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Zhou Y, Luo Q, Gu L, Tian X, Zhao Y, Zhang Y, Wang F. Histone Deacetylase Inhibitors Promote the Anticancer Activity of Cisplatin: Mechanisms and Potential. Pharmaceuticals (Basel) 2025; 18:563. [PMID: 40283998 PMCID: PMC12030095 DOI: 10.3390/ph18040563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Cisplatin is a widely used DNA-targeting anticancer drug. Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation, changing chromatin structure and accessibility of genomic DNA by the genotoxic drug. As a consequence, HDACi could promote cisplatin cytotoxicity. Hence, the underlying mechanisms by which HDACi alter the action pathways of cisplatin to promote its anticancer activity have attracted increasing attention during the past decades. It has been commonly accepted that HDACi elevate the acetylation level of histones to release genomic DNA to cisplatin attack, increasing the level of cisplatin-induced DNA lesions to promote cisplatin cytotoxicity. However, how the HDACi-enhanced cisplatin lesion on DNA impacts the downstream biological processes, and whether the promotion of HDACi to cisplatin activity is attributed to their inherent anticancer activity or to their induced elevation of histone acetylation, have been in debate. Several studies showed that HDACi-enhanced DNA lesion could promote cisplatin-induced apoptosis, cell cycle arrest, and reactive oxygen species (ROS) generation, subsequently promoting cisplatin efficiency. In contrast, HDACi-induced elimination of ROS and inhibition of ferroptosis were thought to be the main ways by which HDACi protect kidneys from acute injury caused by cisplatin. Based on our recent research, we herein review and discuss the advances in research on the mechanisms of HDACi-induced enhancement in cisplatin cytotoxicity. Given that histone acetyltransferase (HAT) inhibitors also show an effect enhancing cisplatin cytotoxicity, we will discuss the diverse roles of histone acetylation in cancer therapy in addition to the synergistic anticancer effect and potential of HDACi with genotoxic drugs and radiotherapy.
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Affiliation(s)
- Yang Zhou
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qun Luo
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liangzhen Gu
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiao Tian
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yao Zhao
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanyan Zhang
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
| | - Fuyi Wang
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- National Centre for Mass Spectrometry in Beijing, Beijing 100190, China
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2
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Yuan X, Rosen JM. Histone acetylation modulators in breast cancer. Breast Cancer Res 2025; 27:49. [PMID: 40165290 PMCID: PMC11959873 DOI: 10.1186/s13058-025-02006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/19/2025] [Indexed: 04/02/2025] Open
Abstract
Breast cancer is the most prevalent cancer in women worldwide. Aberrant epigenetic reprogramming such as dysregulation of histone acetylation has been associated with the development of breast cancer. Histone acetylation modulators have been targeted as potential treatments for breast cancer. This review comprehensively discusses the roles of these modulators and the effects of their inhibitors on breast cancer. In addition, epigenetic reprogramming not only affects breast cancer cells but also the immunosuppressive myeloid cells, which can facilitate breast cancer progression. Therefore, the review also highlights the roles of these immunosuppressive myeloid cells and summarizes how histone acetylation modulators affect their functions and phenotypes. This review provides insights into histone acetylation modulators as potential therapeutic targets for breast cancer.
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Affiliation(s)
- Xueying Yuan
- Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA
| | - Jeffrey M Rosen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA.
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3
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Carreiras MDC, Marco-Contelles J. Hydrazides as Inhibitors of Histone Deacetylases. J Med Chem 2024; 67:13512-13533. [PMID: 39092855 DOI: 10.1021/acs.jmedchem.4c00541] [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: 08/04/2024]
Abstract
In this Perspective, we have brought together available biological evidence on hydrazides as histone deacetylase inhibitors (HDACis) and as a distinct type of Zn-binding group (ZBG) to be reviewed for the first time in the literature. N-Alkyl hydrazides have transformed the field, providing innovative and practical chemical tools for selective and effective inhibition of specific histone deacetylase (HDAC) enzymes, in addition to the usual hydroxamic acid and o-aminoanilide ZBG-bearing HDACis. This has enabled efficient targeting of neurodegenerative diseases such as Alzheimer's disease, cancer, cardiovascular diseases, and protozoal pathologies.
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Affiliation(s)
- Maria do Carmo Carreiras
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal
| | - José Marco-Contelles
- Laboratory of Medicinal Chemistry, Institute of Organic Chemistry CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
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El Omari N, Khalid A, Makeen HA, Alhazmi HA, Albratty M, Mohan S, Tan CS, Ming LC, Chook JB, Bouyahya A. Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat. Heliyon 2024; 10:e33052. [PMID: 39021957 PMCID: PMC11253278 DOI: 10.1016/j.heliyon.2024.e33052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 06/07/2024] [Accepted: 06/13/2024] [Indexed: 07/20/2024] Open
Abstract
The Food and Drug Administration (FDA) has approved vorinostat, also called Zolinza®, for its effectiveness in fighting cancer. This drug is a suberoyl-anilide hydroxamic acid belonging to the class of histone deacetylase inhibitors (HDACis). Its HDAC inhibitory potential allows it to accumulate acetylated histones. This, in turn, can restore normal gene expression in cancer cells and activate multiple signaling pathways. Experiments have proven that vorinostat induces histone acetylation and cytotoxicity in many cancer cell lines, increases the level of p21 cell cycle proteins, and enhances pro-apoptotic factors while decreasing anti-apoptotic factors. Additionally, it regulates the immune response by up-regulating programmed death-ligand 1 (PD-L1) and interferon gamma receptor 1 (IFN-γR1) expression, and can impact proteasome and/or aggresome degradation, endoplasmic reticulum function, cell cycle arrest, apoptosis, tumor microenvironment remodeling, and angiogenesis inhibition. In this study, we sought to elucidate the precise molecular mechanism by which Vorinostat inhibits HDACs. A deeper understanding of these mechanisms could improve our understanding of cancer cell abnormalities and provide new therapeutic possibilities for cancer treatment.
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Affiliation(s)
- Nasreddine El Omari
- High Institute of Nursing Professions and Health Techniques of Tetouan, Tetouan, Morocco
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box 114, Postal Code 45142, Jazan, Saudi Arabia
- Medicinal and Aromatic Plants Research Institute, National Center for Research, P.O. Box: 2424, Khartoum, 11111, Sudan
| | - Hafiz A. Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, Faculty of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Hassan A. Alhazmi
- Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box 114, Postal Code 45142, Jazan, Saudi Arabia
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Postal Code 45142, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Postal Code 45142, Jazan, Saudi Arabia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box 114, Postal Code 45142, Jazan, Saudi Arabia
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ching Siang Tan
- School of Pharmacy, KPJ Healthcare University, Nilai, Malaysia
| | - Long Chiau Ming
- School of Medical and Life Sciences, Sunway University, Sunway City, Malaysia
| | - Jack Bee Chook
- School of Medical and Life Sciences, Sunway University, Sunway City, Malaysia
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat, 10106, Morocco
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Chan JML, Chang YC, Chan HC, Chan HC, Chang WC, Wang LF, Tsai TH, Chen YJ, Huang WC. FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology. Mol Med 2024; 30:73. [PMID: 38822233 PMCID: PMC11143749 DOI: 10.1186/s10020-024-00835-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 05/12/2024] [Indexed: 06/02/2024] Open
Abstract
Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.
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Affiliation(s)
- James Mei-Lin Chan
- Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan
- Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
| | - Yuan-Ching Chang
- Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
| | - Hua-Chen Chan
- Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Center for Lipid Biosciences, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hsiu-Chuan Chan
- PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Chin Chang
- Pathology Department, Taipei Medical University Hospital, Taipei, Taiwan
| | - Liu-Fang Wang
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
| | - Tung-Hu Tsai
- Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Jen Chen
- Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan.
- Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan.
| | - Wen-Chien Huang
- Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan.
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Xiong S, Song K, Xiang H, Luo G. Dual-target inhibitors based on ERα: Novel therapeutic approaches for endocrine resistant breast cancer. Eur J Med Chem 2024; 270:116393. [PMID: 38588626 DOI: 10.1016/j.ejmech.2024.116393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024]
Abstract
Estrogen receptor alpha (ERα), a nuclear transcription factor, is a well-validated therapeutic target for more than 70% of all breast cancers (BCs). Antagonizing ERα either by selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) forms the foundation of endocrine therapy and has achieved great success in the treatment of ERα positive (ERα+) BCs. Unfortunately, despite initial effectiveness, endocrine resistance eventually emerges in up to 30% of ERα+ BC patients and remains a significant medical challenge. Several mechanisms implicated in endocrine resistance have been extensively studied, including aberrantly activated growth factor receptors and downstream signaling pathways. Hence, the crosstalk between ERα and another oncogenic signaling has led to surge of interest to develop combination therapies and dual-target single agents. This review briefly introduces the synergisms between ERα and another anticancer target and summarizes the recent advances of ERα-based dual-targeting inhibitors from a medicinal chemistry perspective. Accordingly, their rational design strategies, structure-activity relationships (SARs) and biological activities are also dissected to provide some perspectives on future directions for ERα-based dual target drug discovery in BC therapy.
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Affiliation(s)
- Shuangshuang Xiong
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ke Song
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua Xiang
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Guoshun Luo
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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7
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Xie S, Leng J, Zhao S, Zhu L, Zhang M, Ning M, Zhao B, Kong L, Yin Y. Design and biological evaluation of dual tubulin/HDAC inhibitors based on millepachine for treatment of prostate cancer. Eur J Med Chem 2024; 268:116301. [PMID: 38452727 DOI: 10.1016/j.ejmech.2024.116301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/26/2024] [Accepted: 03/01/2024] [Indexed: 03/09/2024]
Abstract
In this work, a novel of dual tubulin/HDAC inhibitors were designed and synthesized based on the structure of natural product millepachine, which has been identified as a tubulin polymerization inhibitor. Biological evaluation revealed that compound 9n exhibited an impressive potency against PC-3 cells with the IC50 value of 16 nM and effectively inhibited both microtubule polymerization and HDAC activity. Furthermore, compound 9n not only induced cell cycle arrest at G2/M phase, but also induced PC- 3 cells apoptosis. Further study revealed that the induction of cell apoptosis by 9n was accompanied by a decrease in mitochondrial membrane potential and an elevation in reactive oxygen species levels in PC-3 cells. Additionally, 9n exhibited inhibitory effects on tumor cell migration and angiogenesis. In PC-3 xenograft model, 9n achieved a remarkable tumor inhibition rate of 90.07%@20 mg/kg, significantly surpassing to that of CA-4 (55.62%@20 mg/kg). Meanwhile, 9n exhibited the favorable drug metabolism characteristics in vivo. All the results indicate that 9n is a promising dual tubulin/HDAC inhibitor for chemotherapy of prostate cancer, deserving the further investigation.
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Affiliation(s)
- Shanshan Xie
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Jiafu Leng
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Shifang Zhao
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Liqiao Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Mengyu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Mengdan Ning
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Bo Zhao
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
| | - Yong Yin
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
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El Omari N, Bakrim S, Khalid A, Abdalla AN, Almalki WH, Lee LH, Ardianto C, Ming LC, Bouyahya A. Molecular mechanisms underlying the clinical efficacy of panobinostat involve Stochasticity of epigenetic signaling, sensitization to anticancer drugs, and induction of cellular cell death related to cellular stresses. Biomed Pharmacother 2023; 164:114886. [PMID: 37224752 DOI: 10.1016/j.biopha.2023.114886] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/04/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
Panobinostat, also known as Farydak®, LBH589, PNB, or panobinostat lactate, is a hydroxamic acid that has been approved by the Food and Drug Administration (FDA) for its anti-cancer properties. This orally bioavailable drug is classified as a non-selective histone deacetylase inhibitor (pan-HDACi) that inhibits class I, II, and IV HDACs at nanomolar levels due to its significant histone modifications and epigenetic mechanisms. A mismatch between histone acetyltransferases (HATs) and HDACs can negatively affect the regulation of the genes concerned, which in turn can contribute to tumorigenesis. Indeed, panobinostat inhibits HDACs, potentially leading to acetylated histone accumulation, re-establishing normal gene expression in cancer cells, and helping to drive multiple signaling pathways. These pathways include induction of histone acetylation and cytotoxicity for the majority of tested cancer cell lines, increased levels of p21 cell cycle proteins, enhanced amounts of pro-apoptotic factors (such as caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase (PARP)) associated with decreased levels of anti-apoptotic factors [B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-XL)], as well as regulation of immune response [upregulated programmed death-ligand 1 (PD-L1) and interferon gamma receptor 1 (IFN-γR1) expression] and other events. The therapeutic outcome of panobinostat is therefore mediated by sub-pathways involving proteasome and/or aggresome degradation, endoplasmic reticulum, cell cycle arrest, promotion of extrinsic and intrinsic processes of apoptosis, tumor microenvironment remodeling, and angiogenesis inhibition. In this investigation, we aimed to pinpoint the precise molecular mechanism underlying panobinostat's HDAC inhibitory effect. A more thorough understanding of these mechanisms will greatly advance our knowledge of cancer cell aberrations and, as a result, provide an opportunity for the discovery of significant new therapeutic perspectives through cancer therapeutics.
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Affiliation(s)
- Nasreddine El Omari
- Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco
| | - Saad Bakrim
- Geo-Bio-Environment Engineering and Innovation Laboratory, Molecular Engineering, Biotechnology and Innovation Team, Polydisciplinary Faculty of Taroudant, Ibn Zohr University, Agadir 80000, Morocco
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box: 114, Jazan 45142, Saudi Arabia; Medicinal and Aromatic Plants and Traditional Medicine Research Institute, National Center for Research, P. O. Box 2404, Khartoum, Sudan
| | - Ashraf N Abdalla
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
| | - Waleed Hassan Almalki
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery Research Group (NBDD), Microbiome and Bioresource Research Strength (MBRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Malaysia.
| | - Chrismawan Ardianto
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia.
| | - Long Chiau Ming
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia; PAP Rashidah Sa'adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong, Brunei Darussalam; School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat 10106, Morocco.
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Mehmood SA, Sahu KK, Sengupta S, Partap S, Karpoormath R, Kumar B, Kumar D. Recent advancement of HDAC inhibitors against breast cancer. Med Oncol 2023; 40:201. [PMID: 37294406 DOI: 10.1007/s12032-023-02058-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/22/2023] [Indexed: 06/10/2023]
Abstract
Recent studies highlight the great potential impact of HDAC inhibitors (HDACis) in suppressing TNBC, even though clinical trials including a single HDACis demonstrated unsatisfactory outcomes against TNBC. New compounds created to achieve isoform selectivity and/or a polypharmacological HDAC strategy have also produced interesting results. The current study discusses the HDACis pharmacophoric models and the structural alterations that produced drugs with strong inhibitory effects on TNBC progression. With more than 2 million new cases reported in 2018, breast cancer-the most common cancer among women worldwide-poses a significant financial burden on an already deteriorating public health system. Due to a lack of therapies being developed for triple-negative breast cancers and the development of resistance to the current treatment options, it is imperative to plan novel therapeutics in order to bring new medications to the pipeline. Additionally, HDACs deacetylate a large number of nonhistone cellular substrates that control a variety of biological processes, such as the beginning and development of cancer. The significance of HDACs in cancer and the therapeutic potential of HDAC inhibitor. Furthermore, we also reported molecular docking study with four HDAC inhibitors and performed molecular dynamic stimulation of the best dock score compound. Among the four ligands belinostat compound showed best binding affinity with histone deacetylase protein which was -8.7 kJ/mol. It also formed five conventional hydrogen bond with Gly 841, His 669, His 670, pro 809, and His 709 amino acid residues.
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Affiliation(s)
- Syed Abdulla Mehmood
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Humdard University, New Delhi, India
| | - Kantrol Kumar Sahu
- Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Sounok Sengupta
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India
| | - Sangh Partap
- Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | - Rajshekhar Karpoormath
- Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | - Brajesh Kumar
- Department of Chemistry, TATA College, Kolhan University, Chaibasa, India
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India.
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10
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Yang Y, Liu Q, Wang X, Gou S. Design, synthesis, and biological evaluation of novel HDAC inhibitors with a 3-(benzazol-2-yl)quinoxaline framework. Bioorg Med Chem Lett 2023; 88:129305. [PMID: 37116762 DOI: 10.1016/j.bmcl.2023.129305] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/28/2023] [Accepted: 04/24/2023] [Indexed: 04/30/2023]
Abstract
A series of novel histone deacetylase (HDAC) inhibitors derived from 3-(benzazol-2-yl)quinoxaline derivatives were designed and synthesized by a pharmacophore fusion strategy. In vitro results showed that most of the synthesized compounds exhibited good anti-proliferative activity. Among them, compound 10c showed the most potent cytotoxicity, especially in HCT-116 cells with an IC50 value of 0.91 μM much superior to Vorinostat (5.66 μM). 10c was also found to induce cell apoptosis, arrest the cell cycle at G2/M phase, induce the generation of reactive oxygen species and inhibit cell invasion and migration in HCT-116 cells. Further studies revealed that 10c could up-regulate the acetylation levels of H3 and α-tubulin, exhibit significant Topo I inhibition and induce the release of related apoptotic biomarkers. These results highlight the great potential of 10c to become a promising anti-cancer HDAC inhibitor.
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Affiliation(s)
- Yawen Yang
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China
| | - Qingqing Liu
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; School of Pharmacy, Jilin Medical University, Jilin City 132013, Jilin Province, China
| | - Xinyi Wang
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China
| | - Shaohua Gou
- Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
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11
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Kumar K, Das R, Thapa B, Rakhecha B, Srivastava S, Savita K, Israr M, Chanda D, Banerjee D, Shanker K, Bawankule DU, Santini B, Di Paolo ML, Via LD, Passarella D, Negi AS. Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect. Bioorg Med Chem 2023; 86:117300. [PMID: 37146520 DOI: 10.1016/j.bmc.2023.117300] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/19/2023] [Accepted: 04/23/2023] [Indexed: 05/07/2023]
Abstract
Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.
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Affiliation(s)
- Kapil Kumar
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India
| | - Ranjana Das
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India
| | - Barsha Thapa
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India
| | - Bharti Rakhecha
- CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
| | - Sapna Srivastava
- CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
| | - Kumari Savita
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India
| | - Monazza Israr
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India
| | - Debabrata Chanda
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India
| | - Dibyendu Banerjee
- CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India
| | - Karuna Shanker
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India
| | - D U Bawankule
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India
| | - Benedetta Santini
- Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
| | - Maria Luisa Di Paolo
- Department of Molecular Medicine, University of Padova, via G. Colombo 3, 35131 Padova, Italy
| | - Lisa Dalla Via
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, 35131 Padova, Italy
| | - Daniele Passarella
- Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
| | - Arvind Singh Negi
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India.
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12
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Xiong S, Wang X, Zhu M, Song K, Li Y, Yang J, Liu X, Liu M, Dong H, Chen M, Chen D, Xiang H, Luo G. Structural optimization of tetrahydroisoquinoline-hydroxamate hybrids as potent dual ERα degraders and HDAC inhibitors. Bioorg Chem 2023; 134:106459. [PMID: 36924653 DOI: 10.1016/j.bioorg.2023.106459] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 02/21/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023]
Abstract
Both estrogen receptor α (ERα) and histone deacetylases (HDACs) are valid therapeutic targets for anticancer drug development. Combination therapies using diverse ERα antagonists or degraders and HDAC inhibitors have been proven effective in endocrine-resistant ER + breast cancers based on the crosstalk between ERα and HDAC pathway. In this study, we reported the optimization of a series of methoxyphenyl- or pyridinyl- substituted tetrahydroisoquinoline-hydroxamates, which were optimized from 31, a dual ERα degrader/HDAC inhibitor previously reported by our group. Most of the synthesized compounds displayed potent ERα degradation efficacy and antiproliferative activity. Among them, A04 demonstrated the best anti-proliferation activity (MCF-7 IC50 = 1.96 µM) and HDAC6 inhibitory activity (HDAC6 IC50 = 25.96 nM), which is slightly more potent than the lead compound 31 (MCF-7 IC50 = 4.38 μM, HDAC6 IC50 = 63.03 nM). In addition, compound A04 exerted ERα-independent HDAC6-inhibiting effect without agonistic activity in endometrial cells. These results demonstrated that A04 is a novel and promising dual ERα degrader/HDAC inhibitor worthy of further development.
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Affiliation(s)
- Shuangshuang Xiong
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xin Wang
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Meiqi Zhu
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ke Song
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yefan Li
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jiaqi Yang
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xinyan Liu
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Mofei Liu
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Haijuan Dong
- The Public Laboratory Platform, China Pharmaceutical University, Nanjing 210009, China
| | - Mingqi Chen
- State Key Laboratory of Natural Medicines, National R&D Center for Chinese Herbal Medicine Processing, College of Engineering, China Pharmaceutical University, Nanjing 211109, China
| | - Deying Chen
- Department of Analytical Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Hua Xiang
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Guoshun Luo
- State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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13
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Klieser E, Neumayer B, Di Fazio P, Mayr C, Neureiter D, Kiesslich T. HDACs as an emerging target in endocrine tumors: a comprehensive review. Expert Rev Endocrinol Metab 2023; 18:143-154. [PMID: 36872882 DOI: 10.1080/17446651.2023.2183840] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/20/2023] [Indexed: 02/26/2023]
Abstract
INTRODUCTION The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved. AREAS COVERED Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors. For thyroid, neuroendocrine, and adrenal tumors, various oncogenic mechanisms of HDAC deregulation and effects of HDAC inhibitors (HDACi) have been identified in preclinical studies including direct cancer cell toxicity and modification of differentiation status. EXPERT OPINION Based on positive pre-clinical results, the research on HDAC (inhibition) in the various endocrine tumors should be intensified - yet, it needs to be considered that i) HDACs' oncogenic actions might constitute only a part of epigenetic mechanisms driving cancer, ii) individual HDAC has different roles in different endocrine tumor entities, iii) inhibition of HDACs might be especially attractive in combination with conventional or other targeted therapies, and iv) new HDAC-inhibiting drugs with improved specificity or functionally modified HDACi might further improve their efficacy.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Bettina Neumayer
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Christian Mayr
- Center for Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Tobias Kiesslich
- Center for Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
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14
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Han HH, Wang HM, Jangili P, Li M, Wu L, Zang Y, Sedgwick AC, Li J, He XP, James TD, Kim JS. The design of small-molecule prodrugs and activatable phototherapeutics for cancer therapy. Chem Soc Rev 2023; 52:879-920. [PMID: 36637396 DOI: 10.1039/d2cs00673a] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Cancer remains as one of the most significant health problems, with approximately 19 million people diagnosed worldwide each year. Chemotherapy is a routinely used method to treat cancer patients. However, current treatment options lack the appropriate selectivity for cancer cells, are prone to resistance mechanisms, and are plagued with dose-limiting toxicities. As such, researchers have devoted their attention to developing prodrug-based strategies that have the potential to overcome these limitations. This tutorial review highlights recently developed prodrug strategies for cancer therapy. Prodrug examples that provide an integrated diagnostic (fluorescent, photoacoustic, and magnetic resonance imaging) response, which are referred to as theranostics, are also discussed. Owing to the non-invasive nature of light (and X-rays), we have discussed external excitation prodrug strategies as well as examples of activatable photosensitizers that enhance the precision of photodynamic therapy/photothermal therapy. Activatable photosensitizers/photothermal agents can be seen as analogous to prodrugs, with their phototherapeutic properties at a specific wavelength activated in the presence of disease-related biomarkers. We discuss each design strategy and illustrate the importance of targeting biomarkers specific to the tumour microenvironment and biomarkers that are known to be overexpressed within cancer cells. Moreover, we discuss the advantages of each approach and highlight their inherent limitations. We hope in doing so, the reader will appreciate the current challenges and available opportunities in the field and inspire subsequent generations to pursue this crucial area of cancer research.
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Affiliation(s)
- Hai-Hao Han
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai 200237, P. R. China. .,State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. .,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, P. R. China
| | - Han-Min Wang
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. .,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China
| | - Paramesh Jangili
- Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
| | - Mingle Li
- Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
| | - Luling Wu
- Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
| | - Yi Zang
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. .,Lingang laboratory, Shanghai 201203, China
| | - Adam C Sedgwick
- Chemistry Research Laboratory, University of Oxford, Mansfield Road, OX1 3TA, UK.
| | - Jia Li
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. .,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, P. R. China
| | - Xiao-Peng He
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai 200237, P. R. China. .,The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.,National Center for Liver Cancer, Shanghai 200438, China
| | - Tony D James
- Department of Chemistry, University of Bath, Bath, BA2 7AY, UK. .,School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Jong Seung Kim
- Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
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15
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Piskor EM, Winkler R, Kosan C. Analyzing Lymphoma Development and Progression Using HDACi in Mouse Models. Methods Mol Biol 2023; 2589:3-15. [PMID: 36255614 DOI: 10.1007/978-1-0716-2788-4_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Besides the physiological role of histone deacetalylases in maintaining normal cellular integrity, the acetylation landscape is changed in cancer cells, which has been implicated as a potential target in cancer therapy. The overexpression of certain HDACs correlates with specific cancer types. Therefore, the development of specific HDAC inhibitors may extend the therapeutic strategy for cancer therapy. Here, we describe how to investigate the therapeutic potential of specific HDACi by treatment in a mouse model for B-cell lymphoma, exemplified by the HDAC6 inhibitor Marbostat-100.
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Affiliation(s)
- Eva-Maria Piskor
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Jena, Germany
| | - René Winkler
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Jena, Germany
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
| | - Christian Kosan
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Jena, Germany.
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16
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Sarvari P, Sarvari P, Ramírez-Díaz I, Mahjoubi F, Rubio K. Advances of Epigenetic Biomarkers and Epigenome Editing for Early Diagnosis in Breast Cancer. Int J Mol Sci 2022; 23:ijms23179521. [PMID: 36076918 PMCID: PMC9455804 DOI: 10.3390/ijms23179521] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome are reversible, thus potentially reversed by epi-drugs. Breast cancer, the most common cause of cancer death worldwide in women, encompasses multiple histopathological and molecular subtypes. Several lines of evidence demonstrated distortion of the epigenetic landscape in breast cancer. Interestingly, mammary cells isolated from breast cancer patients and cultured ex vivo maintained the tumorigenic phenotype and exhibited aberrant epigenetic modifications. Recent studies indicated that the therapeutic efficiency for breast cancer regimens has increased over time, resulting in reduced mortality. Future medical treatment for breast cancer patients, however, will likely depend upon a better understanding of epigenetic modifications. The present review aims to outline different epigenetic mechanisms including DNA methylation, histone modifications, and ncRNAs with their impact on breast cancer, as well as to discuss studies highlighting the central role of epigenetic mechanisms in breast cancer pathogenesis. We propose new research areas that may facilitate locus-specific epigenome editing as breast cancer therapeutics.
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Affiliation(s)
- Pourya Sarvari
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran P.O. Box 14965/161, Iran
| | - Pouya Sarvari
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Puebla 72160, Mexico
| | - Ivonne Ramírez-Díaz
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Puebla 72160, Mexico
- Facultad de Biotecnología, Campus Puebla, Universidad Popular Autónoma del Estado de Puebla (UPAEP), Puebla 72410, Mexico
| | - Frouzandeh Mahjoubi
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran P.O. Box 14965/161, Iran
| | - Karla Rubio
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Puebla 72160, Mexico
- Licenciatura en Médico Cirujano, Universidad de la Salud del Estado de Puebla (USEP), Puebla 72000, Mexico
- Correspondence:
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17
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Sher G, Salman NA, Khan AQ, Prabhu KS, Raza A, Kulinski M, Dermime S, Haris M, Junejo K, Uddin S. Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications. Semin Cancer Biol 2022; 83:152-165. [PMID: 32858230 DOI: 10.1016/j.semcancer.2020.08.009] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/17/2020] [Accepted: 08/17/2020] [Indexed: 12/24/2022]
Abstract
The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.
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Affiliation(s)
- Gulab Sher
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Nadia Aziz Salman
- Kingston University London, School of Life Science, Pharmacy and Chemistry, SEC Faculty, Kingston, upon Thames, London, KT1 2EE, UK
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Afsheen Raza
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Michal Kulinski
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Said Dermime
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Mohammad Haris
- Functional and Molecular Imaging Laboratory, Sidra Medicine, P.O. Box 26999, Qatar; Laboratory Animal Research Center, Qatar University, Doha, P.O. Box 2713, Qatar
| | - Kulsoom Junejo
- General Surgery Department, Hamad General Hospital, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar.
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18
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Wu Y, Zhang B, Dong X, Ma S, Hu S. Discovery of Novel Small Molecule HDAC1, 2, 3 Inhibitors -- Combined
Receptor-Based and Ligand-Based Virtual Screening Strategy. LETT DRUG DES DISCOV 2022. [DOI: 10.2174/1570180819666211220124300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Aims:
This study aims to investigate and validate the potential drug target to HDAC1.
Background:
Human histone deacetylase 1 (HDAC1) can catalyze the deacetylation of histones belonging
to the family of human histone deacetylases (HDACs). Amide hydrolase HDAC1 plays a key role in
the development of many serious cancers such as prostate cancer, gastric cancer, lung cancer, esophageal
cancer, colon cancer, and breast cancer. Therefore, HDAC1 inhibitors, promoting the transcription of a
series of key genes such as the p53 gene and inhibiting the development of cancer through various downstream
mechanisms, have great potential for the treatment of cancer.
Objective:
The objective of this study is to discover new skeleton HDAC1 inhibitors efficiently and conveniently
with therapeutic potential for cancer.
Method:
Based on the crystal structure of HDAC1, through the combination of receptor-based and ligand-
based virtual screening from the commercial compound library, the top-ranked compounds are selected
for purchase through binding modes analysis, and their activities were verified through in vitro
HDAC1 inhibitory biological experiments.
Results:
Based on LeDock, 5ICN showed good distinguishing ability and was used as the receptor. According
to the results of the LeDock docking scoring from receptor-based virtual screening, 69 compounds
with binding energy less than -7.5 kcal/mol were obtained and used for ligand-based virtual
screening. A total of 21 novel compounds with high potential HDAC1 inhibitory activity were collected
by combining the similarity searching (NN) and the multinomial Naive Bayes machine learning model
(NB) methods. Through binding modes analysis, 10 compounds with different structures with potential
HDAC1 inhibitory activity were selected and screened HDAC1 inhibitory in vitro. May267 showed moderate
HDAC1 inhibitory activity, and the inhibition rate was 48% at a concentration of 20 μM.
Conclusion:
This study discovers novel small molecule HDAC1 inhibitors by combined receptor-based
and ligand-based virtual screening strategy, which provides an efficient method for the discovery of other
small molecule drugs. May267 shows moderate HDAC1 inhibitory activity, which can be further optimized
as a lead compound. However, it still has the problem of poor kinase selectivity to be solved.
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Affiliation(s)
- Yi Wu
- Department of General Surgery, Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou, Zhejiang
310006, P.R. China
| | - Bo Zhang
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology
and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People\'s Hospital, Cancer Center,
Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative
Medicine, Innovation Institute for Artificial Intelligence in Medicine, College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, Zhejiang 310058, P.R. China
| | - Shenglin Ma
- Department of Oncology, Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou,
Zhejiang 310006, P.R. China
| | - Shengquan Hu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou,
Zhejiang 310058, P.R. China
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19
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Li R, Tian Y, Yang Z, Ji Y, Ding J, Yan A. Classification models and SAR analysis on HDAC1 inhibitors using machine learning methods. Mol Divers 2022:10.1007/s11030-022-10466-w. [PMID: 35737257 DOI: 10.1007/s11030-022-10466-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/19/2022] [Indexed: 10/17/2022]
Abstract
Histone deacetylase (HDAC) 1, a member of the histone deacetylases family, plays a pivotal role in various tumors. In this study, we collected 7313 human HDAC1 inhibitors with bioactivities to form a dataset. Then, the dataset was divided into a training set and a test set using two splitting methods: (1) Kohonen's self-organizing map and (2) random splitting. The molecular structures were represented by MACCS fingerprints, RDKit fingerprints, topological torsions fingerprints and ECFP4 fingerprints. A total of 80 classification models were built by using five machine learning methods, including decision tree (DT), random forest, support vector machine, eXtreme Gradient Boosting and deep neural network. Model 15A_2 built by the XGBoost algorithm based on ECFP4 fingerprints showed the best performance, with an accuracy of 88.08% and an MCC value of 0.76 on the test set. Finally, we clustered the 7313 HDAC1 inhibitors into 31 subsets, and the substructural features in each subset were investigated. Moreover, using DT algorithm we analyzed the structure-activity relationship of HDAC1 inhibitors. It may conclude that some substructures have a significant effect on high activity, such as N-(2-amino-phenyl)-benzamide, benzimidazole, AR-42 analogues, hydroxamic acid with a middle chain alkyl and 4-aryl imidazole with a midchain of alkyl whose α carbon is chiral.
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Affiliation(s)
- Rourou Li
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Yujia Tian
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Zhenwu Yang
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Yueshan Ji
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Jiaqi Ding
- School of International Education, Beijing University of Chemical Technology, Beijing, China
| | - Aixia Yan
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, China.
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20
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Natural Bioactive Compounds Targeting Histone Deacetylases in Human Cancers: Recent Updates. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27082568. [PMID: 35458763 PMCID: PMC9027183 DOI: 10.3390/molecules27082568] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022]
Abstract
Cancer is a complex pathology that causes a large number of deaths worldwide. Several risk factors are involved in tumor transformation, including epigenetic factors. These factors are a set of changes that do not affect the DNA sequence, while modifying the gene’s expression. Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could prevent and treat various human cancers. Accordingly, the present study aimed to evaluate the pharmacodynamic action of different natural compounds extracted from medicinal plants against the enzymatic activity of HDAC.
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21
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Wen Y, Zhang X, Li X, Tian L, Shen S, Ma J, Ai F. Histone deacetylase (HDAC) 11 inhibits matrix metalloproteinase (MMP) 3 expression to suppress colorectal cancer metastasis. J Cancer 2022; 13:1923-1932. [PMID: 35399729 PMCID: PMC8990422 DOI: 10.7150/jca.66914] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/17/2022] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence has implicated invasion and metastasis are the major common reason of treatment failure and the leading cause of death in colorectal cancer (CRC). Many members of the HDAC family have been reported to be key factors in the genesis and progression of cancer. Until now, few research focused on the actual expression patterns of HDAC11 in most malignancies. In the current study, we found that the expression of HDAC11 is decreased in mouse colitis tissues and colitis-associated cancer (CAC) tissue compared with normal colon tissue. Clinically HDAC11 expression is significantly lower in colorectal cancer tissues of patients and correlated with lymph node metastasis. Additionally, HDAC11 is downregulated in the relative high metastatic potential colorectal cancer cells. We also found HDAC11 inhibits the migration and invasion of colorectal cancer cell by downregulating Mmp3 expression. At the molecular level, the expression of HDAC11 inversely correlated with the level of histone H3K9 and H3K14 acetylation. In addition, analysis of chromatin-protein association by ChIP-qPCR demonstrated that the level of H3K9 acetylation correlated with the upregulation of Mmp3. Through a better understanding of this previously unknown role of HDAC11 in migration and invasion of colorectal cancer, HDAC11 may become a novel candidate for developing rational therapeutic strategies.
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Affiliation(s)
- Yuqing Wen
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Changsha, China
| | - Xuemei Zhang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xiayu Li
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Li Tian
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Shourong Shen
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Jian Ma
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Changsha, China
| | - Feiyan Ai
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Changsha, China
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22
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Epigenetic Factors as Etiological Agents, Diagnostic Markers, and Therapeutic Targets for Luminal Breast Cancer. Biomedicines 2022; 10:biomedicines10040748. [PMID: 35453496 PMCID: PMC9031900 DOI: 10.3390/biomedicines10040748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 11/16/2022] Open
Abstract
Luminal breast cancer, an etiologically heterogeneous disease, is characterized by high steroid hormone receptor activity and aberrant gene expression profiles. Endocrine therapy and chemotherapy are promising therapeutic approaches to mitigate breast cancer proliferation and recurrence. However, the treatment of therapy-resistant breast cancer is a major challenge. Recent studies on breast cancer etiology have revealed the critical roles of epigenetic factors in luminal breast cancer tumorigenesis and drug resistance. Tumorigenic epigenetic factor-induced aberrant chromatin dynamics dysregulate the onset of gene expression and consequently promote tumorigenesis and metastasis. Epigenetic dysregulation, a type of somatic mutation, is a high-risk factor for breast cancer progression and therapy resistance. Therefore, epigenetic modulators alone or in combination with other therapies are potential therapeutic agents for breast cancer. Several clinical trials have analyzed the therapeutic efficacy of potential epi-drugs for breast cancer and reported beneficial clinical outcomes, including inhibition of tumor cell adhesion and invasiveness and mitigation of endocrine therapy resistance. This review focuses on recent findings on the mechanisms of epigenetic factors in the progression of luminal breast cancer. Additionally, recent findings on the potential of epigenetic factors as diagnostic biomarkers and therapeutic targets for breast cancer are discussed.
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Abstract
In mammalian cells, genomic DNA is packaged with histone proteins and condensed into chromatin. To gain access to the DNA, chromatin remodelling is required that is enhanced through histone post-translational modifications, which subsequently stimulate processes including DNA repair and transcription. Histone acetylation is one of the most well understood modifications and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes play critical roles in normal cellular functioning, and the dysregulation of HDAC expression in particular has been linked with the development of a number of different cancer types. Conversely, tumour cell killing following radiotherapy is triggered through DNA damage and HDACs can help co-ordinate the cellular DNA damage response which promotes radioresistance. Consequently, HDAC inhibitors have been investigated as potential radiosensitizers in vitro and in vivo to improve the efficacy or radiotherapy in specific tumour types. In this review, we provide an up-to-date summary of HDACs and their cellular functions, including in DNA damage repair. We also review evidence demonstrating that HDAC inhibitors can effectively enhance tumour radiosensitisation, and which therefore show potential for translation into the clinic for cancer patient benefit.
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24
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Avci E, Sarvari P, Savai R, Seeger W, Pullamsetti SS. Epigenetic Mechanisms in Parenchymal Lung Diseases: Bystanders or Therapeutic Targets? Int J Mol Sci 2022; 23:ijms23010546. [PMID: 35008971 PMCID: PMC8745712 DOI: 10.3390/ijms23010546] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 12/17/2022] Open
Abstract
Epigenetic responses due to environmental changes alter chromatin structure, which in turn modifies the phenotype, gene expression profile, and activity of each cell type that has a role in the pathophysiology of a disease. Pulmonary diseases are one of the major causes of death in the world, including lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung tuberculosis, pulmonary embolism, and asthma. Several lines of evidence indicate that epigenetic modifications may be one of the main factors to explain the increasing incidence and prevalence of lung diseases including IPF and COPD. Interestingly, isolated fibroblasts and smooth muscle cells from patients with pulmonary diseases such as IPF and PH that were cultured ex vivo maintained the disease phenotype. The cells often show a hyper-proliferative, apoptosis-resistant phenotype with increased expression of extracellular matrix (ECM) and activated focal adhesions suggesting the presence of an epigenetically imprinted phenotype. Moreover, many abnormalities observed in molecular processes in IPF patients are shown to be epigenetically regulated, such as innate immunity, cellular senescence, and apoptotic cell death. DNA methylation, histone modification, and microRNA regulation constitute the most common epigenetic modification mechanisms.
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MESH Headings
- Animals
- Biomarkers
- Combined Modality Therapy
- DNA Methylation
- Diagnosis, Differential
- Disease Management
- Disease Susceptibility
- Epigenesis, Genetic
- Gene Expression Regulation
- Histones/metabolism
- Humans
- Idiopathic Pulmonary Fibrosis/diagnosis
- Idiopathic Pulmonary Fibrosis/etiology
- Idiopathic Pulmonary Fibrosis/metabolism
- Idiopathic Pulmonary Fibrosis/therapy
- Lung Diseases, Interstitial/diagnosis
- Lung Diseases, Interstitial/etiology
- Lung Diseases, Interstitial/metabolism
- Lung Diseases, Interstitial/therapy
- Pulmonary Disease, Chronic Obstructive/diagnosis
- Pulmonary Disease, Chronic Obstructive/etiology
- Pulmonary Disease, Chronic Obstructive/metabolism
- Pulmonary Disease, Chronic Obstructive/therapy
- Treatment Outcome
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Affiliation(s)
- Edibe Avci
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
| | - Pouya Sarvari
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
| | - Rajkumar Savai
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
| | - Werner Seeger
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
| | - Soni S. Pullamsetti
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany
- Correspondence: ; Tel.: +49-603-270-5380; Fax: +49-603-270-5385
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25
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Experimental, insilico, DFT studies of novel compound 2-{2-[(3,4-dimethoxyphenyl)methylidene]hydrazinecarbonothioyl}-N-methyl-N- phenylhydrazine-1-carbothioamide. RESULTS IN CHEMISTRY 2022. [DOI: 10.1016/j.rechem.2022.100534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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26
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Luo G, Lin X, Ren S, Wu S, Wang X, Ma L, Xiang H. Development of novel tetrahydroisoquinoline-hydroxamate conjugates as potent dual SERDs/HDAC inhibitors for the treatment of breast cancer. Eur J Med Chem 2021; 226:113870. [PMID: 34610548 DOI: 10.1016/j.ejmech.2021.113870] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 12/25/2022]
Abstract
Concomitant inhibition of estrogen receptor alpha (ERα) and histone deacetylase (HDAC) signaling has been proven effective in endocrine-resistant ER+ breast cancers. Herein, a series of tetrahydroisoquinoline (THIQ)-hydroxamate conjugates were rationally designed and synthesized as dual SERDs/HDAC inhibitors by incorporating the hydroxamate, a known HDAC pharmacophore, into a privileged THIQ scaffold of selective ERα degraders (SERDs). Some of these THIQ-hydroxamate conjugates displayed remarkable HDAC6 inhibition and improved antiproliferative activity against MCF-7 cells. Particularly, the most potent HDAC inhibitor 19k also exhibits potent ERα binding affinity, good ERα degradation efficacy and the best antiproliferative activity. Besides, 19k displayed superior antitumor efficacy than the drug combination (Fulvestrant + SAHA) through promoting ERα degradation and histone acetylation in an MCF-7 xenograft model, without causing observable toxicity. Collectively, this study validates the therapeutic potential of a dual-acting compound with potent ERα degradation efficacy and HDAC6 inhibition in breast cancer.
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Affiliation(s)
- Guoshun Luo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Xin Lin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Shengnan Ren
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Shuangjie Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xin Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyu Ma
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua Xiang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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27
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Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors. Bioorg Med Chem 2021; 56:116599. [DOI: 10.1016/j.bmc.2021.116599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 01/26/2023]
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28
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Morales-Tarré O, Alonso-Bastida R, Arcos-Encarnación B, Pérez-Martínez L, Encarnación-Guevara S. Protein lysine acetylation and its role in different human pathologies: a proteomic approach. Expert Rev Proteomics 2021; 18:949-975. [PMID: 34791964 DOI: 10.1080/14789450.2021.2007766] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Lysine acetylation is a reversible post-translational modification (PTM) regulated through the action of specific types of enzymes: lysine acetyltransferases (KATs) and lysine deacetylases (HDACs), in addition to bromodomains, which are a group of conserved domains which identify acetylated lysine residues, several of the players in the process of protein acetylation, including enzymes and bromodomain-containing proteins, have been related to the progression of several diseases. The combination of high-resolution mass spectrometry-based proteomics, and immunoprecipitation to enrich acetylated peptides has contributed in recent years to expand the knowledge about this PTM described initially in histones and nuclear proteins, and is currently reported in more than 5000 human proteins, that are regulated by this PTM. AREAS COVERED This review presents an overview of the main participant elements, the scenario in the development of protein lysine acetylation, and its role in different human pathologies. EXPERT OPINION Acetylation targets are practically all cellular processes in eukaryotes and prokaryotes organisms. Consequently, this modification has been linked to many pathologies like cancer, viral infection, obesity, diabetes, cardiovascular, and nervous system-associated diseases, to mention a few relevant examples. Accordingly, some intermediate mediators in the acetylation process have been projected as therapeutic targets.
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Affiliation(s)
- Orlando Morales-Tarré
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Ramiro Alonso-Bastida
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Bolivar Arcos-Encarnación
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular Y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Leonor Pérez-Martínez
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular Y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Sergio Encarnación-Guevara
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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29
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Roopa, Priya B, Bhalla V, Kumar M, Kumar N. Fluorescent molecular probe-based activity and inhibition monitoring of histone deacetylases. Chem Commun (Camb) 2021; 57:11153-11164. [PMID: 34613324 DOI: 10.1039/d1cc04034k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Extensive studies in recent decades have revealed that gene expression regulation is not limited to genetic mutations but also to processes that do not alter the genetic sequence. Post-translational histone modification is one of these processes in addition to DNA or RNA modifications. Histone modifications are essential in controlling histone functions and play a vital role in cellular gene expression. The reversible histone acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is an example of such modifications. HDACs are involved in the deacetylation of histones and lead to the termination of gene expression. Although this cellular process is essential, upregulation of HDACs is found in numerous cancers. Therefore, research related to the activity and inhibition monitoring of HDACs is necessary to gain profound knowledge of these enzymes and evaluate the success of the therapeutic approach. In this perspective, methodology derived from fluorescent molecular probes is one of the preferable methods. Herein, we describe fluorescent probes developed to target HDACs by considering their activity and inhibition characteristics.
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Affiliation(s)
- Roopa
- Department of Chemical Sciences, IKG-Punjab Technical University, Kapurthala 144603, Punjab, India.
| | - Bhanu Priya
- Department of Chemical Sciences, IKG-Punjab Technical University, Kapurthala 144603, Punjab, India.
| | - Vandana Bhalla
- Department of Chemistry, UGC Center of Advanced Study-II, Guru Nanak Dev University, Amritsar-143005, Punjab, India
| | - Manoj Kumar
- Department of Chemistry, UGC Center of Advanced Study-II, Guru Nanak Dev University, Amritsar-143005, Punjab, India
| | - Naresh Kumar
- Department of Chemistry, SRM University, Delhi-NCR, Sonepat-131029, Haryana, India.
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30
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Gadwal A, Modi A, Khokhar M, Vishnoi JR, Choudhary R, Elhence P, Banerjee M, Purohit P. Critical appraisal of epigenetic regulation of galectins in cancer. Int J Clin Oncol 2021; 27:35-44. [PMID: 34652614 DOI: 10.1007/s10147-021-02048-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/03/2021] [Indexed: 12/31/2022]
Abstract
Galectins are defined as the glycan-binding protein containing either one or two carbohydrate-binding domains and participate in various biological functions such as developmental processes, vascularisation programs, cell migration, and immune-regulation and apoptosis. Galectins are also linked to many diseases, including cancer. They are widely spread in extracellular and intracellular spaces, and their altered expression in cancer leads to tumor progression, metastasis, angiogenesis and stemness through different signalling pathways. Promoter methylation, microRNA, and histone modification constitute the epigenetic changes that regulate galectin activity in cancer. Our review discusses the concept of epigenetics in cancer and how the aforementioned factors i.e., promoter methylation, histone modification, change in miRNAs expression affect the glycomic changes in malignancies.
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Affiliation(s)
- Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Anupama Modi
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Jeewan Ram Vishnoi
- Department of Oncosurgery, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Ramkaran Choudhary
- Department of General Surgery, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Poonam Elhence
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India.
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31
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Sirous H, Campiani G, Calderone V, Brogi S. Discovery of novel hit compounds as potential HDAC1 inhibitors: The case of ligand- and structure-based virtual screening. Comput Biol Med 2021; 137:104808. [PMID: 34478925 DOI: 10.1016/j.compbiomed.2021.104808] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 11/28/2022]
Abstract
Histone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC inhibition has been proven as a compelling strategy for reversing the aberrant epigenetic changes associated with cancer. However, non-selective profile of most developed HDAC inhibitors (HDACIs) leads to the occurrence of various side effects, limiting their clinical utility. This evidence provides a solid ground for ongoing research aimed at identifying isoform-selective inhibitors. Among the isoforms, HDAC1 have particularly gained increased attention as a preferred target for the design of selective HDACIs. Accordingly, in this paper, we have developed a reliable virtual screening process, combining different ligand- and structure-based methods, to identify novel benzamide-based analogs with potential HDAC1 inhibitory activity. For this purpose, a focused library of 736,160 compounds from PubChem database was first compiled based on 80% structural similarity with four known benzamide-based HDAC1 inhibitors, Mocetinostat, Entinostat, Tacedinaline, and Chidamide. Our inclusive in-house 3D-QSAR model, derived from pharmacophore-based alignment, was then employed as a 3D-query to discriminate hits with the highest predicted HDAC1 inhibitory activity. The selected hits were subjected to subsequent structure-based approaches (induced-fit docking (IFD), MM-GBSA calculations and molecular dynamics (MD) simulation) to retrieve potential compounds with the highest binding affinity for HDAC1 active site. Additionally, in silico ADMET properties and PAINS filtration were also considered for selecting an enriched set of the best drug-like molecules. Finally, six top-ranked hit molecules, CID_38265326, CID_56064109, CID_8136932, CID_55802151, CID_133901641 and CID_18150975 were identified to expose the best stability profiles and binding mode in the HDAC1 active site. The IFD and MD results cooperatively confirmed the interactions of the promising selected hits with critical residues within HDAC1 active site. In summary, the presented computational approach can provide a set of guidelines for the further development of improved benzamide-based derivatives targeting HDAC1 isoform.
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Affiliation(s)
- Hajar Sirous
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran.
| | - Giuseppe Campiani
- Department of Excellence of Biotechnology, Chemistry and Pharmacy, 2018-2022, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
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32
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Skwarska A, Calder EDD, Sneddon D, Bolland H, Odyniec ML, Mistry IN, Martin J, Folkes LK, Conway SJ, Hammond EM. Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor. Cell Chem Biol 2021; 28:1258-1270.e13. [PMID: 33910023 PMCID: PMC8460716 DOI: 10.1016/j.chembiol.2021.04.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/15/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022]
Abstract
Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% O2). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.
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Affiliation(s)
- Anna Skwarska
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
| | - Ewen D D Calder
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
| | - Deborah Sneddon
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
| | - Hannah Bolland
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
| | - Maria L Odyniec
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
| | - Ishna N Mistry
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
| | - Jennifer Martin
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
| | - Lisa K Folkes
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
| | - Stuart J Conway
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
| | - Ester M Hammond
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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Meng Y, Qian X, Zhao L, Li N, Wu S, Chen B, Sun T, Wang X. Trichostatin A downregulates bromodomain and extra-terminal proteins to suppress osimertinib resistant non-small cell lung carcinoma. Cancer Cell Int 2021; 21:216. [PMID: 33858423 PMCID: PMC8050891 DOI: 10.1186/s12935-021-01914-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/07/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The third-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown significant therapeutic effects on patients with non-small cell lung carcinoma (NSCLC) who carry active EGFR mutations, as well as those who have developed acquired resistance to the first-generation of EGFR-TKIs due to the T790M mutation. However, most patients develop drug resistance after 8-10 months of treatment. Currently, the mechanism has not been well clarified, and new therapeutic strategies are urgently needed. METHODS Osimertinib resistant cell lines were established by culturing sensitive cells in chronically increasing doses of osimertinib. The anticancer effect of reagents was examined both in vitro and in vivo using the sulforhodamine B assay and a xenograft mouse model. The molecular signals were detected by western blotting. The combination effect was analyzed using CompuSyn software. RESULTS We found that bromodomain and extra-terminal proteins (BETs) were upregulated in osimertinib resistant (H1975-OR) cells compared with those in the paired parental cells (H1975-P), and that knockdown of BETs significantly inhibited the growth of H1975-OR cells. The BET inhibitor JQ1 also exhibited stronger growth-inhibitory effects on H1975-OR cells and a greater expression of BETs and the downstream effector c-Myc than were observed in H1975-P cells. The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) showed stronger growth suppression in H1975-OR cells than in H1975-P cells, but vorinostat, another HDAC inhibitor, showed equal inhibitory efficacy in both cell types. Consistently, downregulation of BET and c-Myc expression was greater with TSA than with vorinostat. TSA restrained the growth of H1975-OR and H1975-P xenograft tumors. The combination of TSA and JQ1 showed synergistic growth-inhibitory effects in parallel with decreased BET and c-Myc expression in both H1975-OR and H1975-P cells and in xenograft nude mouse models. BETs were not upregulated in osimertinib resistant HCC827 cells compared with parental cells, while TSA and vorinostat exhibited equal inhibitory effects on both cell types. CONCLUSION Upregulation of BETs contributed to the osimertinib resistance of H1975 cells. TSA downregulated BET expression and enhanced the growth inhibitory effect of JQ1 both in vitro and in vivo. Our findings provided new strategies for the treatment of osimertinib resistance.
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Affiliation(s)
- Yuting Meng
- Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu Province, China
| | - Xixi Qian
- Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu Province, China
| | - Li Zhao
- Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu Province, China
| | - Nan Li
- Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu Province, China
| | - Shengjie Wu
- Department of Pharmacology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Tong Sun
- Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 101 Longmiandadao, Nanjing, 211166, Jiangsu Province, China.
| | - Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu Province, China. .,Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 101 Longmiandadao, Nanjing, 211166, Jiangsu Province, China.
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Zhang K, Liu Z, Yao Y, Qiu Y, Li F, Chen D, Hamilton DJ, Li Z, Jiang S. Structure-Based Design of a Selective Class I Histone Deacetylase (HDAC) Near-Infrared (NIR) Probe for Epigenetic Regulation Detection in Triple-Negative Breast Cancer (TNBC). J Med Chem 2021; 64:4020-4033. [PMID: 33745280 DOI: 10.1021/acs.jmedchem.0c02161] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Abnormally high levels of class I histone deacetylases (HDACs) are associated with triple-negative breast cancer (TNBC) proliferation, malignant transformation, and poor prognosis of patients. Herein, we report a near-infrared imaging probe for TNBC detection via visualizing class I HDACs. Conjugating Cy5.5 to a cyclic depsipeptide inhibitor, we obtained the probe (20-Cy5.5) that retained desirable class I HDAC affinity and selectivity. Then, this probe could visualize epigenetic changes by class I HDACs in TNBC MDA-MB-231 cells and in xenograft tumor models in real time. Treatment with suberoylanilide hydroxamic acid (SAHA) significantly reduced the uptake of the probe in tumors, suggesting its potential use in evaluation of therapeutic responses of HDACi-mediated therapy. Moreover, 20-Cy5.5 could detect class I HDAC expression in TNBC lung metastasis. This novel NIR probe that achieves tumor class I HDAC imaging not only leads to a better understanding of epigenetic regulation in tumors but also has great potential for improving the TNBC diagnosis and treatment.
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Affiliation(s)
- Kuojun Zhang
- State Key Laboratory of Natural Medicines, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhiyi Liu
- Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, Texas 77030, United States
| | - Yiwu Yao
- State Key Laboratory of Natural Medicines, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yatao Qiu
- State Key Laboratory of Natural Medicines, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Feng Li
- Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, Texas 77030, United States
| | - Dong Chen
- State Key Laboratory of Natural Medicines, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Dale J Hamilton
- Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, Texas 77030, United States
| | - Zheng Li
- Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, Texas 77030, United States
| | - Sheng Jiang
- State Key Laboratory of Natural Medicines, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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Tavares MT, de Almeida LC, Kronenberger T, Monteiro Ferreira G, Fujii de Divitiis T, Franco Zannini Junqueira Toledo M, Mariko Aymoto Hassimotto N, Agostinho Machado-Neto J, Veras Costa-Lotufo L, Parise-Filho R. Structure-activity relationship and mechanistic studies for a series of cinnamyl hydroxamate histone deacetylase inhibitors. Bioorg Med Chem 2021; 35:116085. [PMID: 33668008 DOI: 10.1016/j.bmc.2021.116085] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022]
Abstract
Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential anticancer HDACis. In addition, structure-activity relationship (SAR) studies have been performed in order to verify the influence of the linker on the biological profile of the compounds. All tested compounds demonstrated significant antiproliferative effects against solid and hematological human tumor cell lines. Among them, 11b exhibited nanomolar potency against hematological tumor cells including Jurkat and Namalwa, with IC50 values of 40 and 200 nM, respectively. Cellular and molecular proliferation studies, in presence of compounds 11a-d, showed significant cell growth arrest, apoptosis induction, and up to 43-fold selective cytotoxicity for leukemia cells versus non-tumorigenic cells. Moreover, compounds 11a-d increased acetylated α-tubulin expression levels, which is phenotypically consistent with HDAC inhibition, and indirectly induced DNA damage. In vitro enzymatic assays performed for 11b revealed a potent HDAC6 inhibitory activity (IC50: 8.1 nM) and 402-fold selectivity over HDAC1. Regarding SAR analysis, the distance between the hydroxamate moiety and the aromatic ring as well as the presence of the double bond in the cinnamyl linker were the most relevant chemical feature for the antiproliferative activity of the series. Molecular modeling studies suggest that cinnamyl hydroxamate is the best moiety of the series for binding HDAC6 catalytic pocket whereas exploration of Ser568 by the urea connecting unity (CU) might be related with the selectivity observed for the cinnamyl derivatives. In summary, cinnamyl hydroxamate derived compounds with HDAC6 inhibitory activity exhibited cell growth arrest and increased apoptosis, as well as selectivity to acute lymphoblastic leukemia cells. This study explores interesting compounds to fight against neoplastic hematological cells.
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Affiliation(s)
- Maurício Temotheo Tavares
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Larissa Costa de Almeida
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Thales Kronenberger
- Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, DE 72076 Tübingen, Germany; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland
| | - Glaucio Monteiro Ferreira
- Laboratory of Molecular Biology Applied to Diagnosis (LBMAD), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Thainá Fujii de Divitiis
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Neuza Mariko Aymoto Hassimotto
- Food Research Center-(FoRC-CEPID) and Department of Food Science and Nutrition, Faculty of Pharmaceutical Science, University of São Paulo, São Paulo, SP, Brazil
| | | | - Letícia Veras Costa-Lotufo
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Roberto Parise-Filho
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
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Gediya P, Parikh PK, Vyas VK, Ghate MD. Histone deacetylase 2: A potential therapeutic target for cancer and neurodegenerative disorders. Eur J Med Chem 2021; 216:113332. [PMID: 33714914 DOI: 10.1016/j.ejmech.2021.113332] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 02/20/2021] [Accepted: 02/21/2021] [Indexed: 10/22/2022]
Abstract
Histone deacetylases (HDACs) have been implicated in a number of diseases including cancer, cardiovascular disorders, diabetes mellitus, neurodegenerative disorders and inflammation. For the treatment of epigenetically altered diseases such as cancer, HDAC inhibitors have made a significant progress in terms of development of isoform selective inhibitiors. Isoform specific HDAC inhibitors have less adverse events and better safety profile. A HDAC isoform i.e., HDAC2 demonstrated significant role in the development of variety of diseases, mainly involved in the cancer and neurodegenerative disorders. Discovery and development of selective HDAC2 inhibitors have a great potential for the treatment of target diseases. In the present compilation, we have reviewed the role of HDAC2 in progression of cancer and neurodegenerative disorders, and information on the drug development opportunities for selective HDAC2 inhibition.
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Affiliation(s)
- Piyush Gediya
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India
| | - Palak K Parikh
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India; Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Vivek K Vyas
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India
| | - Manjunath D Ghate
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India.
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Abstract
Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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Leng X, Liu M, Tao D, Yang B, Zhang Y, He T, Xie S, Wang Z, Liu Y, Yang Y. Epigenetic modification-dependent androgen receptor occupancy facilitates the ectopic TSPY1 expression in prostate cancer cells. Cancer Sci 2020; 112:691-702. [PMID: 33185915 PMCID: PMC7894013 DOI: 10.1111/cas.14731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/27/2020] [Accepted: 11/07/2020] [Indexed: 02/06/2023] Open
Abstract
Testis‐specific protein Y‐encoded 1 (TSPY1), a Y chromosome‐linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl‐histone H4 and trimethylated histone H3‐lysine 4, two post–translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1‐CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen‐AR axis‐regulated oncogene, suggesting a novel and potential target for PCa therapy.
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Affiliation(s)
- Xiangyou Leng
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Mohan Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Dachang Tao
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Bo Yang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yangwei Zhang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Tianrong He
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Shengyu Xie
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Zhaokun Wang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yunqiang Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yuan Yang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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Recent progress on HDAC inhibitors with dual targeting capabilities for cancer treatment. Eur J Med Chem 2020; 208:112831. [DOI: 10.1016/j.ejmech.2020.112831] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/31/2020] [Accepted: 09/05/2020] [Indexed: 12/11/2022]
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Xavier PLP, Müller S, Fukumasu H. Epigenetic Mechanisms in Canine Cancer. Front Oncol 2020; 10:591843. [PMID: 33194754 PMCID: PMC7646326 DOI: 10.3389/fonc.2020.591843] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/05/2020] [Indexed: 01/18/2023] Open
Abstract
A plethora of data has highlighted the role of epigenetics in the development of cancer. Initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant DNA methylation, histone modifications, and miRNA expression. At the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. Although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. This review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.
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Affiliation(s)
- Pedro Luiz Porfirio Xavier
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of Sao Paulo, Pirassununga, Brazil
| | - Susanne Müller
- Structural Genomics Consortium and Institute of Pharmaceutical Chemistry, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
| | - Heidge Fukumasu
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of Sao Paulo, Pirassununga, Brazil
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Epigenetic Aberrations in Multiple Myeloma. Cancers (Basel) 2020; 12:cancers12102996. [PMID: 33076518 PMCID: PMC7602661 DOI: 10.3390/cancers12102996] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/12/2020] [Accepted: 10/12/2020] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Multiple Myeloma (MM) is a blood cancer characterized by an uncontrolled growth of cells named plasma cells, within the bone marrow. Patients with MM may present with anemia, bone lesions and kidney impairment. Several studies have been performed in order to provide an explanation to how this tumor may develop. Among them, the so called “epigenetic modifications” certainly represent important players that have been shown to support MM development and disease progression. The present article aims to summarize the current knowledge in the specific are of “epigenetics” in MM. Abstract Multiple myeloma (MM) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. Several advances in defining key processes responsible for MM pathogenesis and disease progression have been made; and dysregulation of epigenetics, including DNA methylation and histone modification, has emerged as a crucial regulator of MM pathogenesis. In the present review article, we will focus on the role of epigenetic modifications within the specific context of MM.
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Wang W, Liu Y, Zhao L. Tambulin Targets Histone Deacetylase 1 Inhibiting Cell Growth and Inducing Apoptosis in Human Lung Squamous Cell Carcinoma. Front Pharmacol 2020; 11:1188. [PMID: 32903420 PMCID: PMC7434869 DOI: 10.3389/fphar.2020.01188] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/22/2020] [Indexed: 12/20/2022] Open
Abstract
There is an urgent unmet need to develop new therapeutics for lung squamous cell carcinoma (LSCC) as the current gold standard treatment regimens are dominated by chemotherapy. In this study, we observed the treatment effects of the natural compound tambulin on LSCC and explored its mechanism of action. LSCC cell lines H226 and H520 were cultured in vitro to observe the effects of tambulin on cell proliferation and apoptosis. Western blotting was used to detect the expression of histone deacetylase 1 (HDAC1) and apoptosis-related proteins. Cell derived xenografts (CDX) of H226 and H520 in nude mice were established to examine the inhibitory effects of tambulin in vivo. Results showed that tambulin inhibited the proliferation of H226 and H520 cells in a dose-dependent manner and inhibited the growth of CDX tumors. Tambulin also promoted the apoptosis of H226 and H520 cells, up-regulated the protein expression of cleaved caspase-3, cleaved caspase-9 and Bax, and down-regulated HDAC1 and Bcl-2 protein expression. In support of this, immunohistochemical analysis of CDX tumors from mice treated with tambulin showed increased expression of cleaved caspase-3 and Bax, while the expression of HDAC1 and Bcl-2 were decreased. What’s more, when HDAC1 was over-expressed via adenovirus transduction in H226 or H520 cells, the effects of tambulin were significantly attenuated. Interestingly, we found that combining tambulin with cisplatin treatment in CDX models was more effective than single drug treatment, suggesting that tambulin may enhance the sensitivity of LSCC to cisplatin. Taken together, this study proves that tambulin has a definite therapeutic effect on LSCC. Mechanistically, tambulin downregulates HDAC1, which in turn regulates the Bcl-2/caspase signaling pathway and promotes cancer cell apoptosis.
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Affiliation(s)
- Wuming Wang
- Department of Thoracic Surgery, Jiangxi Provincial Chest Hospital, Nanchang, China
| | - Yuzhen Liu
- Department of Thoracic Surgery, Jiangxi Provincial Chest Hospital, Nanchang, China
| | - Long Zhao
- Department of Thoracic Surgery, Jiangxi Provincial Chest Hospital, Nanchang, China
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Li H, Li H, Waresijiang Y, Chen Y, Li Y, Yu L, Li Y, Liu L. Clinical significance of HDAC1, -2 and -3 expression levels in esophageal squamous cell carcinoma. Exp Ther Med 2020; 20:315-324. [PMID: 32536999 PMCID: PMC7282189 DOI: 10.3892/etm.2020.8697] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 03/03/2020] [Indexed: 12/28/2022] Open
Abstract
The present study analyzed the expression of the histone deacetylase (HDAC) 1, 2 and 3 in primary esophageal squamous cell carcinoma (ESCC) samples and how their levels correlate with clinicopathological parameters. ESCC patients (n=88) in the present study had received no previous treatment before undergoing surgical excision. The mRNA expression of HDAC1, -2 and -3 were detected by semi-quantified PCR in ESCC samples and distal normal samples. The relationship of HDAC1, -2 and -3 expression with clinicopathological parameters was analyzed by χ2 test. The correlation among these HDACs was analyzed by Pearson's correlation test. Compared with distal normal tissues, ESCC samples had higher expression of HDAC1, but not HDAC2 or HDAC3 (P<0.05). The expression of HDACs was different between Kazak and Han ethnicities. The expression of HDAC2 was correlated with invasion depth (P<0.05), but not with sex, age, metastasis, or the degree of tumor differentiation (P>0.05). There was no association between HDAC1 or HDAC3 and clinicopathological parameters (P>0.05). For the Kazak and Han ethnicities, HDAC1 expression was present in male patients, patients with well/moderate differentiated ESCC and T3 and T4 ESCC (P<0.01). HDAC1 in patients aged <60 was associated with ethnicity (P<0.05). HDAC2 expression was different in positive LN metastasis, well/moderate differentiation and T3 and T4 ESCC (P<0.01). HDAC3 expression in male patients, patients with negative LN metastasis and well/moderate differentiation ESCC was associated with ethnicity (P<0.05). Additionally, the expression levels of HDAC1, -2 and -3 did not correlate with each other. Thus, HDAC1 expression may be used as a risk factor for ESCC and HDAC2 levels may be used to predict invasion depth. The expression of HDAC1, -2 and -3 has ethnic differences.
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Affiliation(s)
- Huiwu Li
- Medical Research Center, Yubei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
| | - Hui Li
- Department of Central Laboratory, Xinjiang Medical University, Xinshi, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Yibulayin Waresijiang
- Department of Thoracic Surgery, Affiliated Cancer Hospital, Xinjiang Medical University, Xinshi, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Yan Chen
- Department of Basic Medical College, Xinjiang Medical University, Xinshi, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Ying Li
- Department of Basic Medical College, Xinjiang Medical University, Xinshi, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Liang Yu
- Medical Research Center, Yubei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
| | - Yike Li
- First Clinical Medical College, Xinjiang Medical University, Xinshi, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Ling Liu
- Department of Basic Medical College, Xinjiang Medical University, Xinshi, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
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Verza FA, Das U, Fachin AL, Dimmock JR, Marins M. Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy. Cancers (Basel) 2020; 12:cancers12061664. [PMID: 32585896 PMCID: PMC7352721 DOI: 10.3390/cancers12061664] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/19/2020] [Accepted: 05/19/2020] [Indexed: 12/23/2022] Open
Abstract
Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.
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Affiliation(s)
- Flávia Alves Verza
- Biotechnology Unit, University of Ribeirão Preto, Ribeirão Preto SP CEP 14096-900, Brazil; (F.A.V.); (A.L.F.)
| | - Umashankar Das
- College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada;
| | - Ana Lúcia Fachin
- Biotechnology Unit, University of Ribeirão Preto, Ribeirão Preto SP CEP 14096-900, Brazil; (F.A.V.); (A.L.F.)
- Medicine School, University of Ribeirão Preto, Ribeirão Preto SP CEP 14096-900, Brazil
| | - Jonathan R. Dimmock
- College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada;
- Correspondence: (J.R.D.); (M.M.); Tel.: +1-306-966-6331 (J.R.D.); +55-16-3603-6728 (M.M.)
| | - Mozart Marins
- Biotechnology Unit, University of Ribeirão Preto, Ribeirão Preto SP CEP 14096-900, Brazil; (F.A.V.); (A.L.F.)
- College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada;
- Medicine School, University of Ribeirão Preto, Ribeirão Preto SP CEP 14096-900, Brazil
- Pharmaceutical Sciences School, University of Ribeirão Preto, Ribeirão Preto SP CEP 14096-900, Brazil
- Correspondence: (J.R.D.); (M.M.); Tel.: +1-306-966-6331 (J.R.D.); +55-16-3603-6728 (M.M.)
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45
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Kulka LAM, Fangmann PV, Panfilova D, Olzscha H. Impact of HDAC Inhibitors on Protein Quality Control Systems: Consequences for Precision Medicine in Malignant Disease. Front Cell Dev Biol 2020; 8:425. [PMID: 32582706 PMCID: PMC7291789 DOI: 10.3389/fcell.2020.00425] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 05/07/2020] [Indexed: 12/21/2022] Open
Abstract
Lysine acetylation is one of the major posttranslational modifications (PTM) in human cells and thus needs to be tightly regulated by the writers of this process, the histone acetyl transferases (HAT), and the erasers, the histone deacetylases (HDAC). Acetylation plays a crucial role in cell signaling, cell cycle control and in epigenetic regulation of gene expression. Bromodomain (BRD)-containing proteins are readers of the acetylation mark, enabling them to transduce the modification signal. HDAC inhibitors (HDACi) have been proven to be efficient in hematologic malignancies with four of them being approved by the FDA. However, the mechanisms by which HDACi exert their cytotoxicity are only partly resolved. It is likely that HDACi alter the acetylation pattern of cytoplasmic proteins, contributing to their anti-cancer potential. Recently, it has been demonstrated that various protein quality control (PQC) systems are involved in recognizing the altered acetylation pattern upon HDACi treatment. In particular, molecular chaperones, the ubiquitin proteasome system (UPS) and autophagy are able to sense the structurally changed proteins, providing additional targets. Recent clinical studies of novel HDACi have proven that proteins of the UPS may serve as biomarkers for stratifying patient groups under HDACi regimes. In addition, members of the PQC systems have been shown to modify the epigenetic readout of HDACi treated cells and alter proteostasis in the nucleus, thus contributing to changing gene expression profiles. Bromodomain (BRD)-containing proteins seem to play a potent role in transducing the signaling process initiating apoptosis, and many clinical trials are under way to test BRD inhibitors. Finally, it has been demonstrated that HDACi treatment leads to protein misfolding and aggregation, which may explain the effect of panobinostat, the latest FDA approved HDACi, in combination with the proteasome inhibitor bortezomib in multiple myeloma. Therefore, proteins of these PQC systems provide valuable targets for precision medicine in cancer. In this review, we give an overview of the impact of HDACi treatment on PQC systems and their implications for malignant disease. We exemplify the development of novel HDACi and how affected proteins belonging to PQC can be used to determine molecular signatures and utilized in precision medicine.
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Affiliation(s)
- Linda Anna Michelle Kulka
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Pia-Victoria Fangmann
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Diana Panfilova
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Heidi Olzscha
- Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
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46
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Jang YG, Ko EB, Choi KC. Gallic acid, a phenolic acid, hinders the progression of prostate cancer by inhibition of histone deacetylase 1 and 2 expression. J Nutr Biochem 2020; 84:108444. [PMID: 32615369 DOI: 10.1016/j.jnutbio.2020.108444] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Gallic acid (GA) is known to possess diverse biological activities, including anticancer. Histone deacetylase (HDACs) are controlled by tumor suppressor gene transcription and are overexpressed in various tumors, resulting in tumor development, progression and poor prognosis. This study aims to demonstrate the effect of GA on inhibition of prostate cancer (PCa) progression by modulating the expression of HDAC1 and 2 in PCa cells. To prove our research rationale, we used diverse experimental methods. GA decreased the cell viability of only PCa cell lines and not normal cells (contrary to another HDAC inhibitor, suberoylanilide hydroxamic acid) and also inhibited colony and tumor spheroid formation. Exposure to GA decreased the mitochondrial membrane potential (ΔΨm), increased the number of apoptotic cells and induced DNA fragmentation. Western blot analysis revealed down-regulated expression of HDAC1 and 2, leading to up-regulation of acetyl-p53 expression at the protein level, subsequent to down-regulating the expression of cell-cycle-related genes, i.e., proliferating cell nuclear antigen (PCNA), Cyclin D1 and E1, up-regulating the expression of cell cycle arrest gene p21 and regulating the expression of apoptosis intrinsic pathway-related genes, such as Bax, Bcl-2, cleaved Caspase-3 and poly (ADP-ribose) polymerase 1 in both PCa cell lines. Furthermore, oral administration of GA for 8 weeks on PC-3 cells-derived tumor xenograft mice model decreases the tumor size, damages the tumor structure and down-regulates the expression of HDAC1 and 2 and PCNA in tumor mass, as confirmed by histological analysis. These results indicated that GA may hinder the PCa progression by inhibiting HDAC1 and 2 expression, thereby demonstrating the potential of GA to be used as HDACs inhibitor and anti-PCa therapeutics.
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Affiliation(s)
- Yin-Gi Jang
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Eul-Bee Ko
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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47
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ElHady AK, Shih SP, Chen YC, Liu YC, Ahmed NS, Keeton AB, Piazza GA, Engel M, Abadi AH, Abdel-Halim M. Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors. Bioorg Chem 2020; 98:103742. [PMID: 32199305 DOI: 10.1016/j.bioorg.2020.103742] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/27/2020] [Accepted: 03/07/2020] [Indexed: 12/17/2022]
Abstract
Herein we present the synthesis and characterization of a novel chemical series of tadalafil analogues that display different pharmacological profiles. Compounds that have the 6R, 12aR configuration and terminal carboxylic acid group at the side chain arising from the piperazinedione nitrogen were potent PDE5 inhibitors, with compound 11 having almost equal potency to tadalafil and superior selectivity over PDE11, the most common off-target for tadalafil. Modifying the stereochemistry into 6S, 12aS configuration and adopting the hydroxamic acid moiety as a terminal group gave rise to compounds that only inhibited HDAC. Dual PDE5/HDAC inhibition could be achieved with compounds having 6R, 12aR configuration and hydroxamic acid moiety as a terminal group. The anticancer activity of the synthesized compounds was evaluated against a diverse number of cell lines of different origin. The compounds elicited anticancer activity against cell lines belonging to lymphoproliferative cancer as well as solid tumors. Despite the previous reports suggesting anticancer activity of PDE5 inhibitors, the growth inhibitory activity of the compounds seemed to be solely dependent on HDAC inhibition. Compound 26 (pan HDAC IC50 = 14 nM, PDE5 IC50 = 46 nM) displayed the most potent anticancer activity in the present series and was shown to induce apoptosis in Molt-4 cells. HDAC isoform selectivity testing for compound 26 showed that it is more selective for HDAC6 and 8 over HDAC1 by more than 20-fold.
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Affiliation(s)
- Ahmed K ElHady
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Shou-Ping Shih
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, 70 Lien-Hai Road, Kaohsiung 804, Taiwan; Doctoral Degree Program in Marine Biotechnology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan
| | - Yu-Cheng Chen
- The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 40402, Taiwan
| | - Yi-Chang Liu
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Nermin S Ahmed
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Adam B Keeton
- Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36608, USA
| | - Gary A Piazza
- Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36608, USA
| | - Matthias Engel
- Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
| | - Ashraf H Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
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48
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Liu T, Wan Y, Xiao Y, Xia C, Duan G. Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy. J Med Chem 2020; 63:8977-9002. [PMID: 32320239 DOI: 10.1021/acs.jmedchem.0c00491] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.
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Affiliation(s)
- Tingting Liu
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Yichao Wan
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, Hunan, China
| | - Yuliang Xiao
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Chengcai Xia
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Guiyun Duan
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
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49
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Hii LW, Chung FFL, Soo JSS, Tan BS, Mai CW, Leong CO. Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously. Breast Cancer Res Treat 2020; 179:615-629. [PMID: 31784862 DOI: 10.1007/s10549-019-05504-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 11/22/2019] [Indexed: 02/05/2023]
Abstract
PURPOSE Breast cancer stem cells (CSCs) are a small subpopulation of cancer cells that have high capability for self-renewal, differentiation, and tumor initiation. CSCs are resistant to chemotherapy and radiotherapy, and are responsible for cancer recurrence and metastasis. METHODS By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs. RESULTS We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype. CONCLUSION In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.
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Affiliation(s)
- Ling-Wei Hii
- Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
- School of Postgraduate Studies and Research, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Felicia Fei-Lei Chung
- Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organization, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France
| | - Jaslyn Sian-Siu Soo
- Cancer Research Malaysia, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Boon Shing Tan
- Institute of Biological Chemistry, Academia Sinica, 128, Academia Road Sec. 2, Nankang, Taipei, 115, Taiwan
| | - Chun-Wai Mai
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
- Centre for Cancer and Stem Cell Research, Institute for Research, Development and Innovation, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Chee-Onn Leong
- Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia.
- Centre for Cancer and Stem Cell Research, Institute for Research, Development and Innovation, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia.
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50
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Urdinguio RG, Lopez V, Bayón GF, Diaz de la Guardia R, Sierra MI, García-Toraño E, Perez RF, García MG, Carella A, Pruneda PC, Prieto C, Dmitrijeva M, Santamarina P, Belmonte T, Mangas C, Diaconu E, Ferrero C, Tejedor JR, Fernandez-Morera JL, Bravo C, Bueno C, Sanjuan-Pla A, Rodriguez RM, Suarez-Alvarez B, López-Larrea C, Bernal T, Colado E, Balbín M, García-Suarez O, Chiara MD, Sáenz-de-Santa-María I, Rodríguez F, Pando-Sandoval A, Rodrigo L, Santos L, Salas A, Vallejo-Díaz J, C Carrera A, Rico D, Hernández-López I, Vayá A, Ricart JM, Seto E, Sima-Teruel N, Vaquero A, Valledor L, Cañal MJ, Pisano D, Graña-Castro O, Thomas T, Voss AK, Menéndez P, Villar-Garea A, Deutzmann R, Fernandez AF, Fraga MF. Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment. Nucleic Acids Res 2019; 47:5016-5037. [PMID: 30923829 PMCID: PMC6547425 DOI: 10.1093/nar/gkz195] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 02/26/2019] [Accepted: 03/15/2019] [Indexed: 12/14/2022] Open
Abstract
Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.
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Affiliation(s)
- Rocio G Urdinguio
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.,Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Virginia Lopez
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain
| | - Gustavo F Bayón
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Rafael Diaz de la Guardia
- Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Cáncer (CIBER-ONC), Barcelona, Spain
| | - Marta I Sierra
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Estela García-Toraño
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Raúl F Perez
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.,Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - María G García
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.,Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Antonella Carella
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.,Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Patricia C Pruneda
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Cristina Prieto
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Marija Dmitrijeva
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Pablo Santamarina
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.,Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Thalía Belmonte
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.,Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Cristina Mangas
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Elena Diaconu
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Cecilia Ferrero
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Juan Ramón Tejedor
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Juan Luis Fernandez-Morera
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Cristina Bravo
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Clara Bueno
- Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Cáncer (CIBER-ONC), Barcelona, Spain
| | - Alejandra Sanjuan-Pla
- Hematology Research Group, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, 46026, Spain
| | - Ramon M Rodriguez
- Translational Immunology Laboratory, Instituto de Investigación Sanitarias del Principado de Asturias (ISPA), Immunology Department, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Beatriz Suarez-Alvarez
- Translational Immunology Laboratory, Instituto de Investigación Sanitarias del Principado de Asturias (ISPA), Immunology Department, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Carlos López-Larrea
- Translational Immunology Laboratory, Instituto de Investigación Sanitarias del Principado de Asturias (ISPA), Immunology Department, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Teresa Bernal
- Servicio de Hematología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Enrique Colado
- Servicio de Hematología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Milagros Balbín
- Service of Molecular Oncology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Olivia García-Suarez
- Department of Morphology and Cellular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - María Dolores Chiara
- Otorhinolaryngology Service, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, CIBERONC, Oviedo, Spain
| | - Inés Sáenz-de-Santa-María
- Otorhinolaryngology Service, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, CIBERONC, Oviedo, Spain
| | - Francisco Rodríguez
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Ana Pando-Sandoval
- Hospital Universitario Central de Asturias (HUCA), Instituto Nacional de Silicosis (INS), Área del Pulmón, Facultad de Medicina, Universidad de Oviedo, Avenida Roma s/n, Oviedo, Asturias 33011, Spain
| | - Luis Rodrigo
- Hospital Universitario Central de Asturias (HUCA), Gastroenterology Service, Facultad de Medicina, Universidad de Oviedo, Avenida de Roma s/n, Oviedo, Asturias 33011, Spain
| | - Laura Santos
- Fundación para la Investigación Biosanitaria de Asturias (FINBA). Instituto de Investigación Sanitaria del Principado de Asturias (ISPA). Avenida de Roma s/n, 33011 Oviedo. Asturias. España
| | - Ana Salas
- Cytometry Service, Servicios Científico-Técnicos (SCTs). Universidad de Oviedo, Oviedo, Spain
| | - Jesús Vallejo-Díaz
- Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, 28049 Madrid, Spain
| | - Ana C Carrera
- Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, 28049 Madrid, Spain
| | - Daniel Rico
- Institute of Cellular Medicine, Newcastle University, UK
| | | | - Amparo Vayá
- Hemorheology and Haemostasis Unit, Service of Clinical Pathology, La Fe University Hospital, Valencia, Spain
| | | | - Edward Seto
- George Washington University Cancer Center, Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC 20037, USA
| | - Núria Sima-Teruel
- Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet, 199-203, 08907- L'Hospitalet de Llobregat, Barcelona, Spain
| | - Alejandro Vaquero
- Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet, 199-203, 08907- L'Hospitalet de Llobregat, Barcelona, Spain
| | - Luis Valledor
- Plant Physiology Lab, Department of Organisms and Systems Biology, Faculty of Biology, University of Oviedo, Oviedo, Asturias, Spain
| | - Maria Jesus Cañal
- Plant Physiology Lab, Department of Organisms and Systems Biology, Faculty of Biology, University of Oviedo, Oviedo, Asturias, Spain
| | - David Pisano
- Bioinformatics Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain
| | - Osvaldo Graña-Castro
- Bioinformatics Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain
| | - Tim Thomas
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
| | - Pablo Menéndez
- Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Cáncer (CIBER-ONC), Barcelona, Spain.,Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Ana Villar-Garea
- Institute of Biochemistry, Genetics and Microbiology, University of Regensburg, 93053 Regensburg, Germany
| | - Rainer Deutzmann
- Institute of Biochemistry, Genetics and Microbiology, University of Regensburg, 93053 Regensburg, Germany
| | - Agustín F Fernandez
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Mario F Fraga
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain
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