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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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Ibrahim S, Khan MU, Khurram I, Ghani MU, Sharifi-Rad J, Calina D. Anticancer efficacy of Spiruchostatin A: current insights into histone deacetylase inhibition and oncologic applications. Eur J Med Res 2025; 30:169. [PMID: 40082963 PMCID: PMC11907871 DOI: 10.1186/s40001-025-02401-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 02/21/2025] [Indexed: 03/16/2025] Open
Abstract
Spiruchostatin A also referred to as YM753 and OBP801, a cyclic peptide-based natural product derived from Pseudomonas sp., is distinguished by its potent inhibition of Class I histone deacetylases (HDACs). The modulation of epigenetic mechanisms by HDAC inhibitors is fundamental for altering gene expression related to cell growth, apoptosis, and differentiation, highlighting their potential in oncologic therapies. This updated review assesses the antitumor efficacy of Spiruchostatin A across diverse cellular and animal models, scrutinizing its viability as a therapeutic agent against various cancers. A systematic literature review was executed by searching databases such as PubMed/MedLine, Scopus, and Web of Science from October 2022 to February 2023. The inclusion criteria focused on studies involving Spiruchostatin A in the context of cancer treatment, including in vitro and in vivo models. The review concentrated on the compound's mechanistic action, biological activity, and clinical applicability. Spiruchostatin A has demonstrated significant antitumor activities, including inducing apoptosis and inhibiting tumor growth effectively in multiple models. Its therapeutic potential is particularly noted in synergistic applications with other anticancer agents, enhancing its efficacy. Mechanistically, the compound facilitates chromatin relaxation and transcriptional activation of key tumor suppressor genes through increased histone acetylation. Spiruchostatin A exhibits substantial potential as an anticancer agent through effective HDAC inhibition and subsequent epigenetic modifications of cancer cell biology. However, comprehensive clinical trials are imperative to validate its efficacy and safety profiles comprehensively. Future research is warranted to elucidate detailed molecular mechanisms and to develop biomarkers for predicting treatment response. Comprehensive longitudinal clinical studies are also critical to establish Spiruchostatin A's role within the broader oncological therapeutic regimen, along with the exploration of its analogs for improved therapeutic outcomes.
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Affiliation(s)
- Saooda Ibrahim
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Umer Khan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
| | - Iqra Khurram
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Usman Ghani
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, Ecuador.
- Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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Wu X, Wu H, Zhong M, Chen Y, Su W, Li P. Epigenetic regulation by naringenin and naringin: A literature review focused on the mechanisms underlying its pharmacological effects. Fitoterapia 2025; 181:106353. [PMID: 39706348 DOI: 10.1016/j.fitote.2024.106353] [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: 08/30/2024] [Revised: 12/06/2024] [Accepted: 12/15/2024] [Indexed: 12/23/2024]
Abstract
Epigenetics refers to heritable changes in gene expression or phenotypic changes that occur without changing the gene sequence. The main methods of epigenetics include non-coding RNA, histone modification, and DNA modification, which play an essential role in gene expression regulation and even the occurrence of diverse diseases. Naringenin, the aglycone form of naringin, is a natural flavonoid compound mainly found in fruits or plant derivatives such as citrus, tomatoes, and cherries. Naringenin and naringin exhibit a broad spectrum of biological activities and pharmacological effects, including anti-cancer, cardiovascular disease improving, anti-inflammatory, and anti-oxidant activities, all of which are advantageous for human health. Recent studies have uncovered that naringenin and naringin influence gene expression by modulating epigenetic pathways, including microRNA (miRNA) regulation. This mechanism plays a crucial role in the therapeutic potential for various diseases. This paper reviews the epigenetic researches on the physiological activities of naringenin and naringin. It highlights how these compounds can exert diverse effects through different signaling pathways, thereby ameliorating associated diseases. These findings provide valuable insights for the future applications of naringenin and naringin.
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Affiliation(s)
- Xiao Wu
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-Evaluation of Post-Marketed TCM, Guangdong Provincial Key Laboratory of Plant Stress Biology, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Hao Wu
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-Evaluation of Post-Marketed TCM, Guangdong Provincial Key Laboratory of Plant Stress Biology, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Mengli Zhong
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-Evaluation of Post-Marketed TCM, Guangdong Provincial Key Laboratory of Plant Stress Biology, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Yixuan Chen
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-Evaluation of Post-Marketed TCM, Guangdong Provincial Key Laboratory of Plant Stress Biology, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Weiwei Su
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-Evaluation of Post-Marketed TCM, Guangdong Provincial Key Laboratory of Plant Stress Biology, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Peibo Li
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-Evaluation of Post-Marketed TCM, Guangdong Provincial Key Laboratory of Plant Stress Biology, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China.
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Zhang Q, Yu J, You Q, Wang L. Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy. J Med Chem 2024; 67:21695-21716. [PMID: 39648992 DOI: 10.1021/acs.jmedchem.4c02624] [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: 12/10/2024]
Abstract
Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development of small molecules for precise regulation of protein phosphorylation holds great potential for drug design. While the traditional kinase/phosphatase small-molecule modulators have shown some success, achieving precise phosphorylation regulation has proven to be challenging. The emergence of heterobifunctional molecules, such as phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected to lead to a breakthrough by specifically recruiting kinase or phosphatase to the protein of interest. Herein, we summarize the drug targets with aberrant phosphorylation in cancer and underscore the potential of correcting phosphorylation in cancer therapy. Through reported cases of heterobifunctional molecules targeting phosphorylation regulation, we highlight the current design strategies and features of these molecules. We also provide a systematic elaboration of the link between aberrantly phosphorylated targets and cancer as well as the existing challenges and future research directions for developing heterobifunctional molecular drugs for phosphorylation regulation.
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Affiliation(s)
- Qiuyue Zhang
- State Key Laboratory of Natural Medicines and 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
| | - Jia Yu
- State Key Laboratory of Natural Medicines and 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
| | - Qidong You
- State Key Laboratory of Natural Medicines and 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
| | - Lei Wang
- State Key Laboratory of Natural Medicines and 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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5
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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: 5] [Impact Index Per Article: 5.0] [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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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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Drakontaeidi A, Pontiki E. A Review on Molecular Docking on HDAC Isoforms: Novel Tool for Designing Selective Inhibitors. Pharmaceuticals (Basel) 2023; 16:1639. [PMID: 38139766 PMCID: PMC10746130 DOI: 10.3390/ph16121639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/01/2023] [Accepted: 11/03/2023] [Indexed: 12/24/2023] Open
Abstract
Research into histone deacetylases (HDACs) has experienced a remarkable surge in recent years. These enzymes are key regulators of several fundamental biological processes, often associated with severe and potentially fatal diseases. Inhibition of their activity represents a promising therapeutic approach and a prospective strategy for the development of new therapeutic agents. A critical aspect of their inhibition is to achieve selectivity in terms of enzyme isoforms, which is essential to improve treatment efficacy while reducing undesirable pleiotropic effects. The development of computational chemistry tools, particularly molecular docking, is greatly enhancing the precision of designing molecules with inherent potential for specific activity. Therefore, it was considered necessary to review the molecular docking studies conducted on the major isozymes of the enzyme in order to identify the specific interactions associated with each selective HDAC inhibitor. In particular, the most critical isozymes of HDAC (1, 2, 3, 6, and 8) have been thoroughly investigated within the scope of this review.
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Affiliation(s)
| | - Eleni Pontiki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
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Lee SW, Frankston CM, Kim J. Epigenome editing in cancer: Advances and challenges for potential therapeutic options. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:191-230. [PMID: 38359969 DOI: 10.1016/bs.ircmb.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Cancers are diseases caused by genetic and non-genetic environmental factors. Epigenetic alterations, some attributed to non-genetic factors, can lead to cancer development. Epigenetic changes can occur in tumor suppressors or oncogenes, or they may contribute to global cell state changes, making cells abnormal. Recent advances in gene editing technology show potential for cancer treatment. Herein, we will discuss our current knowledge of epigenetic alterations occurring in cancer and epigenetic editing technologies that can be applied to developing therapeutic options.
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Affiliation(s)
- Seung-Won Lee
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Connor Mitchell Frankston
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Biomedical Engineering Graduate Program, Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Jungsun Kim
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR, United States; Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States.
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11
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Deng Y, Cheng Q, He J. HDAC inhibitors: Promising agents for leukemia treatment. Biochem Biophys Res Commun 2023; 680:61-72. [PMID: 37722346 DOI: 10.1016/j.bbrc.2023.09.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/04/2023] [Accepted: 09/11/2023] [Indexed: 09/20/2023]
Abstract
The essential role of epigenetic modification in the pathogenesis of a series of cancers have gradually been recognized. Histone deacetylase (HDACs), as well-known epigenetic modulators, are responsible for DNA repair, cell proliferation, differentiation, apoptosis and angiogenesis. Studies have shown that aberrant expression of HDACs is found in many cancer types. Thus, inhibition of HDACs has provided a promising therapeutic approach alternative for these patients. Since HDAC inhibitor (HDACi) vorinostat was first approved by the Food and Drug Administration (FDA) for treating cutaneous T-cell lymphoma (CTCL) in 2006, the combination of HDAC inhibitors with other molecules such as chemotherapeutic drugs has drawn much attention in current cancer treatment, especially in hematological malignancies therapy. Up to now, there have been more than twenty HDAC inhibitors investigated in clinic trials with five approvals being achieved. Indeed, Histone deacetylase inhibitors promote or enhance several different anticancer mechanisms and therefore are in evidence as potential antileukemia agents. In this review, we will focus on possible mechanisms by how HDAC inhibitors exert therapeutic benefit and their clinical utility in leukemia.
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Affiliation(s)
- Yun Deng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Cheng
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jing He
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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12
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Beljkas M, Ilic A, Cebzan A, Radovic B, Djokovic N, Ruzic D, Nikolic K, Oljacic S. Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer. Pharmaceutics 2023; 15:2581. [PMID: 38004560 PMCID: PMC10674519 DOI: 10.3390/pharmaceutics15112581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.
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Affiliation(s)
| | | | | | | | | | | | - Katarina Nikolic
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (M.B.); (A.I.); (A.C.); (B.R.); (N.D.); (D.R.)
| | - Slavica Oljacic
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (M.B.); (A.I.); (A.C.); (B.R.); (N.D.); (D.R.)
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13
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Wang D, Zhang Y, Liao Z, Ge H, Güngör C, Li Y. KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas. Sci Rep 2023; 13:18250. [PMID: 37880235 PMCID: PMC10600175 DOI: 10.1038/s41598-023-44536-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 10/10/2023] [Indexed: 10/27/2023] Open
Abstract
A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients.
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Affiliation(s)
- Dan Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yingjun Zhang
- Hunan Engineering and Technology Research Center for Agricultural Big Data Analysis and Decision-Making, Hunan Agricultural University, Changsha, China
| | - Zhouning Liao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Division of Translational Immunology, III, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Heming Ge
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cenap Güngör
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yuqiang Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
- NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, China.
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14
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Aleksandrova Y, Neganova M. Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases. Int J Mol Sci 2023; 24:14766. [PMID: 37834214 PMCID: PMC10573395 DOI: 10.3390/ijms241914766] [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: 08/10/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
The relationship between oncological pathologies and neurodegenerative disorders is extremely complex and is a topic of concern among a growing number of researchers around the world. In recent years, convincing scientific evidence has accumulated that indicates the contribution of a number of etiological factors and pathophysiological processes to the pathogenesis of these two fundamentally different diseases, thus demonstrating an intriguing relationship between oncology and neurodegeneration. In this review, we establish the general links between three intersecting aspects of oncological pathologies and neurodegenerative disorders, i.e., oxidative stress, epigenetic dysregulation, and metabolic dysfunction, examining each process in detail to establish an unusual epidemiological relationship. We also focus on reviewing the current trends in the research and the clinical application of the most promising chemical structures and therapeutic platforms that have a modulating effect on the above processes. Thus, our comprehensive analysis of the set of molecular determinants that have obvious cross-functional pathways in the pathogenesis of oncological and neurodegenerative diseases can help in the creation of advanced diagnostic tools and in the development of innovative pharmacological strategies.
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Affiliation(s)
- Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Margarita Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 420088 Kazan, Russia
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15
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Wang X, Jia Y, Xu X, Hu Y, Fan G, Jing D, Zhang Z, Wang C, Song C, Qin Y, Peng L. Nuclear receptor coactivator 6 (NCoA6) promotes cell proliferation, migration, and invasion in pancreatic cancer. Cancer Med 2023; 12:18425-18439. [PMID: 37553876 PMCID: PMC10524018 DOI: 10.1002/cam4.6427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 06/27/2023] [Accepted: 07/03/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Nuclear receptor coactivator 6 (NCoA6) is overexpressed in various cancers and considered a multifunctional coactivator of various transcription factors and nuclear receptors. However, the role of NCoA6 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS NCoA6 expression data in PDAC were extracted from TCGA and GTEx databases, and their correlation with survival outcomes were analyzed using the Kaplan-Meier plotter database. NCoA6 protein expression in PDAC tissues was evaluated using immunohistochemistry. RNA-sequencing technology was used to sequence the transcriptome of NCoA6-silenced PANC-1 cells, followed by differential expression, GO/KEGG and GSEA analyses. The effects of NCoA6 on cell proliferation, migration, invasion, cell cycle, and apoptosis were determined in two representative cell lines (PANC-1 and SW1990). Western blotting, qPCR, and co-immunoprecipitation were performed to explore the mechanism of action of NCoA6 in PDAC cells. RESULTS NCoA6 expression was markedly increased in PDAC tissues, and high NCoA6 expression was associated with poor survival prognosis. However, there was no significant relationship between NCoA6 expression and metastasis in PDAC patients. Our RNA-sequencing data analysis found 1194 significant differentially expressed genes between the control and NCoA6-silenced PANC-1 cells. GO/KEGG analysis results mainly focused on cytokine production, cytokine activity, and cytokine-cytokine receptor interactions. GSEA results showed that the knockdown of NCoA6 affected the expression of histone deacetylase 1 (HDAC1) targeted genes. NCoA6 knockdown suppressed proliferation, migration, and invasion of PDAC cells. Finally, western blotting, qPCR, and co-immunoprecipitation results showed that NCoA6 interacted with HDAC1 and that NCoA6 expression was negatively correlated with F-box and WD repeat domain-containing 7 (FBW7) and caudal-related homeobox transcription factor 2 (CDX2) expression in pancreatic cancer. CONCLUSIONS NCoA6 has a profound effect on cell proliferation, migration, invasion, and prognosis of PDAC and is potentially related to the expression of HDAC1, FBW7, and CDX2. Our results may provide novel therapeutic strategies for PDAC patients.
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Affiliation(s)
- Xin Wang
- Department of EmergencyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Yuming Jia
- Department of Hepatobiliary SurgeryThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Xiaowu Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer Institute, Fudan UniversityShanghaiChina
| | - Yuheng Hu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer Institute, Fudan UniversityShanghaiChina
| | - Guixiong Fan
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer Institute, Fudan UniversityShanghaiChina
| | - Desheng Jing
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer Institute, Fudan UniversityShanghaiChina
| | - Zhilei Zhang
- Department of Hepatobiliary SurgeryThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Chao Wang
- Department of Hepatobiliary SurgeryThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Changfeng Song
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer Institute, Fudan UniversityShanghaiChina
| | - Yi Qin
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer Institute, Fudan UniversityShanghaiChina
| | - Li Peng
- Department of Hepatobiliary SurgeryThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
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16
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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: 12] [Impact Index Per Article: 6.0] [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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17
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Wang Z, Muthusamy V, Petrylak DP, Anderson KS. Tackling FGFR3-driven bladder cancer with a promising synergistic FGFR/HDAC targeted therapy. NPJ Precis Oncol 2023; 7:70. [PMID: 37479885 PMCID: PMC10362036 DOI: 10.1038/s41698-023-00417-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 06/23/2023] [Indexed: 07/23/2023] Open
Abstract
Bladder cancer (BC) is one of the most prevalent malignancies worldwide and FGFR3 alterations are particularly common in BC. Despite approval of erdafitinib, durable responses for FGFR inhibitors are still uncommon and most patients relapse to metastatic disease. Given the necessity to discover more efficient therapies for BC, herein, we sought to explore promising synergistic combinations for BC with FGFR3 fusions. Our studies confirmed the synergy between FGFR and HDAC inhibitors in vitro and demonstrated its benefits in vivo. Mechanistic studies revealed that quisinostat can downregulate FGFR3 expression by suppressing FGFR3 translation. Additionally, quisinostat can also sensitize BC cells to erdafitinib by downregulating HDGF. Furthermore, the synergy was also confirmed in BC cells with FGFR3 S249C. This study discovers a new avenue for treatment of FGFR3-driven BC and uncovers new mechanistic insights. These preclinical studies pave the way for a direct translation of this combination to early phase clinical trials.
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Affiliation(s)
- Zechen Wang
- Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA
| | | | | | - Karen S Anderson
- Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA.
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA.
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18
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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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19
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Yang X, Xu L, Yang L. Recent advances in EZH2-based dual inhibitors in the treatment of cancers. Eur J Med Chem 2023; 256:115461. [PMID: 37156182 DOI: 10.1016/j.ejmech.2023.115461] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/04/2023] [Accepted: 05/04/2023] [Indexed: 05/10/2023]
Abstract
The enhancer of zeste homolog 2 (EZH2) protein is the catalytic subunit of one of the histone methyltransferases. EZH2 catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3) and further alters downstream target levels. EZH2 is upregulated in cancer tissues, wherein its levels correlate strongly with cancer genesis, progression, metastasis, and invasion. Consequently, it has emerged as a novel anticancer therapeutic target. Nonetheless, developing EZH2 inhibitors (EZH2i) has encountered numerous difficulties, such as pre-clinical drug resistance and poor therapeutic effect. The EZH2i synergistically suppresses cancers when used in combination with additional antitumor drugs, such as PARP inhibitors, HDAC inhibitors, BRD4 inhibitors, EZH1 inhibitors, and EHMT2 inhibitors. Typically, the use of dual inhibitors of two different targets mediated by one individual molecule has been recognized as the preferred approach for overcoming the limitations of EZH2 monotherapy. The present review discusses the theoretical basis for designing EZH2-based dual-target inhibitors, and also describes some in vitro and in vivo analysis results.
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Affiliation(s)
- Xiaojuan Yang
- School of Pharmacy, Xinxiang University, Xinxiang, 453003, China.
| | - Lu Xu
- School of Pharmacy, Xinxiang University, Xinxiang, 453003, China
| | - Li Yang
- School of Pharmacy, Xinxiang University, Xinxiang, 453003, China
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20
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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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21
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Abstract
Epigenetic alterations during ageing are manifested with altered gene expression linking it to lifespan regulation, genetic instability, and diseases. Diet and epigenetic modifiers exert a profound effect on the lifespan of an organism by modulating the epigenetic marks. However, our understanding of the multifactorial nature of the epigenetic process during ageing and the onset of disease conditions as well as its reversal by epidrugs, diet, or environmental factors is still mystifying. This review covers the key findings in epigenetics related to ageing and age-related diseases. Further, it holds a discussion about the epigenetic clocks and their implications in various age-related disease conditions including cancer. Although, epigenetics is a reversible process how fast the epigenetic alterations can revert to normal is an intriguing question. Therefore, this paper touches on the possibility of utilizing nutrition and MSCs secretome to accelerate the epigenetic reversal and emphasizes the identification of new therapeutic epigenetic modifiers to counter epigenetic alteration during ageing.
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Affiliation(s)
- Shikha Sharma
- Institute for Stem Cell Science and Regenerative Medicine, 429164, Bangalore, India;
| | - Ramesh Bhonde
- Dr D Y Patil Vidyapeeth University, 121766, Pune, Maharashtra, India;
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22
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Zhao M, Yang K, Zhu X, Gao T, Yu W, Liu H, You Z, Liu Z, Qiao X, Song Y. Design, synthesis and biological evaluation of dual Topo II/HDAC inhibitors bearing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs. Eur J Med Chem 2023; 252:115303. [PMID: 36996717 DOI: 10.1016/j.ejmech.2023.115303] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/21/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023]
Abstract
Both topoisomerase II (Topo II) and histone deacetylase (HDAC) are important therapeutic targets for cancer. In this study, two series of novel compounds containing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs were designed and synthesized as dual Topo II/HDAC inhibitors. MTT assay indicated that all the compounds displayed potential antiproliferative activity against three cancer cell lines (MGC-803, MCF-7 and U937) and low cytotoxicity on normal cell line (3T3). In the enzyme activity inhibition experiments, compounds 7d and 8d exhibited excellent dual inhibitory activities against Topo II and HDAC. Cleavage reaction assay showed that 7d was a Topo II poison, which was consistent with the docking results. Further experimental results revealed that compounds 7d and 8d could promote apoptosis and significantly inhibit the migration in MCF-7 cells. Molecular docking showed that compounds 7d and 8d bind Topo II and HDAC at the active sites. Molecular dynamics simulation showed that 7d can stably bind to Topo II and HDAC.
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Affiliation(s)
- Mengmiao Zhao
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Kan Yang
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Xinyue Zhu
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Tian Gao
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Wei Yu
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Han Liu
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Zhihao You
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiaoqiang Qiao
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China.
| | - Yali Song
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China.
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Chandrasekaran B, Tapadar S, Wu B, Saran U, Tyagi A, Johnston A, Gaul DA, Oyelere AK, Damodaran C. Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC). Cancers (Basel) 2023; 15:1769. [PMID: 36980655 PMCID: PMC10046692 DOI: 10.3390/cancers15061769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023] Open
Abstract
BACKGROUND Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). METHODS Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. RESULTS While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. CONCLUSION These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.
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Affiliation(s)
| | - Subhasish Tapadar
- Parker H. Petit Institute for Bioengineering & Biosciences, School of Chemistry and Biochemistry, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Bocheng Wu
- Parker H. Petit Institute for Bioengineering & Biosciences, School of Chemistry and Biochemistry, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Uttara Saran
- Rangel School of Pharmacy, Texas A&M University, College Station, TX 77845, USA
| | - Ashish Tyagi
- Rangel School of Pharmacy, Texas A&M University, College Station, TX 77845, USA
| | - Alexis Johnston
- Parker H. Petit Institute for Bioengineering & Biosciences, School of Chemistry and Biochemistry, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - David A. Gaul
- Parker H. Petit Institute for Bioengineering & Biosciences, School of Chemistry and Biochemistry, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Adegboyega K. Oyelere
- Parker H. Petit Institute for Bioengineering & Biosciences, School of Chemistry and Biochemistry, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Chendil Damodaran
- Rangel School of Pharmacy, Texas A&M University, College Station, TX 77845, USA
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24
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El-Sayed A, Aleya L, Kamel M. Epigenetics and the role of nutraceuticals in health and disease. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:28480-28505. [PMID: 36694069 DOI: 10.1007/s11356-023-25236-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 01/05/2023] [Indexed: 06/17/2023]
Abstract
In the post-genomic era, the data provided by complete genome sequencing could not answer several fundamental questions about the causes of many noninfectious diseases, diagnostic biomarkers, and novel therapeutic approaches. The rapidly expanding understanding of epigenetic mechanisms, as well as widespread acceptance of their hypothesized role in disease induction, facilitated the development of a number of novel diagnostic markers and therapeutic concepts. Epigenetic aberrations are reversible in nature, which enables the treatment of serious incurable diseases. Therefore, the interest in epigenetic modulatory effects has increased over the last decade, so about 60,000 publications discussing the expression of epigenetics could be detected in the PubMed database. Out of these, 58,442 were published alone in the last 10 years, including 17,672 reviews (69 historical articles), 314 clinical trials, 202 case reports, 197 meta-analyses, 156 letters to the editor, 108 randomized controlled trials, 87 observation studies, 40 book chapters, 22 published lectures, and 2 clinical trial protocols. The remaining publications are either miscellaneous or a mixture of the previously mentioned items. According to the species and gender, the publications included 44,589 human studies (17,106 females, 14,509 males, and the gender is not mentioned in the remaining papers) and 30,253 animal studies. In the present work, the role of epigenetic modulations in health and disease and the influencing factors in epigenetics are discussed.
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Affiliation(s)
- Amr El-Sayed
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, 25030, Besançon Cedex, France
| | - Mohamed Kamel
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt.
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25
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Bernal L, Pinzi L, Rastelli G. Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing. Int J Mol Sci 2023; 24:ijms24043135. [PMID: 36834548 PMCID: PMC9964599 DOI: 10.3390/ijms24043135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Prostate cancer (PC) is one of the most common types of cancer in males. Although early stages of PC are generally associated with favorable outcomes, advanced phases of the disease present a significantly poorer prognosis. Moreover, currently available therapeutic options for the treatment of PC are still limited, being mainly focused on androgen deprivation therapies and being characterized by low efficacy in patients. As a consequence, there is a pressing need to identify alternative and more effective therapeutics. In this study, we performed large-scale 2D and 3D similarity analyses between compounds reported in the DrugBank database and ChEMBL molecules with reported anti-proliferative activity on various PC cell lines. The analyses included also the identification of biological targets of ligands with potent activity on PC cells, as well as investigations on the activity annotations and clinical data associated with the more relevant compounds emerging from the ligand-based similarity results. The results led to the prioritization of a set of drugs and/or clinically tested candidates potentially useful in drug repurposing against PC.
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Affiliation(s)
- Leonardo Bernal
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Luca Pinzi
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
| | - Giulio Rastelli
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
- Correspondence: ; Tel.: +39-059-2058564
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26
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Targeting emerging cancer hallmarks by transition metal complexes: Epigenetic reprogramming and epitherapies. Part II. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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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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28
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Shozu K, Kaneko S, Shinkai N, Dozen A, Kosuge H, Nakakido M, Machino H, Takasawa K, Asada K, Komatsu M, Tsumoto K, Ohnuma SI, Hamamoto R. Repression of the PRELP gene is relieved by histone deacetylase inhibitors through acetylation of histone H2B lysine 5 in bladder cancer. Clin Epigenetics 2022; 14:147. [PMID: 36371227 PMCID: PMC9656081 DOI: 10.1186/s13148-022-01370-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Proline/arginine-rich end leucine-rich repeat protein (PRELP) is a member of the small leucine-rich proteoglycan family of extracellular matrix proteins, which is markedly suppressed in the majority of early-stage epithelial cancers and plays a role in regulating the epithelial-mesenchymal transition by altering cell-cell adhesion. Although PRELP is an important factor in the development and progression of bladder cancer, the mechanism of PRELP gene repression remains unclear. RESULTS Here, we show that repression of PRELP mRNA expression in bladder cancer cells is alleviated by HDAC inhibitors (HDACi) through histone acetylation. Using ChIP-qPCR analysis, we found that acetylation of lysine residue 5 of histone H2B in the PRELP gene promoter region is a marker for the de-repression of PRELP expression. CONCLUSIONS These results suggest a mechanism through which HDACi may partially regulate the function of PRELP to suppress the development and progression of bladder cancer. Some HDACi are already in clinical use, and the findings of this study provide a mechanistic basis for further investigation of HDACi-based therapeutic strategies.
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Affiliation(s)
- Kanto Shozu
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.267346.20000 0001 2171 836XDepartment of Obstetrics and Gynecology, University of Toyama, Toyama, Japan
| | - Syuzo Kaneko
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan
| | - Norio Shinkai
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan ,grid.265073.50000 0001 1014 9130Department of NCC Cancer Science, Biomedical Science and Engineering Track, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ai Dozen
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Hirofumi Kosuge
- grid.26999.3d0000 0001 2151 536XSchool of Engineering, The University of Tokyo, Tokyo, Japan
| | - Makoto Nakakido
- grid.26999.3d0000 0001 2151 536XSchool of Engineering, The University of Tokyo, Tokyo, Japan
| | - Hidenori Machino
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan
| | - Ken Takasawa
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan
| | - Ken Asada
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan
| | - Masaaki Komatsu
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan
| | - Kouhei Tsumoto
- grid.26999.3d0000 0001 2151 536XSchool of Engineering, The University of Tokyo, Tokyo, Japan
| | - Shin-Ichi Ohnuma
- grid.83440.3b0000000121901201UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL UK ,grid.5335.00000000121885934Department of Oncology, The Hutchison/MRC Research Center, University of Cambridge, Hills Road, Cambridge, CB2 2XZ UK
| | - Ryuji Hamamoto
- grid.272242.30000 0001 2168 5385Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan ,grid.509456.bRIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Tokyo, Japan
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Karaj E, Sindi SH, Kuganesan N, Koranne RA, Knoff JR, James AW, Fu Y, Kotsull LN, Pflum MK, Shah Z, Taylor WR, Tillekeratne LMV. First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids. J Med Chem 2022; 65:14764-14791. [PMID: 36306372 PMCID: PMC10257520 DOI: 10.1021/acs.jmedchem.2c01276] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
HDAC inhibitors are an attractive class of cytotoxic agents for the design of hybrid molecules. Several HDAC hybrids have emerged over the years, but none combines HDAC inhibition with ferroptosis, a combination which is being extensively studied because it leads to enhanced cytotoxicity and attenuated neuronal toxicity. We combined the pharmacophores of SAHA and CETZOLE molecules to design the first-in-class dual mechanism hybrid molecules, which induce ferroptosis and inhibit HDAC proteins. The involvement of both mechanisms in cytotoxicity was confirmed by a series of biological assays. The cytotoxic effects were evaluated in a series of cancer and neuronal cell lines. Analogue HY-1 demonstrated the best cytotoxic profile with GI50 values as low as 20 nM. Although the increase in activity of the hybrids over the combinations is modest in cellular systems, they have the potential advantage of homogeneous spatiotemporal distribution in in vivo systems.
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Affiliation(s)
- Endri Karaj
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States
| | - Shaimaa H Sindi
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States
| | - Nishanth Kuganesan
- Department of Biological Sciences, College of Natural Sciences and Mathematics, University of Toledo, Toledo, Ohio 43606, United States
| | - Radhika A Koranne
- Department of Biological Sciences, College of Natural Sciences and Mathematics, University of Toledo, Toledo, Ohio 43606, United States
| | - Joseph R Knoff
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
| | - Antonisamy William James
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States
| | - Yu Fu
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States
| | - Lauren N Kotsull
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
| | - Mary Kay Pflum
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
| | - Zahoor Shah
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States
| | - William R Taylor
- Department of Biological Sciences, College of Natural Sciences and Mathematics, University of Toledo, Toledo, Ohio 43606, United States
| | - L M Viranga Tillekeratne
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States
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Ren X, Jiang Z, Xu K. HDAC2 Induces DNA Methyltransferase DNMT3B Expression to Regulate the Wnt Signaling Pathway and Thus Promotes Glioma Development and Progression. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:1948766. [PMID: 36267089 PMCID: PMC9578850 DOI: 10.1155/2022/1948766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/18/2022]
Abstract
Purpose To investigate the role and molecular mechanism of HDAC2 in glioma. Methods GSE16011, GSE31262, and GSE90598 datasets were used to identify co-expressed genes, GO analysis, and KEGG analysis to identify gene enrichment pathways, and PPI networks were constructed to identify gene interrelationships. HDAC2 enrichment on DNMT3B promoter and DNMT3B enrichment on Bcl2 CpG island was detected by a ChIP assay. The expression, prognosis, and hierarchical distribution of HDAC2, DNMT3B, and Bcl2 were examined in the CGGA database, and the correlation between HDAC2 and DNMT3B, Bcl2, and DNMT3B and Bcl2 was assessed. Results The HDAC2-DNMT3B-Bcl2 axis is differentially expressed and interacts in gliomas. HDAC2 activates the transcriptional activity of DNMT3B, and DNMT3B inhibits the expression of Bcl2. HDAC2 and DNMT3B are highly expressed in gliomas and have a poor prognosis, while Bcl2 is lowly expressed in gliomas and has a good prognosis. Conclusion HDAC2 promotes DNMT3B transcriptional repression of Bcl2 expression and Wnt pathway activity, thereby activating glioma cell activity in vitro and in vivo.
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Affiliation(s)
- Xing Ren
- Department of Oncology, Radiotherapy Center, Chongqing General Hospital, Chongqing, China
| | - Zhan Jiang
- Department of Oncology, Radiotherapy Center, Chongqing General Hospital, Chongqing, China
| | - Ke Xu
- Department of Oncology, Radiotherapy Center, Chongqing General Hospital, Chongqing, China
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Garmpis N, Damaskos C, Dimitroulis D, Kouraklis G, Garmpi A, Sarantis P, Koustas E, Patsouras A, Psilopatis I, Antoniou EA, Karamouzis MV, Kontzoglou K, Nonni A. Clinical Significance of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer. J Pers Med 2022; 12:1672. [PMID: 36294811 PMCID: PMC9604828 DOI: 10.3390/jpm12101672] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND/AIM There is a strong association between malignancy and histone deacetylases (HDACs). Histone deacetylase inhibitors (HDACIs) are now being tested as antitumor agents in various clinical trials. We aimed to assess the clinical importance of HDAC-2 in breast cancer (BC). MATERIALS AND METHODS A total of 118 BC specimens were examined immunohistochemically. A statistical analysis was conducted in order to examine the relation between HDAC-2 and the clinicopathological features and survival of the patients. RESULTS Higher HDAC-2 expression was related to lobular histological type of cancer, grade III, and stage III BC. In addition, the disease-free period and overall survival were curtailed and negatively related to the over-expression of HDAC-2. Other factors correlating with worse survival were histological types other than ductal or lobular, and the stage of the disease. CONCLUSIONS This study showed a relationship between HDAC-2 and BC. Further studies are required in order to eventually potentiate the role of HDACIs as anticancer agents in BC.
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Affiliation(s)
- Nikolaos Garmpis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christos Damaskos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Gregory Kouraklis
- Department of Surgery, Evgenideio Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Alexandros Patsouras
- Second Department of Pulmonology, Sotiria General Hospital, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Efstathios A. Antoniou
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Afroditi Nonni
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Cetin MM, Peng W, Unruh D, Mayer MF, Mechref Y, Yelekci K. Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper(I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs. Front Pharmacol 2022; 13:980479. [PMID: 36267272 PMCID: PMC9578020 DOI: 10.3389/fphar.2022.980479] [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: 06/28/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is the second type of cancer with a high probability of brain metastasis and has always been one of the main problems of breast cancer research due to the lack of effective treatment methods. Demand for developing an effective drug against breast cancer brain metastasis and finding molecular mechanisms that play a role in effective treatment are gradually increasing. However, there is no effective anticancer therapeutic drug or treatment method specific to breast cancer, in particular, for patients with a high risk of brain metastases. It is known that mTOR and HDAC enzymes play essential roles in the development of breast cancer brain metastasis. Therefore, it is vital to develop some new drugs and conduct studies toward the inhibition of these enzymes that might be a possible solution to treat breast cancer brain metastasis. In this study, a series of 1,10-phenanthroline and Prodigiosin derivatives consisting of their copper(I) complexes have been synthesized and characterized. Their biological activities were tested in vitro on six different cell lines (including the normal cell line). To obtain additional parallel validations of the experimental data, some in silico modeling studies were carried out with mTOR and HDAC1 enzymes, which are very crucial drug targets, to discover novel and potent drugs for breast cancer and related brain metastases disease.
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Affiliation(s)
- M. Mustafa Cetin
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, Istanbul, Turkey
- *Correspondence: M. Mustafa Cetin, ; Kemal Yelekci, ; Yehia Mechref,
| | - Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Daniel Unruh
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Michael F. Mayer
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
- *Correspondence: M. Mustafa Cetin, ; Kemal Yelekci, ; Yehia Mechref,
| | - Kemal Yelekci
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, Istanbul, Turkey
- *Correspondence: M. Mustafa Cetin, ; Kemal Yelekci, ; Yehia Mechref,
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Korkmaz IN, Özdemir H. Synthesis and Anticancer Potential of New Hydroxamic Acid Derivatives as Chemotherapeutic Agents. Appl Biochem Biotechnol 2022; 194:6349-6366. [PMID: 35917102 DOI: 10.1007/s12010-022-04107-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2022] [Indexed: 11/25/2022]
Abstract
Histone deacetylase (HDAC) inhibitors have been shown to induce differentiation, cell cycle arrest, and apoptosis due to their low toxicity, inhibiting migration, invasion, and angiogenesis in many cancer cells. Studies show that hydroxamic acids are generally used as anticancers. For this reason, it is aimed to synthesize new derivatives of hydroxamic acids, to examine the anticancer properties of these candidate inhibitors, and to investigate the inhibition effects on some enzymes that cause multidrug resistance in cancer cells. For this reason, new (4-amino-2-methoxy benzohydroxamic acid (a), 4-amino-3-methyl benzohydroxamic acid (b), 3-amino-5-methyl benzohydroxamic acid (c)) amino benzohydroxamic acid derivatives were synthesized in this study. The effects on healthy fibroblast, lung (A549), and cervical (HeLa) cancer cells were investigated. In addition, their effects on TRXR1, GST, and GR activities, which are important for the development of chemotherapeutic strategies, were also examined. It was determined that molecule b was the most effective molecule in HeLa cancer cells with the lowest IC50 value of 0.54. It was determined that molecule c was the most effective molecules for A549 and HeLa cancer cells, with the lowest IC50 values of 0.78 mM and 0.25 mM, respectively. It was determined that b and c molecules directed cancer cells to necrosis rather than apoptosis. c molecule showed anticancer effect in A549 and HeLa cancer cells. It was found that molecule c significantly suppressed both GR and TRXR1 activities. In GST activities, however, inhibitors did not have a significant effect on cancer cells.
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Affiliation(s)
- Işıl Nihan Korkmaz
- Faculty of Science, Department of Chemistry, Atatürk University, Erzurum, 25240, Turkey
| | - Hasan Özdemir
- Faculty of Science, Department of Chemistry, Atatürk University, Erzurum, 25240, Turkey.
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Hess L, Moos V, Lauber AA, Reiter W, Schuster M, Hartl N, Lackner D, Boenke T, Koren A, Guzzardo PM, Gundacker B, Riegler A, Vician P, Miccolo C, Leiter S, Chandrasekharan MB, Vcelkova T, Tanzer A, Jun JQ, Bradner J, Brosch G, Hartl M, Bock C, Bürckstümmer T, Kubicek S, Chiocca S, Bhaskara S, Seiser C. A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation. PLoS Genet 2022; 18:e1010376. [PMID: 35994477 PMCID: PMC9436093 DOI: 10.1371/journal.pgen.1010376] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 09/01/2022] [Accepted: 08/06/2022] [Indexed: 02/07/2023] Open
Abstract
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.
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Affiliation(s)
- Lena Hess
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Verena Moos
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Arnel A. Lauber
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Reiter
- Mass Spectrometry Core Facility, Max Perutz Labs, Vienna BioCenter, Vienna, Austria
- Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Vienna, Austria
| | - Michael Schuster
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Natascha Hartl
- Mass Spectrometry Core Facility, Max Perutz Labs, Vienna BioCenter, Vienna, Austria
| | | | - Thorina Boenke
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Anna Koren
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | | | - Brigitte Gundacker
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Anna Riegler
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Petra Vician
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Claudia Miccolo
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Susanna Leiter
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Mahesh B. Chandrasekharan
- Department of Radiation Oncology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Terezia Vcelkova
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Andrea Tanzer
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Jun Qi Jun
- Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - James Bradner
- Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Gerald Brosch
- Institute of Molecular Biology, Innsbruck Medical University, Innsbruck, Austria
| | - Markus Hartl
- Mass Spectrometry Core Facility, Max Perutz Labs, Vienna BioCenter, Vienna, Austria
- Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Vienna, Austria
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Artificial Intelligence, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | | | - Stefan Kubicek
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Srividya Bhaskara
- Department of Radiation Oncology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Christian Seiser
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
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Mo H, Zhang R, Chen Y, Li S, Wang Y, Zou W, Lin Q, Zhao DG, Du Y, Zhang K, Ma YY. Synthesis and anticancer activity of novel histone deacetylase inhibitors that inhibit autophagy and induce apoptosis. Eur J Med Chem 2022; 243:114705. [PMID: 36215854 DOI: 10.1016/j.ejmech.2022.114705] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/10/2022] [Accepted: 08/19/2022] [Indexed: 12/01/2022]
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Alseksek RK, Ramadan WS, Saleh E, El-Awady R. The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention. Int J Mol Sci 2022; 23:8141. [PMID: 35897717 PMCID: PMC9331760 DOI: 10.3390/ijms23158141] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 02/01/2023] Open
Abstract
Throughout the process of carcinogenesis, cancer cells develop intricate networks to adapt to a variety of stressful conditions including DNA damage, nutrient deprivation, and hypoxia. These molecular networks encounter genomic instability and mutations coupled with changes in the gene expression programs due to genetic and epigenetic alterations. Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. Elucidation of the signaling pathways involved in the adaptive responses to cellular stress and the role of HDACs may lead to the development of novel therapeutic agents. In this article, we overview the dominant stress types including metabolic, oxidative, genotoxic, and proteotoxic stress imposed on cancer cells in the context of HDACs, which guide stress adaptation responses. Next, we expose a closer view on the therapeutic interventions and clinical trials that involve HDACs inhibitors, in addition to highlighting the impact of using HDAC inhibitors in combination with stress-inducing agents for the management of cancer and to overcome the resistance to current cancer therapy.
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Affiliation(s)
- Rahma K. Alseksek
- College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates;
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Wafaa S. Ramadan
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Ekram Saleh
- Clinical Biochemistry and Molecular Biology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 12613, Egypt;
| | - Raafat El-Awady
- College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates;
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
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37
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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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38
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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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Govindarajan V, Shah AH, Di L, Rivas S, Suter RK, Eichberg DG, Luther E, Lu V, Morell AA, Ivan ME, Komotar RJ, Ayad N, De La Fuente M. Systematic Review of Epigenetic Therapies for Treatment of IDH-mutant Glioma. World Neurosurg 2022; 162:47-56. [PMID: 35314408 PMCID: PMC9177782 DOI: 10.1016/j.wneu.2022.03.051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/11/2022] [Accepted: 03/12/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Isocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the oncometabolite 2-hydroxyglutarate. Therefore, therapies targeting reversal of epigenetic dysregulation in gliomas have been suggested. However, the utility of epigenetic treatments in gliomas remains unclear. Here, we present the first clinical systematic review of epigenetic therapies in treatment of IDH-mutant gliomas and highlight their safety and efficacy. METHODS We conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safety/tolerability of epigenetic therapies and progression-free survival/overall survival, respectively. RESULTS A total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3/grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%. CONCLUSION IDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.
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Affiliation(s)
- Vaidya Govindarajan
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ashish H Shah
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
| | - Long Di
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Sarah Rivas
- Surgical Neurology Branch, National Institute of Health, Bethesda, Maryland, USA
| | - Robert K Suter
- Department of Oncology, Georgetown University, Washington, DC, USA
| | - Daniel G Eichberg
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Evan Luther
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Victor Lu
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Alexis A Morell
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Michael E Ivan
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ricardo J Komotar
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Nagi Ayad
- Department of Oncology, Georgetown University, Washington, DC, USA
| | - Macarena De La Fuente
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
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Zhao W, Jiang X, Weisenthal K, Ma J, Botticelli EM, Zhou Y, Hedley-Whyte ET, Wang B, Swearingen B, Soberman RJ, Klibanski A, Zhang X. High Histone Deacetylase 2/3 Expression in Non-Functioning Pituitary Tumors. Front Oncol 2022; 12:875122. [PMID: 35646715 PMCID: PMC9136140 DOI: 10.3389/fonc.2022.875122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Epigenetic modification of chromatin is involved in non-malignant pituitary neoplasia by causing abnormal expression of tumor suppressors and oncogenes. These changes are potentially reversible, suggesting the possibility of targeting tumor cells by restoring the expression of epigenetically silenced tumor suppressors. The role of the histone deacetylase (HDAC) family in pituitary tumorigenesis is not known. We report that HDAC2 and 3, Class I HDAC members, are highly expressed in clinically non-functioning pituitary adenomas (NFPAs) compared to normal pituitary (NP) samples as determined by RT-PCR and immunohistochemical staining (IHC). Treatment of a human NFPA derived folliculostellate cell line, PDFS, with the HDAC3 inhibitor RGFP966 for 96 hours resulted in inhibition of cell proliferation by 70%. Furthermore, the combination of RGFP966 with a methyltransferase/DNMT inhibitor, 5’-aza-2’-deoxycytidine, led to the restoration of the expression of several tumor suppressor genes, including STAT1, P16, PTEN, and the large non-coding RNA tumor suppressor MEG3, in PDFS cells. Our data support the hypothesis that both histone modification and DNA methylation are involved in the pathogenesis of human NFPAs and suggest that targeting HDACs and DNA methylation can be incorporated into future therapies.
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Affiliation(s)
- Wenxiu Zhao
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Xiaobin Jiang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Karrin Weisenthal
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Jun Ma
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Erin M. Botticelli
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Yunli Zhou
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - E. Tessa Hedley-Whyte
- Neuropathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Baiyao Wang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Brooke Swearingen
- Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Roy J. Soberman
- Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Anne Klibanski
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Xun Zhang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- *Correspondence: Xun Zhang,
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Barbosa-Silva A, Magalhães M, Da Silva GF, Da Silva FAB, Carneiro FRG, Carels N. A Data Science Approach for the Identification of Molecular Signatures of Aggressive Cancers. Cancers (Basel) 2022; 14:2325. [PMID: 35565454 PMCID: PMC9103663 DOI: 10.3390/cancers14092325] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/04/2022] [Accepted: 03/12/2022] [Indexed: 02/05/2023] Open
Abstract
The main hallmarks of cancer include sustaining proliferative signaling and resisting cell death. We analyzed the genes of the WNT pathway and seven cross-linked pathways that may explain the differences in aggressiveness among cancer types. We divided six cancer types (liver, lung, stomach, kidney, prostate, and thyroid) into classes of high (H) and low (L) aggressiveness considering the TCGA data, and their correlations between Shannon entropy and 5-year overall survival (OS). Then, we used principal component analysis (PCA), a random forest classifier (RFC), and protein-protein interactions (PPI) to find the genes that correlated with aggressiveness. Using PCA, we found GRB2, CTNNB1, SKP1, CSNK2A1, PRKDC, HDAC1, YWHAZ, YWHAB, and PSMD2. Except for PSMD2, the RFC analysis showed a different list, which was CAD, PSMD14, APH1A, PSMD2, SHC1, TMEFF2, PSMD11, H2AFZ, PSMB5, and NOTCH1. Both methods use different algorithmic approaches and have different purposes, which explains the discrepancy between the two gene lists. The key genes of aggressiveness found by PCA were those that maximized the separation of H and L classes according to its third component, which represented 19% of the total variance. By contrast, RFC classified whether the RNA-seq of a tumor sample was of the H or L type. Interestingly, PPIs showed that the genes of PCA and RFC lists were connected neighbors in the PPI signaling network of WNT and cross-linked pathways.
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Affiliation(s)
- Adriano Barbosa-Silva
- Center for Medical Statistics, Informatics and Intelligent Systems, Institute for Artificial Intelligence, Medical University of Vienna, 1090 Vienna, Austria
- Centre for Translational Bioinformatics, William Harvey Research Institute, Queen Mary University of London, London E14NS, UK
- ITTM S.A.-Information Technology for Translational Medicine, Esch-sur-Alzette, 4354 Luxembourg, Luxembourg
| | - Milena Magalhães
- Plataforma de Modelagem de Sistemas Biológicos, Center for Technology Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040900, Brazil
| | - Gilberto Ferreira Da Silva
- Plataforma de Modelagem de Sistemas Biológicos, Center for Technology Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040900, Brazil
| | - Fabricio Alves Barbosa Da Silva
- Laboratório de Modelagem Computacional de Sistemas Biológicos, Scientific Computing Program, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040900, Brazil
| | - Flávia Raquel Gonçalves Carneiro
- Center for Technology Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040900, Brazil
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040900, Brazil
- Program of Immunology and Tumor Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231050, Brazil
| | - Nicolas Carels
- Plataforma de Modelagem de Sistemas Biológicos, Center for Technology Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040900, Brazil
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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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Lacoursiere RE, Hadi D, Shaw GS. Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road. Biomolecules 2022; 12:biom12030467. [PMID: 35327659 PMCID: PMC8946176 DOI: 10.3390/biom12030467] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 02/06/2023] Open
Abstract
Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is complex due to the combinatorial power of ~35 E2 and ~1000 E3 enzymes involved and the multiple lysine residues on ubiquitin that can be used to assemble polyubiquitin chains. Recently, mass spectrometric methods have identified that most enzymes in the ubiquitination cascade can be further modified through acetylation or phosphorylation under particular cellular conditions and altered modifications have been noted in different cancers and neurodegenerative diseases. This review provides a cohesive summary of ubiquitination, acetylation, and phosphorylation sites in ubiquitin, the human E1 enzyme UBA1, all E2 enzymes, and some representative E3 enzymes. The potential impacts these post-translational modifications might have on each protein function are highlighted, as well as the observations from human disease.
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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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The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions. Biomolecules 2022; 12:biom12030367. [PMID: 35327559 PMCID: PMC8945214 DOI: 10.3390/biom12030367] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer is a complex disease resulting from the genetic and epigenetic disruption of normal cells. The mechanistic understanding of the pathways involved in tumor transformation has implicated a priori predominance of epigenetic perturbations and a posteriori genetic instability. In this work, we aimed to explain the mechanistic involvement of epigenetic pathways in the cancer process, as well as the abilities of natural bioactive compounds isolated from medicinal plants (flavonoids, phenolic acids, stilbenes, and ketones) to specifically target the epigenome of tumor cells. The molecular events leading to transformation, angiogenesis, and dissemination are often complex, stochastic, and take turns. On the other hand, the decisive advances in genomics, epigenomics, transcriptomics, and proteomics have allowed, in recent years, for the mechanistic decryption of the molecular pathways of the cancerization process. This could explain the possibility of specifically targeting this or that mechanism leading to cancerization. With the plasticity and flexibility of epigenetic modifications, some studies have started the pharmacological screening of natural substances against different epigenetic pathways (DNA methylation, histone acetylation, histone methylation, and chromatin remodeling) to restore the cellular memory lost during tumor transformation. These substances can inhibit DNMTs, modify chromatin remodeling, and adjust histone modifications in favor of pre-established cell identity by the differentiation program. Epidrugs are molecules that target the epigenome program and can therefore restore cell memory in cancerous diseases. Natural products isolated from medicinal plants such as flavonoids and phenolic acids have shown their ability to exhibit several actions on epigenetic modifiers, such as the inhibition of DNMT, HMT, and HAT. The mechanisms of these substances are specific and pleiotropic and can sometimes be stochastic, and their use as anticancer epidrugs is currently a remarkable avenue in the fight against human cancers.
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Adewole K, Ishola A, Olaoye I. In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2022. [DOI: 10.1186/s43088-021-00191-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
Background
Cancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are now considering inhibition of HDAC as a strategy for the treatment of cancer. In this study, a receptor-based in silico screening was exploited to identify potential HDAC inhibitors among the compounds isolated from Cajanus cajan, since reports have earlier confirmed the antiproliferative properties of compounds isolated from this plant.
Results
Cajanus cajan-derived phytochemicals were docked with selected HDACs, with givinostat as the reference HDAC inhibitor, using AutodockVina and Discovery Studio Visualizer, BIOVIA, 2020. Furthermore, absorption, distribution, metabolism and excretion (ADME) drug-likeness analysis was done using the Swiss online ADME web tool. From the results obtained, 4 compounds; betulinic acid, genistin, orientin and vitexin, were identified as potential inhibitors of the selected HDACs, while only 3 compounds (betulinic acid, genistin and vitexin) passed the filter of drug-likeness. The molecular dynamic result revealed the best level of flexibility on HDAC1 and HDAC3 compared to the wild-type HDACs and moderate flexibility of HDAC7 and HDAC8.
Conclusions
The results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs. This knowledge can be used to guide experimental investigation on Cajanus cajan-derived compounds as potential HDAC inhibitors.
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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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li X, Huo F, Zhang Y, Cheng F, Yin C. Enzyme-activated Prodrugs and Their Release Mechanisms for Treatment of Cancer. J Mater Chem B 2022; 10:5504-5519. [DOI: 10.1039/d2tb00922f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Enzyme-activated prodrugs have received a lot of attention in recent years. These prodrugs have low toxicity to cells before they are activated, and when they interact with specific enzymes, they...
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Quaas CE, Long DT. Targeting (de)acetylation: A Diversity of Mechanism and Disease. COMPREHENSIVE PHARMACOLOGY 2022:469-492. [DOI: 10.1016/b978-0-12-820472-6.00076-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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50
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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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