenes or proteins often leads to cancer recurrence due to tumor heterogeneity and development of chemoresistance. This challenge can be overcome by mechanochemical disruption of cancer cells via focused ultrasound (FUS) and sensitizing chemical agents such as ethanol. We demonstrate that this disruptive therapy decreases the viability, proliferation rate, tumorigenicity, endothelial adhesion, and migratory ability of prostate cancer cells in vitro. It sensitized the cells to TNFR1-- and Fas--mediated apoptosis and reduced the expression of metastatic markers CD44 and CD29. Using a prostate cancer xenograft model, we observed that the mechanochemical disruption led to complete tumor regression in vivo. This switch to a nonaggressive cell phenotype was caused by ROS and Hsp70 overproduction and subsequent impairment of NFκB signaling. FUS induces mechanical perturbations of diverse cancer cell populations, and its combination with agents that amplify and guide remedial cellular responses can stop lethal cancer progression. IMPLICATIONS: Mechanochemical disruption therapy in which FUS is combined with ethanol can be curative for locally aggressive and castration-resistant prostate cancer.
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Affiliation(s)
- Hakm Y Murad
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Heng Yu
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Daishen Luo
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Emma P Bortz
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Gray M Halliburton
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana
| | - Andrew B Sholl
- Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana
| | - Damir B Khismatullin
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana. .,Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, New Orleans, Louisiana.,Tulane Cancer Center, Tulane University, New Orleans, Louisiana
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21
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Fountzilas E, Palmer G, Vining D, Tsimberidou AM. Prolonged Partial Response to Bevacizumab and Valproic Acid in a Patient With Glioblastoma. JCO Precis Oncol 2018; 2. [PMID: 31544169 DOI: 10.1200/po.18.00282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
| | | | - David Vining
- The University of Texas MD Anderson Cancer Center, Houston, TX
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22
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Tran LNK, Kichenadasse G, Sykes PJ. Combination Therapies Using Metformin and/or Valproic Acid in Prostate Cancer: Possible Mechanistic Interactions. Curr Cancer Drug Targets 2018; 19:368-381. [PMID: 30039761 DOI: 10.2174/1568009618666180724111604] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/25/2018] [Accepted: 07/10/2018] [Indexed: 12/22/2022]
Abstract
Prostate cancer (PCa) is the most frequent cancer in men. The evolution from local PCa to castration-resistant PCa, an end-stage of disease, is often associated with changes in genes such as p53, androgen receptor, PTEN, and ETS gene fusion products. Evidence is accumulating that repurposing of metformin (MET) and valproic acid (VPA) either when used alone, or in combination, with another therapy, could potentially play a role in slowing down PCa progression. This review provides an overview of the application of MET and VPA, both alone and in combination with other drugs for PCa treatment, correlates the responses to these drugs with common molecular changes in PCa, and then describes the potential for combined MET and VPA as a systemic therapy for prostate cancer, based on potential interacting mechanisms.
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Affiliation(s)
- Linh N K Tran
- Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, Australia.,University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam
| | - Ganessan Kichenadasse
- Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, Australia
| | - Pamela J Sykes
- Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, Australia
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23
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24
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Ma Y, Liu W, Zhang L, Jia G. Effects of Histone Deacetylase Inhibitor Panobinostat (LBH589) on Bone Marrow Mononuclear Cells of Relapsed or Refractory Multiple Myeloma Patients and Its Mechanisms. Med Sci Monit 2017; 23:5150-5157. [PMID: 29080899 PMCID: PMC5674922 DOI: 10.12659/msm.904232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background The aim of this study was to explore the impact of LBH589 alone or in combination with proteasome inhibitor bortezomib on multiple myeloma (MM) cell proliferation and its mechanism. Material/Methods MM cell line U266 and RRMM-BMMNC were treated with different concentrations of LBH589 alone or in combination with bortezomib. Cell proliferation was detected by MTT assay. Cell cycle and apoptosis was analyzed by flow cytometry. The protein and mRNA level of related genes was determined by Western blotting and qRT-PCR respectively. Results U266 cell and RRMM-BMMNC proliferation were inhibited by different concentrations of LBH589 (0, 10, 20, and 50 nmol/L) alone or 50 nmol/L of LBH589 in combination with bortezomib (10 and 20 nmol/L) in a dose- and time-dependent manner. LBH589 significantly induced G0/G1phase arrest and apoptosis in RRMM-BMMNC in a dose-dependent manner. The effects were significantly higher in all combined groups than in single-agent groups (all P<0.05). The mRNA level of Caspase3 and APAF1 were up-regulated gradually, while TOSO gene expression in RRMM-BMMNC was down-regulated gradually in a dose- and time-dependent manner. Moreover, LBH589 significantly induced hyperacetylation of histone H4, the protein level of PARP notably increased, and the level of Bcl-X decreased. Conclusions LBH589 can inhibit MM cell growth, block the cell cycle, and induce cell apoptosis, which has an anti-resistant effect on multidrug-resistant cells. LBH589 in combination with bortezomib has a synergistic effect on myeloma cells; its mechanism and reversal of drug resistance mechanism is involved in multiple changes in gene expression.
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Affiliation(s)
- Yanping Ma
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Wenhua Liu
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Ling Zhang
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Gu Jia
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
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25
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Enhanced anticancer efficacy of histone deacetyl inhibitor, suberoylanilide hydroxamic acid, in combination with a phosphodiesterase inhibitor, pentoxifylline, in human cancer cell lines and in-vivo tumor xenografts. Anticancer Drugs 2017; 28:1002-1017. [DOI: 10.1097/cad.0000000000000544] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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26
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Sato H, Uzu M, Kashiba T, Suzuki R, Fujiwara T, Okuzawa H, Ueno K. Sodium butyrate enhances the growth inhibitory effect of sunitinib in human renal cell carcinoma cells. Oncol Lett 2017; 14:937-943. [PMID: 28693255 DOI: 10.3892/ol.2017.6217] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 03/14/2017] [Indexed: 12/12/2022] Open
Abstract
Sunitinib (SU) is a small molecule that inhibits the receptor tyrosine kinase (RTK) signaling pathway, and has been clinically used to treat advanced renal cell carcinoma (RCC). However, SU is not always effective as RCC is a highly chemoresistant type of cancer. One of the factors that confer chemoresistance to RCC is a hypoxic condition. Lack of oxygen activates hypoxia-inducible factor (HIF) protein, which is followed by the upregulation of growth factors, including vascular endothelial growth factor and activation of the RTK signaling pathway. In this context, histone deacetylase inhibitors (HDACIs) are considered prominent combined agents for SU as they downregulate the expression of HIFs. Therefore, the present study aimed to investigate the effectiveness of combined treatment with SU and sodium butyrate (NaBu), an HDACI. Long-term exposure to these agents exerted a stronger growth inhibitory effect in RCC cell lines compared with single treatment groups. Furthermore, combined treatment suppressed HIF-2α protein, which was induced under hypoxic conditions. In addition, this combination sustained the activity of the RTK signaling pathway to the level of intact cells, although a single treatment with SU or NaBu was demonstrated to increase this activity. Overall, it is suggested that the combination of SU and NaBu is effective for overcoming drug resistance in RCC.
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Affiliation(s)
- Hiromi Sato
- Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Miaki Uzu
- Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Tatsuro Kashiba
- Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Rina Suzuki
- Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Takuya Fujiwara
- Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Hiroko Okuzawa
- Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Koichi Ueno
- Center of Preventive Medical Science, Chiba University, Chuo-ku, Chiba 260-8675, Japan
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27
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Berndsen RH, Abdul UK, Weiss A, Zoetemelk M, te Winkel MT, Dyson PJ, Griffioen AW, Nowak-Sliwinska P. Epigenetic approach for angiostatic therapy: promising combinations for cancer treatment. Angiogenesis 2017; 20:245-267. [DOI: 10.1007/s10456-017-9551-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 03/10/2017] [Indexed: 12/15/2022]
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28
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Pili R, Liu G, Chintala S, Verheul H, Rehman S, Attwood K, Lodge MA, Wahl R, Martin JI, Miles KM, Paesante S, Adelaiye R, Godoy A, King S, Zwiebel J, Carducci MA. Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial. Br J Cancer 2017; 116:874-883. [PMID: 28222071 PMCID: PMC5379145 DOI: 10.1038/bjc.2017.33] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 01/04/2017] [Accepted: 01/20/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus. METHODS Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs. RESULTS Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1-11.0) and 13.9 months (CI: 9.8-20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit. CONCLUSIONS The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.
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Affiliation(s)
- Roberto Pili
- Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
| | - Glenn Liu
- University of Wisconsin Carbone Cancer Center, Wisconsin, WI, USA
| | - Sreenivasulu Chintala
- Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
| | - Hendrick Verheul
- Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands
| | | | | | | | - Richard Wahl
- Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | | | | | | | - Remi Adelaiye
- Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
| | | | - Serina King
- Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
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Abstract
Chimeric compounds combine the structural features of inhibitors of histone deacetylases (HDACi) and tyrosine kinase inhibitors (TKi), and therefore unite the effects of a dual-targeting strategy in one compound. Here, we describe the generation of such hybrid molecules. Small molecules, known as TKi, are combined with a Zn2+ chelating motive, preferentially a hydroxamic acid, in addition. The resulting small molecules also can inhibit histone deacetylases, which are dependent on the catalytically active Zn2+. Moreover, we summarize how the growth-inhibitory effects of these combined compounds can be determined with a simple proliferation assay with a leukemic cell line.
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Affiliation(s)
- Siavosh Mahboobi
- Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, Regensburg, D-93040, Germany.
| | - Bernadette Pilsl
- Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, Regensburg, D-93040, Germany
| | - Andreas Sellmer
- Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, Regensburg, D-93040, Germany
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30
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Wang G, Wang JJ, Fu XL, Guang R, To SST. Advances in the targeting of HIF-1α and future therapeutic strategies for glioblastoma multiforme (Review). Oncol Rep 2016; 37:657-670. [PMID: 27959421 DOI: 10.3892/or.2016.5309] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/09/2016] [Indexed: 11/06/2022] Open
Abstract
Cell metabolism can be reprogrammed by tissue hypoxia leading to cell transformation and glioblastoma multiforme (GBM) progression. In response to hypoxia, GBM cells are able to express a transcription factor called hypoxia inducible factor-1 (HIF-1). HIF-1 belongs to a family of heterodimeric proteins that includes HIF-1α and HIF-1β subunits. HIF-1α has been reported to play a pivotal role in GBM development and progression. In the present review, we discuss the role of HIF-1α in glucose uptake, cancer proliferation, cell mobility and chemoresistance in GBM. Evidence from previous studies indicates that HIF-1α regulates angiogenesis, metabolic and transcriptional signaling pathways. Examples of such are the EGFR, PI3K/Akt and MAPK/ERK pathways. It affects cell migration and invasion by regulating glucose metabolism and growth in GBM cells. The present review focuses on the strategies through which to target HIF-1α and the related downstream genes highlighting their regulatory roles in angiogenesis, apoptosis, migration and glucose metabolism for the development of future GBM therapeutics. Combined treatment with inhibitors of HIF-1α and glycolysis may enhance antitumor effects in clinical settings.
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Affiliation(s)
- Gang Wang
- Department of Hospital Pharmacy, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Jun-Jie Wang
- Department of Hospital Pharmacy, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Xing-Li Fu
- Department of Hospital Pharmacy, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Rui Guang
- Department of Hospital Pharmacy, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Shing-Shun Tony To
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, Kowloon Hong Kong, SAR, P.R. China
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31
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Ramakrishnan S, Ku S, Ciamporcero E, Miles KM, Attwood K, Chintala S, Shen L, Ellis L, Sotomayor P, Swetzig W, Huang R, Conroy D, Orillion A, Das G, Pili R. HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma. BMC Cancer 2016; 16:617. [PMID: 27506904 PMCID: PMC4977667 DOI: 10.1186/s12885-016-2604-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 07/22/2016] [Indexed: 01/09/2023] Open
Abstract
Background Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. Methods Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student’s T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. Results Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. Conclusions Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2604-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Swathi Ramakrishnan
- Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.,Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - ShengYu Ku
- Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.,Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Eric Ciamporcero
- Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy
| | | | - Kris Attwood
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Sreenivasulu Chintala
- Genitourinary Program, Indiana University- Simon Cancer Center, Indianapolis, IN, USA
| | - Li Shen
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Leigh Ellis
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Paula Sotomayor
- Center for Integrative Medicine and Innovative Science-Universidad Andres Bello, Santiago, Chile
| | - Wendy Swetzig
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Ray Huang
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Dylan Conroy
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Ashley Orillion
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.,Genitourinary Program, Indiana University- Simon Cancer Center, Indianapolis, IN, USA
| | - Gokul Das
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Roberto Pili
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA. .,Genitourinary Program, Indiana University- Simon Cancer Center, Indianapolis, IN, USA.
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Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients. J Hum Genet 2016; 61:823-30. [PMID: 27251006 DOI: 10.1038/jhg.2016.61] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 04/25/2016] [Accepted: 05/06/2016] [Indexed: 01/14/2023]
Abstract
Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.
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Tandon N, Ramakrishnan V, Kumar SK. Clinical use and applications of histone deacetylase inhibitors in multiple myeloma. Clin Pharmacol 2016; 8:35-44. [PMID: 27226735 PMCID: PMC4866749 DOI: 10.2147/cpaa.s94021] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The incorporation of various novel therapies has resulted in a significant survival benefit in newly diagnosed and relapsed patients with multiple myeloma (MM) over the past decade. Despite these advances, resistance to therapy leads to eventual relapse and fatal outcomes in the vast majority of patients. Hence, there is an unmet need for new safe and efficacious therapies for continued improvement in outcomes. Given the role of epigenetic aberrations in the pathogenesis and progression of MM and the success of histone deacetylase inhibitors (HDACi) in other malignancies, many HDACi have been tried in MM. Various preclinical studies helped us to understand the antimyeloma activity of different HDACi in MM as a single agent or in combination with conventional, novel, and immune therapies. The early clinical trials of HDACi depicted only modest single-agent activity, but recent studies have revealed encouraging clinical response rates in combination with other antimyeloma agents, especially proteasome inhibitors. This led to the approval of the combination of panobinostat and bortezomib for the treatment of relapsed/refractory MM patients with two prior lines of treatment by the US Food and Drug Administration. However, it remains yet to be defined how we can incorporate HDACi in the current therapeutic paradigms for MM that will help to achieve longer disease control and significant survival benefits. In addition, isoform-selective and/or class-selective HDAC inhibition to reduce unfavorable side effects needs further evaluation.
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Affiliation(s)
- Nidhi Tandon
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | - Shaji K Kumar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
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Stahl M, Gore SD, Vey N, Prebet T. Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Expert Opin Investig Drugs 2016; 25:307-17. [DOI: 10.1517/13543784.2016.1146251] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Mendonca J, Sharma A, Kim HS, Hammers H, Meeker A, De Marzo A, Carducci M, Kauffman M, Shacham S, Kachhap S. Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. Oncotarget 2015; 5:6102-12. [PMID: 25026284 PMCID: PMC4171616 DOI: 10.18632/oncotarget.2174] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mislocalization of proteins is a common feature of cancer cells. Since localization of proteins is tightly linked to its function, cancer cells can inactivate function of a tumor suppressor protein through mislocalization. The nuclear exportin CRM1/XPO 1 is upregulated in many cancers. Targeting XPO 1 can lead to nuclear retention of cargo proteins such as p53, Foxo, and BRCA1 leading to cell cycle arrest and apoptosis. We demonstrate that selective inhibitors of nuclear export (SINE) can functionally inactivate XPO 1 in prostate cancer cells. Unlike the potent, but toxic, XPO 1 inhibitor leptomycin B, SINE inhibitors (KPT-185, KPT-330, and KPT-251) cause a decrease in XPO 1 protein level through the proteasomal pathway. Treatment of prostate cancer cells with SINE inhibitors lead to XPO 1 inhibition, as evaluated by RevGFP export assay, leading to nuclear retention of p53 and Foxo proteins, consequently, triggering apoptosis. Our data reveal that treatment with SINE inhibitors at nanomolar concentrations results in decrease in proliferation and colonogenic capacity of prostate cancer cells by triggering apoptosis without causing any cell cycle arrest. We further demonstrate that SINE inhibitors can be combined with other chemotherapeutics like doxorubicin to achieve enhanced growth inhibition of prostate cancer cells. Since SINE inhibitors offer increased bioavailability, reduced toxicity to normal cells, and are orally available they can serve as effective therapeutics against prostate cancer. In conclusion, our data reveals that nucleocytoplasmic transport in prostate cancer can be effectively targeted by SINE inhibitors.
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Affiliation(s)
- Janet Mendonca
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD; These authors contributed equally to this work
| | - Anup Sharma
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD; These authors contributed equally to this work
| | - Hae-Soo Kim
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Hans Hammers
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Alan Meeker
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Angelo De Marzo
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Michael Carducci
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | | | | | - Sushant Kachhap
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
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Kato Y, Egusa C, Maeda T, Tsuboi R. Combination of retinoid and histone deacetylase inhibitor produced an anti-tumor effect in cutaneous T-cell lymphoma by restoring tumor suppressor gene, retinoic acid receptorβ2, via histone acetylation. J Dermatol Sci 2015; 81:17-25. [PMID: 26596218 DOI: 10.1016/j.jdermsci.2015.10.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 09/24/2015] [Accepted: 10/21/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Retinoids exert anti-proliferative, differentiative, and apoptosis-inducing effects through their receptors. Retinoic acid receptor (RAR) β2 behaves as a tumor suppressor gene, and its expression is suppressible by DNA methylation in many malignancies. OBJECTIVE We aimed to determine whether combining a retinoid, Am 80, with a histone deacetylase inhibitor, MS-275, could suppress tumor growth in a RARβ2-negative human cutaneous T cell lymphoma (CTCL) cell lines and freshly isolated primary CTCL cells, and to elucidate the epigenetic mechanism behind the phenomena. METHODS SeAx cells were implanted subcutaneously in NOD-SCID mice which were randomly divided into four groups and treated with either Am80, MS-275 by oral gavage (five days/week), or a combination of the two agents. Cell proliferation assay, methylation-specific PCR, flow cytometric analysis of cell cycle and apoptosis and chromatin immunoprecipitation assay were employed. RESULTS Quantitative PCR analysis revealed that RARβ2 gene expression was restored only by this combination rather than by either of the agents singly. Restored retinoid sensitivity was observed in combining retinoid with a histone deacetylase inhibitor significantly inhibited cell growth in vitro, suppressed subcutaneously transplanted tumor growth, and prolonged survival of tumor-bearing mice in vivo by more strongly inducing apoptosis and p21 expression in CTCL cells than either agent alone. In the combination treatment, the histone H4 acetylation level at lysine 12 and 16 in the promoter region increased after restoration of RARβ2 expression although the DNA methylation of RARβ2 remained unchanged. CONCLUSION This is the first report of histone acetylation as the primary event in the restoration of RARβ2. Inducible RARβ2 expression may serve as a reliable predictor for tumor response in patients undergoing 'epigenetic & differentiation' therapy.
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Affiliation(s)
- Yukihiko Kato
- Department of Dermatology, Tokyo Medical University, Tokyo Japan; Department of Dermatology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.
| | - Chizu Egusa
- Department of Dermatology, Tokyo Medical University, Tokyo Japan
| | - Tatsuo Maeda
- Department of Dermatology, Tokyo Medical University, Tokyo Japan
| | - Ryoji Tsuboi
- Department of Dermatology, Tokyo Medical University, Tokyo Japan
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Ganai SA. Strategy for enhancing the therapeutic efficacy of histone deacetylase inhibitor dacinostat: the novel paradigm to tackle monotonous cancer chemoresistance. Arch Pharm Res 2015:10.1007/s12272-015-0673-9. [PMID: 26481010 DOI: 10.1007/s12272-015-0673-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/13/2015] [Indexed: 01/01/2023]
Abstract
Histone deacetylases (HDACs) regulate gene expression by creating the closed state of chromatin via histone hypoacetylation. Histone acetylation deregulation caused by aberrant expression of classical HDACs leads to imprecise gene regulation culminating in various diseases including cancer. Histone deacetylase inhibitors (HDACi), the small-molecules modulating the biological function of HDACs have shown promising results in inducing cell cycle arrest, differentiation and apoptosis in tumour models. HDACi do not show desired cytotoxic effect when used in monotherapy due to triggering of various resistance mechanisms in cancer cells emphasizing the desperate need of novel strategies that can be used to overcome such challenges. The present article provides intricate details about the novel HDACi dacinostat (LAQ-824) against multiple myeloma and acute myeloid leukaemia. The distinct molecular mechanisms modulated by dacinostat in exerting cytotoxic effect against the defined malignancies have also been detailed. The article also explains the strategy that can be used to circumvent the conventional therapy resistant cases and for enhancing the therapeutic efficacy of dacinostat for effective anticancer therapy.
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Affiliation(s)
- Shabir Ahmad Ganai
- Plant Virology and Molecular Pathology Laboratory, Division of Plant Pathology, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Srinagar, 190025, India.
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Nidhyanandan S, Boreddy TS, Chandrasekhar KB, Reddy ND, Kulkarni NM, Narayanan S. Phosphodiesterase inhibitor, pentoxifylline enhances anticancer activity of histone deacetylase inhibitor, MS-275 in human breast cancer in vitro and in vivo. Eur J Pharmacol 2015. [PMID: 26209365 DOI: 10.1016/j.ejphar.2015.07.048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
MS-275, a histone deacetylase inhibitor (HDACi), is undergoing clinical trials for treatment of various cancers. Pentoxifylline, a nonselective phosphodiesterase (PDE) inhibitor, has been shown to increase the effectiveness of antitumor chemotherapy. In the present study, the potential anti-cancer activity of MS-275 in combination with pentoxifylline in panel of cell lines and human breast cancer xenograft model were examined. A Panel of cancer cell lines were treated with MS-275 and pentoxifylline to determine their impact on cellular proliferation, cell cycle regulation, apoptosis, anti-angiogenesis. The in vivo activities of MS-275 and pentoxifylline were assessed in a Matrigel plug angiogenesis model and human breast cancer (MDA-MB-231) xenograft model. Combination of MS-275 with pentoxifylline showed enhanced anti-proliferative activity in a panel of cancer cell lines (HCT 116, MCF-7, PC3 and MDA-MB-231). Apoptotic studies performed using, Hoechst staining and cell cycle analysis reveal that this combination at the lower concentrations induces apoptosis downstream of the HDAC inhibition and PDE regulation. Further, combination showed enhanced antiangiogenic activity in Matrigel tube formation assay using HUVECs and in Matrigel plug assay in vivo. A significant inhibition (P<0.001) of tumor growth was observed in mice bearing MDA-MB-231 breast cancer xenograft treated with the combination of MS-275 (5mg/kg p.o.) and pentoxifylline (60 mg/kg i.p.) than treatments alone, without much signs of toxicity. Taken together, our study demonstrated enhanced anticancer activity of MS-275 and pentoxifylline combination both in vitro and in vivo with reduced toxicity. However, further studies are required to understand the mechanism for this combination effect.
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Affiliation(s)
- Saranya Nidhyanandan
- Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Old Mahabalipuram Road, Sozhanganallur, Chennai 600119, Tamil Nadu, India; Jawaharlal Nehru Technological University Anantapur, Anantapur, 515 002 Andhra Pradesh, India.
| | - Thippeswamy S Boreddy
- Department of Biomedical Science, College of Pharmacy, Shaqra University, Al-Dawadmi, Kingdom of Saudi Arabia
| | | | - Neetinkumar D Reddy
- Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Old Mahabalipuram Road, Sozhanganallur, Chennai 600119, Tamil Nadu, India
| | - Nagaraj M Kulkarni
- Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Old Mahabalipuram Road, Sozhanganallur, Chennai 600119, Tamil Nadu, India
| | - Shridhar Narayanan
- Foundation for Neglected Disease Research, Sir M Visvesvaraya Institute of Technology, International Airport Road, Yelahanka, Bangaluru 562157, India
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Yu XD, Guo ZS. Epigenetic drugs for cancer treatment and prevention: mechanisms of action. Biomol Concepts 2015; 1:239-51. [PMID: 25962000 DOI: 10.1515/bmc.2010.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
This review provides a brief overview of the basic principles of epigenetic gene regulation and then focuses on recent development of epigenetic drugs for cancer treatment and prevention with an emphasis on the molecular mechanisms of action. The approved epigenetic drugs are either inhibitors of DNA methyltransferases or histone deacetylases (HDACs). Future epigenetic drugs could include inhibitors for histone methyltransferases and histone demethylases and other epigenetic enzymes. Epigenetic drugs often function in two separate yet interrelated ways. First, as epigenetic drugs per se, they modulate the epigenomes of premalignant and malignant cells to reverse deregulated epigenetic mechanisms, leading to an effective therapeutic strategy (epigenetic therapy). Second, HDACs and other epigenetic enzymes also target non-histone proteins that have regulatory roles in cell proliferation, migration and cell death. Through these processes, these drugs induce cancer cell growth arrest, cell differentiation, inhibition of tumor angiogenesis, or cell death via apoptosis, necrosis, autophagy or mitotic catastrophe (chemotherapy). As they modulate genes which lead to enhanced chemosensitivity, immunogenicity or dampened innate antiviral response of cancer cells, epigenetic drugs often show better efficacy when combined with chemotherapy, immunotherapy or oncolytic virotherapy. In chemoprevention, dietary phytochemicals such as epigallocatechin-3-gallate and sulforaphane act as epigenetic agents and show efficacy by targeting both cancer cells and the tumor microenvironment. Further understanding of how epigenetic mechanisms function in carcinogenesis and cancer progression as well as in normal physiology will enable us to establish a new paradigm for intelligent drug design in the treatment and prevention of cancer.
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Attenuation of choroidal neovascularization by histone deacetylase inhibitor. PLoS One 2015; 10:e0120587. [PMID: 25807249 PMCID: PMC4373846 DOI: 10.1371/journal.pone.0120587] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 01/24/2015] [Indexed: 01/13/2023] Open
Abstract
Choroidal neovascularization (CNV) is a blinding complication of age-related macular degeneration that manifests as the growth of immature choroidal blood vessels through Bruch’s membrane, where they can leak fluid or hemorrhage under the retina. Here, we demonstrate that the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) can down-regulate the pro-angiogenic hypoxia-inducible factor-1α and vascular endothelial growth factor (VEGF), and up-regulate the anti-angiogenic and neuro-protective pigment epithelium derived factor in human retinal pigment epithelial (RPE) cells. Most strikingly, TSA markedly down-regulates the expression of VEGF receptor-2 in human vascular endothelial cells and, thus, can knock down pro-angiogenic cell signaling. Additionally, TSA suppresses CNV-associated wound healing response and RPE epithelial-mesenchymal transdifferentiation. In the laser-induced model of CNV using C57Bl/6 mice, systemic administration of TSA significantly reduces fluorescein leakage and the size of CNV lesions at post—laser days 7 and 14 as well as the immunohistochemical expression of VEGF, VEGFR2, and smooth muscle actin in CNV lesions at post-laser day 7. This report suggests that TSA, and possibly HDACi’s in general, should be further evaluated for their therapeutic potential for the treatment of CNV.
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Lee EQ, Reardon DA, Schiff D, Drappatz J, Muzikansky A, Grimm SA, Norden AD, Nayak L, Beroukhim R, Rinne ML, Chi AS, Batchelor TT, Hempfling K, McCluskey C, Smith KH, Gaffey SC, Wrigley B, Ligon KL, Raizer JJ, Wen PY. Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro Oncol 2015; 17:862-7. [PMID: 25572329 DOI: 10.1093/neuonc/nou350] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 12/05/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Panobinostat is a histone deacetylase inhibitor with antineoplastic and antiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat combined with bevacizumab in patients with recurrent high-grade glioma (HGG). METHODS Patients with recurrent HGG were treated with oral panobinostat 30 mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrent glioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory arm of the study. RESULTS At interim analysis, the GBM arm did not meet criteria for continued accrual, and the GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 rate was 30.4% (95%, CI 12.4%-50.7%), median PFS was 5 months (range, 3-9 months), and median overall survival (OS) was 9 months (range, 6-19 months). Accrual in the AG arm continued to completion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%-73%), median PFS was 7 months (range, 2-10 months), and median OS was 17 months (range, 5 months-27 months). CONCLUSIONS This phase II study of panobinostat and bevacizumab in participants with recurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed. Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did not significantly improve PFS6 compared with historical controls of bevacizumab monotherapy in either cohort.
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Affiliation(s)
- Eudocia Q Lee
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - David A Reardon
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - David Schiff
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Jan Drappatz
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Alona Muzikansky
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Sean A Grimm
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Andrew D Norden
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Lakshmi Nayak
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Rameen Beroukhim
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Mikael L Rinne
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Andrew S Chi
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Tracy T Batchelor
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Kelly Hempfling
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Christine McCluskey
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Katrina H Smith
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Sarah C Gaffey
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Brendan Wrigley
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Keith L Ligon
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Jeffrey J Raizer
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
| | - Patrick Y Wen
- Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.)
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Ahn SH, Choi JY, Kim DW, Lee DY, Jeon EH, Jeong WJ, Paik JH. Targeting HIF1α Peri-operatively Increased Post-surgery Survival in a Tongue Cancer Animal Model. Ann Surg Oncol 2015; 22:3041-8. [DOI: 10.1245/s10434-014-4323-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Indexed: 12/22/2022]
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Wu CP, Hsiao SH, Su CY, Luo SY, Li YQ, Huang YH, Hsieh CH, Huang CW. Human ATP-Binding Cassette transporters ABCB1 and ABCG2 confer resistance to CUDC-101, a multi-acting inhibitor of histone deacetylase, epidermal growth factor receptor and human epidermal growth factor receptor 2. Biochem Pharmacol 2014; 92:567-76. [PMID: 25450670 DOI: 10.1016/j.bcp.2014.10.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/06/2014] [Accepted: 10/07/2014] [Indexed: 01/01/2023]
Abstract
CUDC-101 is the first small-molecule inhibitor designed to simultaneously inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and histone deacetylase (HDAC) in cancer cells. Recently, in its first in human phase I study, CUDC-101 showed promising single agent activity against advanced solid tumors and favorable pharmacodynamic profile. However, the risk of developing drug resistance to CUDC-101 can still present a significant therapeutic challenge to clinicians in the future. One of the most common mechanisms of developing multidrug resistance (MDR) in cancer is associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2. Together, they are able to reduce the efficacy and modify the pharmacological properties of anti-cancer agents, including many small molecule tyrosine kinase inhibitors (TKIs). Here, we have investigated the impact of ABCB1 and ABCG2 on the efficacy of CUDC-101 in human cancer cells. We revealed that although CUDC-101 has potent antiproliferative and proapoptotic activities against most cancer cell lines, the overexpression of ABCB1 or ABCG2 in cancer cells significantly reduced the activity of CUDC-101 against HDAC, EGFR and HER2, as well as its cytotoxicity and proapoptotic activity. Moreover, we showed that CUDC-101 modulated the function of both transporters without affecting the protein expression of either ABCB1 or ABCG2. More importantly, our study provides support for the rationale of combining CUDC-101 with modulators of ABC drug transporters to improve drug efficacy and overcome multidrug resistance associated with the overexpression of ABCB1 and ABCG2.
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Affiliation(s)
- Chung-Pu Wu
- Department of Physiology and Pharmacology; Graduate Institute of Biomedical Sciences; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
| | | | | | - Shi-Yu Luo
- Graduate Institute of Biomedical Sciences
| | | | - Yang-Hui Huang
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Chia-Hung Hsieh
- Graduate Institute of Basic Medical Science; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chiun-Wei Huang
- Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
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Monitoring Tumor Response After Histone Deacetylase Inhibitor Treatment Using 3′-Deoxy-3′-[18F]-fluorothymidine PET. Mol Imaging Biol 2014; 17:394-402. [PMID: 25323103 DOI: 10.1007/s11307-014-0774-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Multitarget inhibitors derived from crosstalk mechanism involving VEGFR2. Future Med Chem 2014; 6:1771-89. [DOI: 10.4155/fmc.14.112] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Seven VEGFR small-molecule inhibitors have been approved by the US FDA as anticancer drugs, which confirms the therapeutic value of angiogenesis inhibitors. However, much more evidence indicates that VEGFR inhibition alone is usually not sufficient to block the tumor progress. The potential of some agents targeting VEGFR owes partially to the simultaneous inhibition of additional targets in other signaling pathways. In this review, the crosstalk between VEGFR2 and the additional targets in other signaling pathways, such as EGFR, MET, FGFR, PDGFR, c-Kit, Raf, PI3K and HDAC, and the synergistic effects derived from multitarget activities against these crosstalks are discussed. We also briefly describe the multitarget inhibitors in clinical trials or reported in the literature and patents under the different multitarget categories involving VEGFR2.
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Bose P, Dai Y, Grant S. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. Pharmacol Ther 2014; 143:323-336. [PMID: 24769080 PMCID: PMC4117710 DOI: 10.1016/j.pharmthera.2014.04.004] [Citation(s) in RCA: 215] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 04/10/2014] [Indexed: 02/05/2023]
Abstract
Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.
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Affiliation(s)
- Prithviraj Bose
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yun Dai
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Steven Grant
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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Andersen CL, Bjørn ME, McMullin MF, Harrison C, Samuelsson J, Ejerblad E, Zweegman S, Fernandes S, Bareford D, Knapper S, Löfvenberg E, Linder O, Andreasson B, Ahlstrand E, Jensen MK, Bjerrum OW, Vestergaard H, Larsen H, Klausen TW, Mourits-Andersen T, Skov V, Thomassen M, Kruse T, Grønbæk K, Hasselbalch HC. Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat. Leuk Res 2014; 38:816-21. [DOI: 10.1016/j.leukres.2014.04.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 04/02/2014] [Accepted: 04/04/2014] [Indexed: 11/26/2022]
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Li XQ, Ouyang ZG, Zhang SH, Liu H, Shang Y, Li Y, Zhen YS. Synergy of enediyne antibiotic lidamycin and temozolomide in suppressing glioma growth with potentiated apoptosis induction. J Neurooncol 2014; 119:91-100. [PMID: 24842385 DOI: 10.1007/s11060-014-1477-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 04/30/2014] [Indexed: 12/15/2022]
Abstract
The present work evaluated the synergistic efficacy of an enediyne antibiotic lidamycin (LDM) plus temozolomide (TMZ) against glioma in vitro and in vivo. LDM plus TMZ inhibited the proliferations of rat glioma C6 cells and human glioma U87 cells more efficiently than the single usage of LDM or TMZ. In addition, LDM also potentiated the apoptosis inductions by TMZ in rat C6 cells and human U87 cells. Meanwhile, the results of TdT-mediated dUTP Nick End Labeling assay for subcutaneous U87 tumor sections indicated an enhanced apoptosis induction in vivo by LDM plus TMZ, which confirmed the high potency of the combination for glioma therapy. As determined by Western blot, apoptosis signal pathways in C6 cells and U87 cells were markedly affected by the synergistic alteration of P53, bax, procaspase 3, and bcd-2 expression. In both subcutaneous U87 xenograft and C6 intracerebral orthotopic implant model, TMZ-induced glioma growth suppression was dramatically potentiated by LDM. As shown, the combination therapy efficiently reduced the tumor volumes and tumor weights of the human glioma U87 xenograft. Kaplan-Meier assay revealed that LDM plus TMZ dramatically prolonged the life span of C6 intracerebral tumor-bearing rats with decreased tumor size. This study indicates that the combination of LDM with TMZ might be a promising strategy for glioma therapy.
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Affiliation(s)
- Xing-Qi Li
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
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Bezecny P. Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience. Med Oncol 2014; 31:985. [PMID: 24838514 DOI: 10.1007/s12032-014-0985-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Accepted: 04/26/2014] [Indexed: 12/22/2022]
Abstract
Epigenetic mechanisms are increasingly recognized as a major factor contributing to pathogenesis of cancer including glioblastoma, the most common and most malignant primary brain tumour in adults. Enzymatic modifications of histone proteins regulating gene expression are being exploited for therapeutic drug targeting. Over the last decade, numerous studies have shown promising results with histone deacetylase (HDAC) inhibitors in various malignancies. This article provides a brief overview of mechanism of anti-cancer effect and pharmacology of HDAC inhibitors and summarizes results from pre-clinical and clinical studies in glioblastoma. It analyses experience with HDAC inhibitors as single agents as well as in combination with targeted agents, cytotoxic chemotherapy and radiotherapy. Hallmark features of glioblastoma, such as uncontrolled cellular proliferation, invasion, angiogenesis and resistance to apoptosis, have been shown to be targeted by HDAC inhibitors in experiments with glioblastoma cell lines. Vorinostat is the most advanced HDAC inhibitor that entered clinical trials in glioblastoma, showing activity in recurrent disease. Multiple phase II trials with vorinostat in combination with targeted agents, temozolomide and radiotherapy are currently recruiting. While the results from pre-clinical studies are encouraging, early clinical trials showed only modest benefit and the value of HDAC inhibitors for clinical practice will need to be confirmed in larger prospective trials. Further research in epigenetic mechanisms driving glioblastoma pathogenesis and identification of molecular subtypes of glioblastoma is needed. This will hopefully lead to better selection of patients who will benefit from treatment with HDAC inhibitors.
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Affiliation(s)
- Pavel Bezecny
- Rosemere Cancer Centre, Lancashire Teaching Hospitals NHS Foundation Trust, Sharoe Green Lane, Preston, PR2 9HT, UK,
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Zhang L, Han Y, Jiang Q, Wang C, Chen X, Li X, Xu F, Jiang Y, Wang Q, Xu W. Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy. Med Res Rev 2014; 35:63-84. [PMID: 24782318 DOI: 10.1002/med.21320] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Pharmacological inhibition of histone deacetylases (HDACs) has been successfully applied in the treatment of a wide range of disorders, including Parkinson's disease, infection, cardiac diseases, inflammation, and especially cancer. HDAC inhibitors (HDACIs) have been proved to be effective antitumor agents by various stages of investigation. At present, there are two opposite focuses of HDACI design in the cancer therapy, highly selective inhibitor strategy and dual- or multitargeted inhibitors. The former method, which is supposed to elucidate the function of individual HDAC and provide candidate inhibitors with fewer side effects, has been widely accepted by the inhibitor developer. The latter approach, though less practiced, has promising potential for the antitumor therapy based on HDACIs. Effective HDACIs, some of which are in clinic anticancer research, have been developed by both methods. In order to gain insight into HDACI design, the strategies and achievements of the two diverse methods are reviewed.
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Affiliation(s)
- Lei Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, China
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