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Zou Z, Zhong L. Anaplastic thyroid cancer: Genetic roles, targeted therapy, and immunotherapy. Genes Dis 2025; 12:101403. [PMID: 40271195 PMCID: PMC12018003 DOI: 10.1016/j.gendis.2024.101403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/02/2024] [Accepted: 08/02/2024] [Indexed: 04/25/2025] Open
Abstract
Anaplastic thyroid cancer (ATC) stands as the most formidable form of thyroid malignancy, presenting a persistent challenge in clinical management. Recent years have witnessed a gradual unveiling of the intricate genetic underpinnings governing ATC through next-generation sequencing. The emergence of this genetic landscape has paved the way for the exploration of targeted therapies and immunotherapies in clinical trials. Despite these strides, the precise mechanisms governing ATC pathogenesis and the identification of efficacious treatments demand further investigation. Our comprehensive review stems from an extensive literature search focusing on the genetic implications, notably the pivotal MAPK and PI3K-AKT-mTOR signaling pathways, along with targeted therapies and immunotherapies in ATC. Moreover, we screen and summarize the advances and challenges in the current diagnostic approaches for ATC, including the invasive tissue sampling represented by fine needle aspiration and core needle biopsy, immunohistochemistry, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography. We also investigate enormous studies on the prognosis of ATC and outline independent prognostic factors for future clinical assessment and therapy for ATC. By synthesizing this literature, we aim to encapsulate the evolving landscape of ATC oncology, potentially shedding light on novel pathogenic mechanisms and avenues for therapeutic exploration.
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Affiliation(s)
- Zhao Zou
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Linhong Zhong
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging and Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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Mosna MJ, Garde FJ, Stinson MG, Pastore CD, Carcagno AL. The chorioallantoic membrane (CAM) model: From its origins in developmental biology to its role in cancer research. Dev Biol 2025; 519:79-95. [PMID: 39694172 DOI: 10.1016/j.ydbio.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/24/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024]
Abstract
Over the past century, the chick embryo model, historically employed for research in developmental biology, has become a valuable tool for cancer research. The characteristics of the chick chorioallantoic membrane (CAM) make it a convenient model for the study of cancer, leading to the establishment of the CAM assay as an alternative to traditional in vivo cancer models. In this review we will explore the characteristics of the CAM that make it suitable for cancer research, as well as its consolidation as a versatile platform in this field. We will put particular emphasis on describing the key features that make this model an important asset for studying the hallmarks of cancer and for testing a wide variety of therapeutic strategies for its treatment, and which make it a suitable host for patient-derived xenografts (PDX). Additionally, we will examine the wide spectrum of methodological approaches available to study these subjects, highlighting some innovative cases. Finally, we will discuss the advantages and disadvantages of the chick CAM as a model for cancer research and how we can improve this model to its full potential.
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Affiliation(s)
- María Jimena Mosna
- Laboratorio de Diferenciación Celular y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina
| | - Federico J Garde
- Laboratorio de Diferenciación Celular y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina
| | - Marcelo G Stinson
- Laboratorio de Diferenciación Celular y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina
| | - Candela D Pastore
- Laboratorio de Diferenciación Celular y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina
| | - Abel L Carcagno
- Laboratorio de Diferenciación Celular y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina; Departamento de Ecología, Genética y Evolución, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de, Buenos Aires, C1428EGA, Argentina.
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Vatankhah A, Moghaddam SH, Afshari S, Afshari AR, Kesharwani P, Sahebkar A. Recent update on anti-tumor mechanisms of valproic acid in glioblastoma multiforme. Pathol Res Pract 2024; 263:155636. [PMID: 39395298 DOI: 10.1016/j.prp.2024.155636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Glioblastoma multiforme (GBM) is a malignant tumor of the brain that is considered to be incurable. Currently, surgical removal of tumors, chemotherapy with temozolomide, and radiation treatment remain established options for treatment. Nevertheless, the prognosis of those with GBM continues to be poor owing to the inherent characteristics of tumor growth and spread, as well as the resistance to treatment. To effectively deal with the present circumstances, it is vital to do extensive study to understand GBM thoroughly. The following piece provides a concise overview of the most recent advancements in using valproic acid, an antiseizure medication licensed by the FDA, for treating GBM. In this review, we outline the most recent developments of valproic acid in treating GBM, as well as its fundamental mechanisms and practical consequences. Our goal is to provide a greater understanding of the clinical use of valproic acid as a potential therapeutic agent for GBM.
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Affiliation(s)
- Abulfazl Vatankhah
- School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | | | - Sadaf Afshari
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Basic Sciences, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Amirhossein Sahebkar
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Neefjes J, Gurova K, Sarthy J, Szabó G, Henikoff S. Chromatin as an old and new anticancer target. Trends Cancer 2024; 10:696-707. [PMID: 38825423 PMCID: PMC11479676 DOI: 10.1016/j.trecan.2024.05.005] [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: 01/13/2024] [Revised: 05/08/2024] [Accepted: 05/13/2024] [Indexed: 06/04/2024]
Abstract
Recent genome-wide analyses identified chromatin modifiers as one of the most frequently mutated classes of genes across all cancers. However, chemotherapies developed for cancers involving DNA damage remain the standard of care for chromatin-deranged malignancies. In this review we address this conundrum by establishing the concept of 'chromatin damage': the non-genetic damage to protein-DNA interactions induced by certain small molecules. We highlight anthracyclines, a class of chemotherapeutic agents ubiquitously applied in oncology, as an example of overlooked chromatin-targeting agents. We discuss our current understanding of this phenomenon and explore emerging chromatin-damaging agents as a basis for further studies to maximize their impact in modern cancer treatment.
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Affiliation(s)
- Jacques Neefjes
- Department of Cell and Chemical Biology and Oncode Institute, LUMC, Einthovenweg 20, 2333, ZC, Leiden, The Netherlands
| | - Katerina Gurova
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
| | - Jay Sarthy
- Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, 1920 Terry Ave, Seattle, WA 98109, USA
| | - Gábor Szabó
- Faculty of Medicine, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Egyetem tér 1, 4032, Hungary
| | - Steven Henikoff
- Basic Sciences Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
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Klieser E, Neumayer B, Di Fazio P, Mayr C, Neureiter D, Kiesslich T. HDACs as an emerging target in endocrine tumors: a comprehensive review. Expert Rev Endocrinol Metab 2023; 18:143-154. [PMID: 36872882 DOI: 10.1080/17446651.2023.2183840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/20/2023] [Indexed: 02/26/2023]
Abstract
INTRODUCTION The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved. AREAS COVERED Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors. For thyroid, neuroendocrine, and adrenal tumors, various oncogenic mechanisms of HDAC deregulation and effects of HDAC inhibitors (HDACi) have been identified in preclinical studies including direct cancer cell toxicity and modification of differentiation status. EXPERT OPINION Based on positive pre-clinical results, the research on HDAC (inhibition) in the various endocrine tumors should be intensified - yet, it needs to be considered that i) HDACs' oncogenic actions might constitute only a part of epigenetic mechanisms driving cancer, ii) individual HDAC has different roles in different endocrine tumor entities, iii) inhibition of HDACs might be especially attractive in combination with conventional or other targeted therapies, and iv) new HDAC-inhibiting drugs with improved specificity or functionally modified HDACi might further improve their efficacy.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Bettina Neumayer
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Christian Mayr
- Center for Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Tobias Kiesslich
- Center for Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
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Abstract
Thyroid cancer is the most common malignancy of the endocrine system, and its incidence has been steadily increasing. Advances in sequencing have allowed analysis of the entire cancer genome, and has provided new information on the genetic lesions and modifications responsible for the onset, progression, dedifferentiation and metastasis of thyroid carcinomas. Moreover, integrated genomics has advanced our understanding of the development of cancer and its behavior, and has facilitated the identification of new genetic mutations and molecular pathways. The functional analysis of epigenetic modifications, such as DNA methylation, histone acetylation and non-coding RNAs, have contributed to define new regulatory mechanisms that control cell malignancy in thyroid cancer, especially aggressive forms. Here we review the most recent advances in genomics and epigenomics of thyroid cancer, which have resulted in a new classification and interpretation of the initiation and progression of thyroid tumors, providing new tools and opportunities for further investigation and for the clinical development of new treatment strategies.
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Affiliation(s)
- Adrián Acuña-Ruiz
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
| | - Carlos Carrasco-López
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
| | - Pilar Santisteban
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Yuan J, Guo Y. Targeted Therapy for Anaplastic Thyroid Carcinoma: Advances and Management. Cancers (Basel) 2022; 15:cancers15010179. [PMID: 36612173 PMCID: PMC9818071 DOI: 10.3390/cancers15010179] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/17/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Anaplastic thyroid carcinoma (ATC) is a rare and highly fatal cancer with the worst prognosis of all thyroid carcinoma (TC) histological subtypes and no standard treatment. In recent years, the explosion of investigations on ATC-targeted agents has provided a new treatment strategy for this malignant condition, and a review of these studies is warranted. We conducted a comprehensive literature search for ATC-targeted drug studies and compiled a summary of their efficacy and adverse effects (AEs) to provide new insights. Multiple clinical trials have demonstrated the efficacy and safety of dabrafenib in combination with trametinib for the treatment of ATC, but vemurafenib and NTRK inhibitors showed limited clinical responses. We found that the previously valued therapeutic effect of lenvatinib may be unsatisfactory; combining tyrosine kinase (TK) inhibitors (TKIs) with other agents results in a higher rate of clinical benefit. In addition, specific medications, including RET inhibitors, mTOR inhibitors, CDK4/6 inhibitors, and Combretastatin A4-phosphate (CA4P), offer tremendous therapeutic potential. The AEs reported for all agents are relatively numerous but largely manageable clinically. More clinical trials are expected to further confirm the effectiveness and safety of these targeted drugs for ATC.
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Affiliation(s)
- Jiaqian Yuan
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yong Guo
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310001, China
- Correspondence:
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Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2022. [DOI: 10.5812/ijcm-120224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Valproic acid (VPA), a branched short-chain fatty acid and histone deacetylase (HDAC) inhibitor, has diverse biological activities in human cells, including anti-cancer properties. Objectives: In the present study, we tested the cytotoxicity of VPA on the proliferation, cell cycle, and apoptosis of the human cervical cancer cell line, HeLa. Methods: HeLa cell line was cultured in Dulbecco’s modified eagle medium (DMEM) and the cytotoxicity effect of VPA (at 0 - 100 mM) on the HeLa cell was evaluated, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay for 3 incubation times (24, 48, and 72 h). The effects of VPA on cell cycle arrest and apoptosis were evaluated, using flow cytometry. In addition, the alterations in the expression of Bax, Bcl-2, p53, and p21 were assessed with real‐time polymerase chain reaction (PCR). Results: Valproic acid reduced the viability of HeLa cells in a concentration- and time-dependent manner, and the IC50 values at 24, 48, and 72 h were 32.06, 21.29, and 14.51 mM, respectively. Further, VPA treatment remarkably increased the apoptosis of HeLa cells and arrested cells at the sub-G1 phase with a significant reduction in G2-M phase populations. The real-time PCR results demonstrated a significant increase in the expression of pro-apoptotic genes, including Bax, p53, and p21, as well as a reduction in the levels of the anti-apoptotic gene, Bcl-2. Conclusions: Valproic acid inhibits the proliferation of the HeLa cell line through the induction of the intrinsic pathway of apoptosis in a p35-dependent manner.
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Elsaid HH, Badary OA, Shouman SA, Elmazar M, El-Khatib AS. Enhanced antitumor activity of combined methotrexate and histone deacetylase inhibitor valproic acid on mammary cancer in vitro and in vivo. Can J Physiol Pharmacol 2022; 100:915-925. [PMID: 35679619 DOI: 10.1139/cjpp-2021-0799] [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
Histone deacetylase inhibitors (HDACIs) act as antiproliferative agents by promoting differentiation and inducing apoptosis. Valproic acid (VPA) is an HDACI that shows promising chemotherapeutic effect in several tumor cells. The present study aimed to investigate the inhibitory effect of VPA on the viability of mammary cancer cells and its enhancing effect with methotrexate (MTX) in vitro and in vivo. Treatment with VPA or MTX alone induced concentration-dependent cytotoxic effects in two breast cancer cell lines. VPA significantly increased the cytotoxicity of MTX 3 times against MCF7. VPA addition to MTX, however, did not produce any significant changes on MTX cytotoxicity against MDA-MB231. VPA (150 and 200 mg/kg) significantly inhibited the growth of IP and SC Ehrlich ascites carcinoma tumor mouse models and improved results were achieved for tumor inhibition when VPA was combined with MTX (1 and 2 mg/kg) in vivo. The antitumor activity was not associated with a significant increase in toxicity or mice mortality rate. All these findings suggest that the combination of MTX and VPA may have clinical and/or adjuvant therapeutic application in the treatment of mammary cancer.
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Affiliation(s)
- Hadia Hosny Elsaid
- The British University in Egypt, 120633, Department of Pharmacology and Biochemistry, El Shorouk, Cairo, Egypt;
| | - Osama A Badary
- The British University in Egypt, 120633, Department of Clinical Pharmacy Practice, El Shorouk, Cairo, Egypt;
| | - Samia A Shouman
- National Cancer Institute Cairo University, 68804, Cairo, Egypt;
| | - Mohey Elmazar
- The British University in Egypt, 120633, Department of Pharmacology and Biochemistry, Cairo,, Cairo, Egypt;
| | - Aiman S El-Khatib
- Cairo University Faculty of Pharmacy, 110154, Pharmacology and Toxicology, Cairo, Egypt;
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Wu S, Huang Y, Wang T, Li K, Lu J, Huang M, Dong G, Sheng C. Evodiamine-Inspired Topoisomerase-Histone Deacetylase Dual Inhibitors: Novel Orally Active Antitumor Agents for Leukemia Therapy. J Med Chem 2022; 65:4818-4831. [PMID: 35238576 DOI: 10.1021/acs.jmedchem.1c02026] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
On the basis of the synergism of topoisomerase (Top) and histone deacetylase (HDAC) inhibitors in antitumor therapy, a series of novel Top/HDAC dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. After systematic structure-activity relationship studies, lead compound 16j was identified to simultaneously inhibit both Top and HDAC with good potency, which showed potent antiproliferative activities with a broad spectrum. Mechanistic studies indicated that compound 16j efficiently induced apoptosis with S cell-cycle arrest in HEL cancer cells. It was orally active in HEL xenograft models and exhibited excellent in vivo antitumor efficacy (TGI = 68.5%; 10 mg/kg). Altogether, this work highlights the therapeutic potential of evodiamine-inspired Top/HDAC dual inhibitors and provides a valuable lead compound for the development of novel antitumor agents for leukemia therapy.
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Affiliation(s)
- Shanchao Wu
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Yahui Huang
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Ting Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Keliang Li
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Junjie Lu
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Min Huang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Guoqiang Dong
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Chunquan Sheng
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
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Wawruszak A, Halasa M, Okon E, Kukula-Koch W, Stepulak A. Valproic Acid and Breast Cancer: State of the Art in 2021. Cancers (Basel) 2021; 13:3409. [PMID: 34298623 PMCID: PMC8306563 DOI: 10.3390/cancers13143409] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Valproic acid (2-propylpentanoic acid, VPA) is a short-chain fatty acid, a member of the group of histone deacetylase inhibitors (HDIs). VPA has been successfully used in the treatment of epilepsy, bipolar disorders, and schizophrenia for over 50 years. Numerous in vitro and in vivo pre-clinical studies suggest that this well-known anticonvulsant drug significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. Breast cancer (BC) is the most common malignancy affecting women worldwide. Despite significant progress in the treatment of BC, serious adverse effects, high toxicity to normal cells, and the occurrence of multi-drug resistance (MDR) still limit the effective therapy of BC patients. Thus, new agents which improve the effectiveness of currently used methods, decrease the emergence of MDR, and increase disease-free survival are highly needed. This review focuses on in vitro and in vivo experimental data on VPA, applied individually or in combination with other anti-cancer agents, in the treatment of different histological subtypes of BC.
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Affiliation(s)
- Anna Wawruszak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
| | - Marta Halasa
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
| | - Estera Okon
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
| | - Wirginia Kukula-Koch
- Department of Pharmacognosy, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
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12
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Chan AM, Fletcher S. Shifting the paradigm in treating multi-factorial diseases: polypharmacological co-inhibitors of HDAC6. RSC Med Chem 2021; 12:178-196. [PMID: 34046608 PMCID: PMC8127619 DOI: 10.1039/d0md00286k] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 10/28/2020] [Indexed: 01/20/2023] Open
Abstract
Multi-factorial diseases are illnesses that exploit multiple cellular processes, or stages within one process, and thus highly targeted therapies often succumb to the disease, losing efficacy as resistance sets in. Combination therapies have become a mainstay to battle these diseases, however these regimens are plagued with caveats. An emerging avenue to treat multi-factorial diseases is polypharmacology, wherein a single drug is rationally designed to bind multiple targets, and is widely touted to be superior to combination therapy by inherently addressing the latter's shortcomings, which include poor patient compliance, narrow therapeutic windows and spiraling healthcare costs. Through its roles in intracellular trafficking, cell motility, mitosis, protein folding and as a back-up to the proteasome pathway, HDAC6 has rapidly become an exciting new target for therapeutics, particularly in the discovery of new drugs to treat Alzheimer's disease and cancer. Herein, we describe recent efforts to marry together HDAC pharmacophores, with a particular emphasis on HDAC6 selectivity, with those of other targets towards the discovery of potent therapeutics to treat these evasive diseases. Such polypharmacological agents may supercede combination therapies through inherent synergism, permitting reduced dosing, wider therapeutic windows and improved compliance.
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Affiliation(s)
- Alexandria M Chan
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy 20 N Pine St Baltimore MD 21201 USA
| | - Steven Fletcher
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy 20 N Pine St Baltimore MD 21201 USA
- University of Maryland Greenebaum Cancer Center 22 S Greene St Baltimore MD 21201 USA
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Rapid In Vivo Validation of HDAC Inhibitor-Based Treatments in Neuroblastoma Zebrafish Xenografts. Pharmaceuticals (Basel) 2020; 13:ph13110345. [PMID: 33121173 PMCID: PMC7692187 DOI: 10.3390/ph13110345] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/23/2020] [Accepted: 10/26/2020] [Indexed: 01/01/2023] Open
Abstract
The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing models are urgently needed. Zebrafish are a powerful vertebrate model in preclinical cancer research. Here, we describe a zebrafish neuroblastoma yolk sac model to evaluate efficacy and toxicity of histone deacetylase (HDAC) inhibitor treatments. Larvae were engrafted with fluorescently labeled, genetically diverse, established cell lines and short-term cultures of patient-derived primary cells. Engrafted tumors progressed locally and disseminated remotely in an intact environment. Combination treatments involving the standard chemotherapy doxorubicin and HDAC inhibitors substantially reduced tumor volume, induced tumor cell death, and inhibited tumor cell dissemination to the tail region. Hence, this model allows for fast, cost-efficient, and reliable in vivo evaluation of toxicity and response of the primary and metastatic tumor sites to drug combinations.
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Guenter R, Patel Z, Chen H. Notch Signaling in Thyroid Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1287:155-168. [PMID: 33034031 DOI: 10.1007/978-3-030-55031-8_10] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Thyroid cancer is the most common malignancy of the endocrine system with a steadily rising incidence. The term "thyroid cancer" encompasses a spectrum of subtypes, namely papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer. Each subtype differs histopathologically and in degrees of cellular differentiation, which may be in part due to signaling of the Notch pathway. The Notch pathway is an evolutionarily conserved signal transduction mechanism that regulates cell proliferation, differentiation, survival, stem cell maintenance, embryonic and adult development, epithelial-mesenchymal transition, and angiogenesis. Its role in cancer biology is controversial, as it has been shown to play both an oncogenic and tumor-suppressive role in many different types of cancers. This discordance holds true for each subtype of thyroid cancer, indicating that Notch signaling is likely cell type and context dependent. Whether oncogenic or not, Notch signaling has proven to be significantly involved in the tumorigenesis of thyroid cancer and has thus earned interest as a therapeutic target. Advancement in the understanding of Notch signaling in thyroid cancer holds great promise for the development of novel treatment strategies to benefit patients.
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Affiliation(s)
- Rachael Guenter
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zeelu Patel
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
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15
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N-(2'-Hydroxyphenyl)-2-Propylpentanamide (HO-AAVPA) Inhibits HDAC1 and Increases the Translocation of HMGB1 Levels in Human Cervical Cancer Cells. Int J Mol Sci 2020; 21:ijms21165873. [PMID: 32824279 PMCID: PMC7461584 DOI: 10.3390/ijms21165873] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/13/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022] Open
Abstract
N-(2′-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a VPA derivative designed to be a histone deacetylase (HDAC) inhibitor. HO-AAVPA has better antiproliferative effect than VPA in cancer cell lines. Therefore, in this work, the inhibitory effect of HO-AAVPA on HDAC1, HDAC6, and HDAC8 was determined by in silico and in vitro enzymatic assay. Furthermore, its antiproliferative effect on the cervical cancer cell line (SiHa) and the translocation of HMGB1 and ROS production were evaluated. The results showed that HO-AAVPA inhibits HDAC1, which could be related with HMGB1 translocation from the nucleus to the cytoplasm due to HDAC1 being involved in the deacetylation of HMGB1. Furthermore, an increase in ROS production was observed after the treatment with HO-AAVPA, which also could contribute to HMGB1 translocation. Therefore, the results suggest that one of the possible antiproliferative mechanisms of HO-AAVPA is by HDAC1 inhibition which entails HMGB1 translocation and ROS increased levels that could trigger the cell apoptosis.
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Zhang B, Zhang Q, Liu Z, Wang N, Jin H, Liu F, Zhang C, He S. Synthesis and Anticancer Research of
N
‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors. ChemistrySelect 2020. [DOI: 10.1002/slct.202001880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Bin Zhang
- College of Food and Pharmaceutical Sciences Ningbo University Ningbo Zhejiang 315211 China
- State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical Biology Tsinghua Shenzhen International Graduate School Shenzhen 518055 China
| | - Qiting Zhang
- Institute of Drug Discovery Technology Ningbo University Ningbo Zhejiang 315211 China
| | - Zedong Liu
- College of Food and Pharmaceutical Sciences Ningbo University Ningbo Zhejiang 315211 China
| | - Ning Wang
- Institute of Drug Discovery Technology Ningbo University Ningbo Zhejiang 315211 China
- State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical Biology Tsinghua Shenzhen International Graduate School Shenzhen 518055 China
| | - Haixiao Jin
- College of Food and Pharmaceutical Sciences Ningbo University Ningbo Zhejiang 315211 China
| | - Feng Liu
- State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical Biology Tsinghua Shenzhen International Graduate School Shenzhen 518055 China
| | - Cunlong Zhang
- State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical Biology Tsinghua Shenzhen International Graduate School Shenzhen 518055 China
| | - Shan He
- College of Food and Pharmaceutical Sciences Ningbo University Ningbo Zhejiang 315211 China
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Sun M, He L, Fan Z, Tang R, Du J. Effective treatment of drug-resistant lung cancer via a nanogel capable of reactivating cisplatin and enhancing early apoptosis. Biomaterials 2020; 257:120252. [PMID: 32738659 DOI: 10.1016/j.biomaterials.2020.120252] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 07/06/2020] [Accepted: 07/19/2020] [Indexed: 12/17/2022]
Abstract
Cisplatin resistance is a daunting obstacle in cancer therapy and one of the major causes for treatment failure due to the inadequate drug activity and apoptosis induction. To overcome cisplatin resistance, we proposed a multifunctional nanogel (designated as Valproate-D-Nanogel) capable of reactivating cisplatin and enhancing early apoptosis. This Valproate-D-Nanogel was prepared through copolymerizing carboxymethyl chitosan with diallyl disulfide and subsequent grafting with valproate to reverse the drug-resistance in cisplatin-resistant human lung adenocarcinoma cancer. It can significantly increase the proportion of G2/M phase (up to 3.2-fold enhancement) to reactivate cisplatin via high level of G2/M arrest induced by valproate. Meanwhile, the intracellular ROS-P53 crosstalk can be upregulated by diallyl disulfide (up to 8-fold increase of ROS) and valproate (up to 18-fold increase of P53) to enhance early apoptosis. The synchronization of enhanced G2/M arrest and ROS-P53 crosstalk devotes to reverse the cisplatin resistance with a high level of resistance reversion index (50.22). As a result, improved in vivo tumor inhibition (up to 15-fold higher compared to free cisplatin) and decreased systemic toxicity was observed after treatment with Valproate-D-Nanogels. Overall, this nanogel can effectively inhibit cisplatin-resistance cancer through combined pathways and provides an effective approach for overcoming cisplatin-resistance in cancer treatment.
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Affiliation(s)
- Min Sun
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai, 201804, China; Engineering Research Center for Biomedical Materials, School of Life Science, Anhui, Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, China
| | - Le He
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui, Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, China
| | - Zhen Fan
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai, 201804, China.
| | - Rupei Tang
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui, Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, China.
| | - Jianzhong Du
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai, 201804, China.
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18
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Hegedűs L, Rittler D, Garay T, Stockhammer P, Kovács I, Döme B, Theurer S, Hager T, Herold T, Kalbourtzis S, Bankfalvi A, Schmid KW, Führer D, Aigner C, Hegedűs B. HDAC Inhibition Induces PD-L1 Expression in a Novel Anaplastic Thyroid Cancer Cell Line. Pathol Oncol Res 2020; 26:2523-2535. [PMID: 32591993 PMCID: PMC7471186 DOI: 10.1007/s12253-020-00834-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022]
Abstract
While papillary thyroid cancer (PTC) has largely favorable prognosis, anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy with grim clinical outcome. Even though new therapeutic options are emerging for ATC, additional preclinical models and novel combinations are needed for specific subsets of patients. We established a novel cell line (PF49) from the malignant pleural effusion of a 68-year-old male patient with ATC that rapidly transformed from a BRAF and TERT promoter mutant PTC. PF49 cells demonstrated a robust migratory activity in vitro and strong invasive capacity in vivo in a pleural carcinosis model. Combined BRAF and MEK inhibition decreased the proliferation and migration of PF49 cells, however could not induce cell death. Importantly, HDAC inhibitor treatment with SAHA or valproic acid induced cell cycle arrest and strongly increased PD-L1 expression of the tumor cells. Induction of PD-L1 expression was also present when paclitaxel-cisplatin chemotherapeutic treatment was combined with HDAC inhibitor treatment. Increased PD-L1 expression after HDAC inhibition was recapitulated in an international ATC cell model. Our data suggest that HDAC inhibition alone or in combination with standard chemotherapy may potentiate anaplastic thyroid cancer cells for immunotherapy.
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Affiliation(s)
- Luca Hegedűs
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Essen, Germany
| | - Dominika Rittler
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Tamás Garay
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.,Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Paul Stockhammer
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Essen, Germany.,Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Ildikó Kovács
- National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Balázs Döme
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.,National Korányi Institute of Pulmonology, Budapest, Hungary.,Department of Thoracic Surgery, Semmelweis University-National Institute of Oncology, Budapest, Hungary
| | - Sarah Theurer
- Institute of Pathology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Thomas Hager
- Institute of Pathology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Thomas Herold
- Institute of Pathology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Stavros Kalbourtzis
- Institute of Pathology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Agnes Bankfalvi
- Institute of Pathology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Kurt W Schmid
- Institute of Pathology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
| | - Clemens Aigner
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Essen, Germany
| | - Balázs Hegedűs
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Essen, Germany. .,2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
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19
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Liu T, Wan Y, Xiao Y, Xia C, Duan G. Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy. J Med Chem 2020; 63:8977-9002. [PMID: 32320239 DOI: 10.1021/acs.jmedchem.0c00491] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.
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Affiliation(s)
- Tingting Liu
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Yichao Wan
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, Hunan, China
| | - Yuliang Xiao
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Chengcai Xia
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Guiyun Duan
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
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20
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Amnekar RV, Khan SA, Rashid M, Khade B, Thorat R, Gera P, Shrikhande SV, Smoot DT, Ashktorab H, Gupta S. Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer. World J Gastroenterol 2020; 26:598-613. [PMID: 32103870 PMCID: PMC7029347 DOI: 10.3748/wjg.v26.i6.598] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/20/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be partly due to the lack of patient stratification for effective treatments.
AIM To study the need of patient stratification before HDACi treatment, and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.
METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues. The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays, chromatin remodeling and cell death.
RESULTS In the present study, the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypo-acetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer. The data highlights for the first time that pre-treatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation, chromatin relaxation and cell cycle arrest. Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes, including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin, exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.
CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification. Furthermore, HDACi therapy in pre-treatment regimes is more effective with chemotherapy drugs, and may aid in predicting individual patient prognosis.
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Affiliation(s)
- Ramchandra Vigay Amnekar
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400085, India
| | - Shafqat Ali Khan
- Department of Developmental Biology, School of Medicine, Washington University in St. Louis, Saint Louis, MO 63130, United States
| | - Mudasir Rashid
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400085, India
| | - Bharat Khade
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Rahul Thorat
- Animal House Facility, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Poonam Gera
- Biorepository Lab, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Shailesh V Shrikhande
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai 400012, India
| | - Duane T Smoot
- Department of Medicine, Meharry Medical Center, Nashville, TN 37208, United States
| | - Hassan Ashktorab
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington DC, WA 20060, United States
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400085, India
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21
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Valproic acid promotes the epithelial-to-mesenchymal transition of breast cancer cells through stabilization of Snail and transcriptional upregulation of Zeb1. Eur J Pharmacol 2019; 865:172745. [PMID: 31639340 DOI: 10.1016/j.ejphar.2019.172745] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/11/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
Histone deacetylases (HDACs) can regulate cancer progression and its inhibitors (HDACIs) have been widely used for cancer therapy. Valproic acid (VPA, 2-propylpentanoic acid) can inhibit the class I HDAC and suppress the malignancy of solid cancers. Our present study revealed that 1 mM VPA, which has no effect on cell proliferation, can significantly increase the migration and induce epithelial to mesenchymal transition (EMT) like properties of breast cancer cells. Further, VPA increased the expression of EMT-transcription factors (EMT-TFs) Snail and Zeb1. Knockdown of Snail and Zeb1 can attenuate VPA induced cell migration and EMT. Mechanistically, VPA increased the protein stability of Snail via suppression its phosphorylation at Ser 11. As to Zeb1, VPA can increase its promoter activity and transcription via a HDAC2 dependent manner. Over expression of HDAC2 can block VPA induced expression of Zeb1. Collectively, our data revealed that VPA can trigger the EMT of breast cancer cells via upregulation of Snail and Zeb1. It indicated that more attention should be paid to the effects of VPA on the clinical therapy of breast cancer.
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22
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Kim D, Kim Y, Kim Y. Effects of β-carotene on Expression of Selected MicroRNAs, Histone Acetylation, and DNA Methylation in Colon Cancer Stem Cells. J Cancer Prev 2019; 24:224-232. [PMID: 31950022 PMCID: PMC6951318 DOI: 10.15430/jcp.2019.24.4.224] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/15/2019] [Accepted: 12/16/2019] [Indexed: 12/24/2022] Open
Abstract
Background Beta-carotene (BC) is a carotenoid which exerts anti-cancer effects in several types of cancer, including colorectal cancer. Epigenetic modifications of genes, such as histone deacetylation and DNA hypermethylation, have also been detected in various types of cancer. To understand the molecular mechanism underlying cancer preventive and therapeutic effects of BC, microRNAs (miRNAs), histone acetylation, and global DNA methylation in colon cancer stem cells (CSCs) were investigated. Methods HCT116 colon cancer cells positive for expression of CD44 and CD133 were sorted by flow cytometry and used in subsequent experiments. Cell proliferation was examined by the MTT assay and self-renewal capacity was analyzed by the sphere formation assay. The miRNA sequencing array was used to detect miRNAs regulated by BC. Histone acetylation levels were measured by the Western blot analysis. mRNA expression of DNA methyltransferases (DNMTs) was examined by qPCR and global DNA methylation levels were determined by enzyme-linked immunosorbent assay. Results Treatment of CD44+CD133+ colon CSCs with BC caused a reduction in both cell proliferation and sphere formation. Analysis of the miRNA sequencing array showed that BC regulated expression of miRNAs associated with histone acetylation. Histone H3 and H4 acetylation levels were elevated by BC treatment. In addition, BC treatment down-regulated DNMT3A mRNA expression and global DNA methylation in colon CSCs. Conclusions These results suggest that BC regulates epigenetic modifications for its anti-cancer effects in colon CSCs.
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Affiliation(s)
- Daeun Kim
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
| | - Yerin Kim
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
| | - Yuri Kim
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
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23
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Kenny RG, Marmion CJ. Toward Multi-Targeted Platinum and Ruthenium Drugs-A New Paradigm in Cancer Drug Treatment Regimens? Chem Rev 2019; 119:1058-1137. [PMID: 30640441 DOI: 10.1021/acs.chemrev.8b00271] [Citation(s) in RCA: 433] [Impact Index Per Article: 72.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we are moving from a single- toward a multitargeted approach. This approach lies at the very heart of medicinal inorganic chemistry. In this review, we have endeavored to showcase how a "multitargeted" approach to drug design has led to new families of metallodrugs which may not only reduce systemic toxicities associated with modern day chemotherapeutics but also address resistance issues that are plaguing many chemotherapeutic regimens. We have focused our attention on metallodrugs incorporating platinum and ruthenium ions given that complexes containing these metal ions are already in clinical use or have advanced to clinical trials as anticancer agents. The "multitargeted" complexes described herein not only target DNA but also contain either vectors to enable them to target cancer cells selectively and/or moieties that target enzymes, peptides, and intracellular proteins. Multitargeted complexes which have been designed to target the mitochondria or complexes inspired by natural product activity are also described. A summary of advances in this field over the past decade or so will be provided.
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Affiliation(s)
- Reece G Kenny
- Centre for Synthesis and Chemical Biology, Department of Chemistry , Royal College of Surgeons in Ireland , 123 St. Stephen's Green , Dublin 2 , Ireland
| | - Celine J Marmion
- Centre for Synthesis and Chemical Biology, Department of Chemistry , Royal College of Surgeons in Ireland , 123 St. Stephen's Green , Dublin 2 , Ireland
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24
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Chen J, Li D, Li W, Yin J, Zhang Y, Yuan Z, Gao C, Liu F, Jiang Y. Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors. Bioorg Med Chem 2018; 26:3958-3966. [DOI: 10.1016/j.bmc.2018.06.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/12/2018] [Accepted: 06/13/2018] [Indexed: 02/06/2023]
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25
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Celano M, Mio C, Sponziello M, Verrienti A, Bulotta S, Durante C, Damante G, Russo D. Targeting post-translational histone modifications for the treatment of non-medullary thyroid cancer. Mol Cell Endocrinol 2018; 469:38-47. [PMID: 28579118 DOI: 10.1016/j.mce.2017.05.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/25/2017] [Accepted: 05/30/2017] [Indexed: 02/07/2023]
Abstract
Genomic and epigenetic alterations are now being exploited as molecular targets in cancer treatment. Abnormalities involving the post-translational modification of histones have been demonstrated in thyroid cancer, and they are regarded as promising molecular targets for novel drug treatment of tumors that are resistant to conventional therapies. After a brief overview of the histone modifications most commonly associated with human malignancies, we will review recently published preclinical and clinical findings regarding the use of histone-activity modulators in thyroid cancers. Particular attention will be focused on their use as re-differentiating or anti-proliferating agents, the differential effects observed when they are used alone and in combination with other targeted drugs, and current prospects for their use in the treatment of thyroid cancer.
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Affiliation(s)
- Marilena Celano
- Department of Health Sciences, "Magna Graecia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Catia Mio
- Department of Medical Area, University of Udine, 33100 Udine, Italy
| | - Marialuisa Sponziello
- Department of Internal Medicine and Medical Specialties, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Antonella Verrienti
- Department of Internal Medicine and Medical Specialties, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Stefania Bulotta
- Department of Health Sciences, "Magna Graecia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Cosimo Durante
- Department of Internal Medicine and Medical Specialties, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Giuseppe Damante
- Department of Medical Area, University of Udine, 33100 Udine, Italy
| | - Diego Russo
- Department of Health Sciences, "Magna Graecia" University of Catanzaro, 88100 Catanzaro, Italy.
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Barneh F, Salimi M, Goshadrou F, Ashtiani M, Mirzaie M, Zali H, Jafari M. Valproic acid inhibits the protective effects of stromal cells against chemotherapy in breast cancer: Insights from proteomics and systems biology. J Cell Biochem 2018; 119:9270-9283. [PMID: 29953653 DOI: 10.1002/jcb.27196] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/24/2018] [Indexed: 12/14/2022]
Abstract
Interaction between tumor and stromal cells is beginning to be decoded as a contributor to chemotherapy resistance. Here, we aim to take a system-level approach to explore a mechanism by which stromal cells induce chemoresistance in cancer cells and subsequently identify a drug that can inhibit such interaction. Using a proteomic dataset containing quantitative data on secretome of stromal cells, we performed multivariate analyses and found that bone-marrow mesenchymal stem cells (BM-MSCs) play the most protective role against chemotherapeutics. Pathway enrichment tests showed that secreted cytokines from BM-MSCs activated 4 signaling pathways including Janus kinase-signal transducer and activator of transcription, phosphatidylinositol 3-kinase-protein kinase B, and mitogen-activated protein kinase, transforming growth factor-β in cancer cells collectively leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) transcription factor activation. Based on the data from integrated Library of Integrated Network-Based Cellular Signatures (iLINCs) program, we found that among different drugs, valproic acid (VA) affected the expression of 34 genes within the identified pathways that are activated by stromal cells. Our in vitro experiments confirmed that VA inhibits NF-kB activation in cancer cells. In addition, analyzing gene expression data in patients taking oral VA showed that this drug decreased expression of antioxidant enzymes culminating in increased oxidative stress in tumor cells. These results suggest that VA confines the protective role of stromal cells by inhibiting the adaptation mechanisms toward oxidative stress which is potentiated by stromal cells. Since VA is an already prescribed drug manifesting anticancer effects, this study provides a mechanistic insight for combination of VA with chemotherapy in the clinical setting.
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Affiliation(s)
- Farnaz Barneh
- Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Iran.,Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mona Salimi
- Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Goshadrou
- Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Minoo Ashtiani
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.,Department of Computer Science and Statistics, Faculty of Mathematics, K. N. Toosi University of Technology, Tehran, Iran
| | - Mehdi Mirzaie
- Department of Applied Mathematics, Faculty of Mathematical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hakimeh Zali
- School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical sciences, Tehran, Iran
| | - Mohieddin Jafari
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ, Lee SJ. Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells. J Endocrinol Invest 2018; 41:677-689. [PMID: 29147952 DOI: 10.1007/s40618-017-0792-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 11/02/2017] [Indexed: 02/08/2023]
Abstract
PURPOSE The influence of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the histone deacetylase inhibitor PXD101 on survival of thyroid carcinoma cells was investigated. METHODS SW1736, TPC-1, 8505C and BCPAP human thyroid carcinoma cells were used. To assess cell survival, cell viability, the percentage of viable cells and dead cells, cytotoxic activity, ATP levels and FACS analysis were measured. To validate the impact of gemigliptin combined with PXD101, the interactions were estimated by obtaining combination index in cells treated with two agents. RESULTS In cells treated with gemigliptin or PXD101, cell viability, the percentage of viable cells and ATP levels were reduced, and the percentage of dead cells and cytotoxic activity were elevated. In cells treated with both gemigliptin and PXD101, compared with PXD101 alone, cell death was augmented, and all of the combination index values were lower than 1.0, suggesting the synergism between gemigliptin and PXD101. The percentage of apoptotic cells, and the protein levels of Bcl2 and cleaved poly (ADP-ribose) polymerase were elevated, and the protein levels of xIAP and survivin were reduced. The protein levels of phospho-Akt and phospho-AMPK were elevated, and cell migration was reduced. CONCLUSIONS Our results demonstrate that gemigliptin induces cytotoxicity in thyroid carcinoma cells. Moreover, gemigliptin has a synergistic activity with PXD101 in the induction of cell death through involvement of Bcl2 family proteins, xIAP and survivin as well as mediation of Akt and AMPK in thyroid carcinoma cells.
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Affiliation(s)
- S H Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - J G Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - C S Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - S-H Ihm
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - M G Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - H J Yoo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - S J Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
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28
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Yamashita M, Tahara T, Hayakawa S, Matsumoto H, Wada SI, Tomioka K, Iida A. Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors. Bioorg Med Chem 2018. [DOI: 10.1016/j.bmc.2018.02.042] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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29
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Milelli A, Marchetti C, Turrini E, Catanzaro E, Mazzone R, Tomaselli D, Fimognari C, Tumiatti V, Minarini A. Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors. Bioorg Med Chem Lett 2018; 28:1001-1004. [DOI: 10.1016/j.bmcl.2018.02.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/15/2018] [Accepted: 02/16/2018] [Indexed: 11/30/2022]
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30
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Gazon H, Belrose G, Terol M, Meniane JC, Mesnard JM, Césaire R, Peloponese JM. Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients. Oncotarget 2017; 7:30258-75. [PMID: 26849145 PMCID: PMC5058679 DOI: 10.18632/oncotarget.7162] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 01/20/2016] [Indexed: 12/21/2022] Open
Abstract
Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.
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Affiliation(s)
- Hélène Gazon
- CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France.,Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique
| | - Gildas Belrose
- Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique
| | - Marie Terol
- CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France.,Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique
| | - Jean-Come Meniane
- Service Hématologie Clinique, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique
| | | | - Raymond Césaire
- Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique
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Raghavendra NM, Pingili D, Kadasi S, Mettu A, Prasad SVUM. Dual or multi-targeting inhibitors: The next generation anticancer agents. Eur J Med Chem 2017; 143:1277-1300. [PMID: 29126724 DOI: 10.1016/j.ejmech.2017.10.021] [Citation(s) in RCA: 191] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/04/2017] [Accepted: 10/09/2017] [Indexed: 12/17/2022]
Abstract
Dual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. An increasing interest in this approach is indicated by a steady upsurge in the number of articles on targeting dual/multi proteins published in the last 5 years. Combining different inhibitors that destiny specific single target is the standard treatment for cancer. A new generation of dual or multi-targeting drugs is emerging, where a single chemical entity can act on multiple molecular targets. Dual/Multi-targeting agents are beneficial for solving limited efficiencies, poor safety and resistant profiles of an individual target. Designing dual/multi-target inhibitors with predefined biological profiles present a challenge. The latest advances in bioinformatic tools and the availability of detailed structural information of target proteins have shown a way of discovering multi-targeting molecules. This neoteric artifice that amalgamates the molecular docking of small molecules with protein-based common pharmacophore to design multi-targeting inhibitors is gaining great importance in anticancer drug discovery. Current review focus on the discoveries of dual targeting agents in cancer therapy using rational, computational, proteomic, bioinformatics and polypharmacological approach that enables the discovery and rational design of effective and safe multi-target anticancer agents.
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Affiliation(s)
- Nulgumnalli Manjunathaiah Raghavendra
- Center for Technological Development in Health, National Institute of Science and Technology on Innovation on Neglected Diseases, Fiocruz, Rio de Janeiro, Brazil.
| | - Divya Pingili
- Sri Venkateshwara College of Pharmacy, Osmania University, Hyderabad, India; Department of Pharmacy, Jawaharlal Nehru Technological University, Kakinada, India
| | - Sundeep Kadasi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Osmania University, Hyderabad, India
| | - Akhila Mettu
- Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India
| | - S V U M Prasad
- Department of Pharmacy, Jawaharlal Nehru Technological University, Kakinada, India
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32
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Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells. Int J Mol Sci 2017; 18:ijms18051048. [PMID: 28498322 PMCID: PMC5454960 DOI: 10.3390/ijms18051048] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/03/2017] [Accepted: 05/08/2017] [Indexed: 02/07/2023] Open
Abstract
Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono- and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.
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33
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Zhao G, Wang G, Bai H, Li T, Gong F, Yang H, Wen J, Wang W. Targeted inhibition of HDAC8 increases the doxorubicin sensitivity of neuroblastoma cells via up regulation of miR-137. Eur J Pharmacol 2017; 802:20-26. [PMID: 28223126 DOI: 10.1016/j.ejphar.2017.02.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 02/11/2017] [Accepted: 02/17/2017] [Indexed: 11/30/2022]
Abstract
Histone deacetylases (HDACs) have been suggested to be potential therapeutic targets for cancer treatment. Recent studies revealed that HDAC8 expression was associated with poor prognostic markers and poor overall survival rate of neuroblastoma (NB). Our present study revealed that among the four members of class I HDACs, HDAC8 is significantly over expressed in NB cells as compared with the normal fibroblast 3T3 cells or primary normal human astrocytes (NHA) cells. Targeted inhibition of HDAC8 by its specific siRNA (si-HDAC8) can inhibit the in vitro growth of NB cells. Furthermore, si-HDAC8 significantly increases the sensitivity of NB cells to doxorubicin (Dox). Silencing of HDAC8 can increase the expression of miR-137, which has been suggested to mediate the Dox sensitivity of NB cells. Knockdown of miR-137 can attenuate si-HDAC8 enhanced Dox sensitivity. Further, si-HDAC8 can also inhibit the expression of multi-drug resistance gene 1 (MDR1). While knockdown of miR-137 can attenuate si-HDAC8 induced down regulation of MDR1. Collectively, our data revealed that targeted inhibition of HDAC8 can suppress the growth of NB cells and increase Dox sensitivity via up regulation of miR-137 and suppression of MDR1. Therefor, combination of HDAC8 inhibitor will be helpful to elevate the treatment outcome of NB patients.
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Affiliation(s)
- Gang Zhao
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
| | - Guoliang Wang
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
| | - Hongmin Bai
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
| | - Tiandong Li
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
| | - Fanghe Gong
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
| | - Huan Yang
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
| | - Jinchong Wen
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
| | - Weimin Wang
- Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China
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Nilubol N, Merkel R, Yang L, Patel D, Reynolds JC, Sadowski SM, Neychev V, Kebebew E. A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin. Clin Endocrinol (Oxf) 2017; 86:128-133. [PMID: 27392538 PMCID: PMC5581405 DOI: 10.1111/cen.13154] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/19/2016] [Accepted: 07/02/2016] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. DESIGN An open-label Simon two-stage phase II trial. PATIENTS AND MEASUREMENTS Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. RESULTS Thirteen patients with a median age of 66 years (50-78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hürthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. CONCLUSIONS Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin.
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Affiliation(s)
- Naris Nilubol
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Roxanne Merkel
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Lily Yang
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Dhaval Patel
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Samira M. Sadowski
- Thoracic and Endocrine Surgery, University Hospitals of Geneva, Geneva, Switzerland
| | - Vladimir Neychev
- Department of Surgery, University Multiprofile Hospital for Active Treatment “Alexandrovska”, Medical University, Sofia, Bulgaria
| | - Electron Kebebew
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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35
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Marano F, Argenziano M, Frairia R, Adamini A, Bosco O, Rinella L, Fortunati N, Cavalli R, Catalano MG. Doxorubicin-Loaded Nanobubbles Combined with Extracorporeal Shock Waves: Basis for a New Drug Delivery Tool in Anaplastic Thyroid Cancer. Thyroid 2016; 26:705-16. [PMID: 26906083 DOI: 10.1089/thy.2015.0342] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND No standard chemotherapy is available for anaplastic thyroid cancer (ATC). Drug-loaded nanobubbles (NBs) are a promising innovative anticancer drug formulation, and combining them with an externally applied trigger may further control drug release at the target region. Extracorporeal shock waves (ESWs) are acoustic waves widely used in urology and orthopedics, with no side effects. The aim of the present work was to combine ESWs and new doxorubicin-loaded glycol chitosan NBs in order to target doxorubicin and enhance its antitumor effect in ATC cell lines. METHODS CAL-62 and 8305C cells were treated with empty NBs, fluorescent NBs, free doxorubicin, and doxorubicin-loaded NBs in the presence or in the absence of ESWs. NB entrance was evaluated by fluorescence microscopy and flow cytofluorimetry. Cell viability was assessed by Trypan Blue exclusion and WST-1 proliferation assays. Doxorubicin intracellular content was measured by high-performance liquid chromatography. RESULTS Treatment with empty NBs and ESWs, even in combination, was safe, as cell viability and growth were not affected. Loading NBs with doxorubicin and combining them with ESWs generated the highest cytotoxic effect, resulting in drug GI50 reduction of about 40%. Mechanistically, ESWs triggered intracellular drug release from NBs, resulting in the highest nuclear drug content. CONCLUSIONS Combined treatment with doxorubicin-loaded NBs and ESWs is a promising drug delivery tool for ATC treatment with the possibility of using lower doxorubicin doses and thus limiting its systemic side effects.
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Affiliation(s)
- Francesca Marano
- 1 Department of Medical Sciences, University of Turin , Turin, Italy
| | - Monica Argenziano
- 2 Department of Drug Science and Technology, University of Turin , Turin, Italy
| | - Roberto Frairia
- 1 Department of Medical Sciences, University of Turin , Turin, Italy
| | - Aloe Adamini
- 1 Department of Medical Sciences, University of Turin , Turin, Italy
| | - Ornella Bosco
- 1 Department of Medical Sciences, University of Turin , Turin, Italy
| | - Letizia Rinella
- 1 Department of Medical Sciences, University of Turin , Turin, Italy
| | - Nicoletta Fortunati
- 3 Oncological Endocrinology, AO Città della Salute e della Scienza di Torino, Turin, Italy
| | - Roberta Cavalli
- 2 Department of Drug Science and Technology, University of Turin , Turin, Italy
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Ye P, Xing H, Lou F, Wang K, Pan Q, Zhou X, Gong L, Li D. Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription. Cancer Chemother Pharmacol 2016; 77:613-21. [DOI: 10.1007/s00280-016-2979-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 01/26/2016] [Indexed: 02/07/2023]
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37
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Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ, Lee SJ. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells. Endocrine 2016. [PMID: 26219406 DOI: 10.1007/s12020-015-0706-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and CAL62 cells, SNX5422 caused cell death with concomitant changes in the expression of hsp90 client proteins. After treatment of both SNX5422 and PXD101, SAHA and TSA, compared with treatment of SNX5422 alone, cell viability was diminished, whereas inhibition rate and cytotoxic activity were enhanced. All of the combination index values were lower than 1.0, suggesting the synergism between SNX5422 and PXD101, SAHA and TSA in induction of cell death. In cells treated with both SNX5422 and PXD101, SAHA and TSA, compared with cells treated with SNX5422 alone, the protein levels of Akt, phospho-4EBP1, phospho-S6 K, and survivin were diminished, while those of γH2AX, acetyl. histone H3, acetyl. histone H4, cleaved PARP, and cleaved caspase-3 were enhanced. In conclusion, these results demonstrate that SNX5422 has a cytotoxic activity in conjunction with alterations in the expression of hsp90 client proteins in ATC cells. Moreover, SNX5422 synergizes with HDAC inhibitors in induction of cytotoxicity accompanied by the suppression of PI3K/Akt/mTOR signaling and survivin, and the overexpression of DNA damage-related proteins in ATC cells.
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Affiliation(s)
- Si Hyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jun Goo Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Chul Sik Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Sung-Hee Ihm
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Moon Gi Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Hyung Joon Yoo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Seong Jin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
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38
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Catalano MG, Pugliese M, Gallo M, Brignardello E, Milla P, Orlandi F, Limone PP, Arvat E, Boccuzzi G, Piovesan A. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial. Int J Endocrinol 2016; 2016:2930414. [PMID: 27766105 PMCID: PMC5059567 DOI: 10.1155/2016/2930414] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 09/08/2016] [Indexed: 01/04/2023] Open
Abstract
Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11.
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Affiliation(s)
| | | | - Marco Gallo
- Oncological Endocrinology, A.O.U. “Città della Salute e della Scienza di Torino” Hospital, Turin, Italy
| | - Enrico Brignardello
- Transition Unit for Childhood Cancer Survivors, A.O.U. “Città della Salute e della Scienza di Torino” Hospital, Turin, Italy
| | - Paola Milla
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Fabio Orlandi
- Section of Endocrinology, Division of Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Paolo Piero Limone
- Endocrinology, Diabetes, and Metabolism Unit, A.O. Ordine Mauriziano di Torino, “Umberto I” Hospital, Turin, Italy
| | - Emanuela Arvat
- Department of Medical Sciences, University of Turin, Turin, Italy
- Oncological Endocrinology, A.O.U. “Città della Salute e della Scienza di Torino” Hospital, Turin, Italy
| | | | - Alessandro Piovesan
- Oncological Endocrinology, A.O.U. “Città della Salute e della Scienza di Torino” Hospital, Turin, Italy
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Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation. Cancer Gene Ther 2015; 22:410-6. [PMID: 26251030 DOI: 10.1038/cgt.2015.37] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 06/24/2015] [Accepted: 07/10/2015] [Indexed: 01/07/2023]
Abstract
To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half-maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21(WAF1) and p27(Kip1) increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid-stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re-differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy.
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He S, Dong G, Wang Z, Chen W, Huang Y, Li Z, Jiang Y, Liu N, Yao J, Miao Z, Zhang W, Sheng C. Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors. ACS Med Chem Lett 2015; 6:239-43. [PMID: 25815139 DOI: 10.1021/ml500327q] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 01/14/2015] [Indexed: 01/02/2023] Open
Abstract
Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of-concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents.
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Affiliation(s)
- Shipeng He
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou, Fujian 350122, P. R. China
| | - Guoqiang Dong
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Zhibin Wang
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Wei Chen
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Yahui Huang
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Zhengang Li
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Yan Jiang
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Na Liu
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Jianzhong Yao
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Zhenyuan Miao
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Wannian Zhang
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Chunquan Sheng
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou, Fujian 350122, P. R. China
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
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Baldan F, Mio C, Allegri L, Puppin C, Russo D, Filetti S, Damante G. Synergy between HDAC and PARP Inhibitors on Proliferation of a Human Anaplastic Thyroid Cancer-Derived Cell Line. Int J Endocrinol 2015; 2015:978371. [PMID: 25705225 PMCID: PMC4326215 DOI: 10.1155/2015/978371] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 09/09/2014] [Indexed: 12/19/2022] Open
Abstract
Anaplastic thyroid carcinoma (ATC) is a very aggressive human malignancy, having a marked degree of invasiveness and no features of thyroid differentiation. It is known that either HDAC inhibitors or PARP inhibitors have antiproliferative effects on thyroid cancer cells. Therefore, in this study the possible synergy between the two types of compounds has been investigated. The ATC-derived cell line SW1736 has been treated with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and the PARP inhibitor PJ34, alone or in combination. In terms of cell viability, the combination index value was always lower than 1 at various tested dosages, indicating, therefore, synergy in a wide range of doses for both compounds. Synergy was also observed in induction of apoptosis. In terms of thyroid-specific gene expression, synergy was observed for TSHR mRNA levels but not for NIS, TTF1, TTF2, and PAX8 mRNA levels. Altogether, these data suggest that the combined use of HDAC and PARP inhibitors may be a useful strategy for treatment of ATC.
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Affiliation(s)
- Federica Baldan
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy
| | - Catia Mio
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy
| | - Lorenzo Allegri
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy
| | - Cinzia Puppin
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy
| | - Diego Russo
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Sebastiano Filetti
- Department of Internal Medicine and Medical Specialties, University of Roma “La Sapienza”, 00198 Rome, Italy
| | - Giuseppe Damante
- Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy
- Institute of Medical Genetics, University Hospital “S. Maria della Misericordia”, 33100 Udine, Italy
- *Giuseppe Damante:
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Cowell IG, Papageorgiou N, Padget K, Watters GP, Austin CA. Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin. Nucleus 2014. [DOI: 10.4161/nucl.14194] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Song Q, Tan S, Zhuang X, Guo Y, Zhao Y, Wu T, Ye Q, Si L, Zhang Z. Nitric oxide releasing d-α-tocopheryl polyethylene glycol succinate for enhancing antitumor activity of doxorubicin. Mol Pharm 2014; 11:4118-29. [PMID: 25222114 DOI: 10.1021/mp5003009] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when codelivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized d-α-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release ∼90% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO3 could also serve as an enhancer for the common chemotherapeutic drug doxorubicin (DOX). Codelivering TNO3 with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (∼6.25-fold lower IC50). Moreover, for DOX-based chemotherapy in tumor-bearing mice, coadministration with TNO3 significantly extended the blood circulation time of DOX (14.7-fold t1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO3, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.
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Affiliation(s)
- Qingle Song
- Tongji School of Pharmacy and ‡National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology , Wuhan 430030, China
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Weinlander E, Somnay Y, Harrison AD, Wang C, Cheng YQ, Jaskula-Sztul R, Yu XM, Chen H. The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth. J Surg Res 2014; 190:191-7. [PMID: 24679699 PMCID: PMC4063213 DOI: 10.1016/j.jss.2014.02.042] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/20/2014] [Accepted: 02/22/2014] [Indexed: 11/22/2022]
Abstract
BACKGROUND Anaplastic thyroid cancer (ATC) remains refractory to available surgical and medical interventions. Histone deacetylase (HDAC) inhibitors are an emerging targeted therapy with antiproliferative activity in a variety of thyroid cancer cell lines. Thailandepsin A (TDP-A) is a novel class I HDAC inhibitor whose efficacy remains largely unknown in ATC. Therefore, we aimed to characterize the effect of TDP-A on ATC. METHODS Human-derived ATC cells were treated with TDP-A. IC50 was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid colorimetric assay, and cell proliferation was measured by viable cell count. Molecular mechanisms of cell growth inhibition were investigated by Western blot analysis of canonical apoptosis markers, intrinsic and extrinsic apoptosis regulators, and cell cycle regulatory proteins. Cell cycle staging was determined with propidium iodide flow cytometry. RESULTS TDP-A dose- and time-dependently reduced cell proliferation. Increased cleavage of the apoptosis markers Caspase-9, Caspase-3, and poly adenosine diphosphate ribose polymerase were observed with TDP-A treatment. Levels of the intrinsic apoptosis pathway proteins BAD, Bcl-XL, and BAX remained unchanged. Importantly, the extrinsic apoptosis activator cleaved Caspase-8 increased dose-dependently, and the antiapoptotic proteins Survivin and Bcl-2 decreased. Among the cell cycle regulatory proteins, levels of CDK inhibitors p21/WAF1 and p27/KIP increased. Flow cytometry showed that ATC cells were arrested in G2/M phase with diminished S phase after TDP-A treatment. CONCLUSIONS TDP-A induces a notable dose- and time-dependent antiproliferative effect on ATC, which is mainly attributed to extrinsic apoptosis with concomitant cell cycle arrest. TDP-A therefore warrants further preclinical and clinical investigations.
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Affiliation(s)
- Eric Weinlander
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Yash Somnay
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - April D Harrison
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Cheng Wang
- Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin
| | - Yi-Qiang Cheng
- Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin; UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas
| | - Renata Jaskula-Sztul
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Xiao-Min Yu
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
| | - Herbert Chen
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Vu-Phan D, Koenig RJ. Genetics and epigenetics of sporadic thyroid cancer. Mol Cell Endocrinol 2014; 386:55-66. [PMID: 23933154 PMCID: PMC3867574 DOI: 10.1016/j.mce.2013.07.030] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/31/2013] [Accepted: 07/31/2013] [Indexed: 12/23/2022]
Abstract
Thyroid carcinoma is the most common endocrine malignancy, and although the disease generally has an excellent prognosis, therapeutic options are limited for patients not cured by surgery and radioiodine. Thyroid carcinomas commonly contain one of a small number of recurrent genetic mutations. The identification and study of these mutations has led to a deeper understanding of the pathophysiology of this disease and is providing new approaches to diagnosis and therapy. Papillary thyroid carcinomas usually contain an activating mutation in the RAS cascade, most commonly in BRAF and less commonly in RAS itself or through gene fusions that activate RET. A chromosomal translocation that results in production of a PAX8-PPARG fusion protein is found in follicular carcinomas. Anaplastic carcinomas may contain some of the above changes as well as additional mutations. Therapies that are targeted to these mutations are being used in patient care and clinical trials.
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Affiliation(s)
- Dang Vu-Phan
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
| | - Ronald J Koenig
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
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Dodurga Y, Gundogdu G, Tekin V, Koc T, Satiroglu-Tufan NL, Bagci G, Kucukatay V. Valproic acid inhibits the proliferation of SHSY5Y neuroblastoma cancer cells by downregulating URG4/URGCP and CCND1 gene expression. Mol Biol Rep 2014; 41:4595-9. [DOI: 10.1007/s11033-014-3330-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 03/10/2014] [Indexed: 01/17/2023]
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Morani F, Titone R, Pagano L, Galetto A, Alabiso O, Aimaretti G, Isidoro C. Autophagy and thyroid carcinogenesis: genetic and epigenetic links. Endocr Relat Cancer 2014; 21:R13-29. [PMID: 24163390 DOI: 10.1530/erc-13-0271] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancers.
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Affiliation(s)
- Federica Morani
- Laboratory of Molecular Pathology, Department of Health SciencesUnit of Clinical Endocrinology Unit of Oncology, Department of Translational Medicine, Università del Piemonte Orientale 'A. Avogadro', Via Solaroli 17, 28100 Novara, Italy
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Rasheed W, Bishton M, Johnstone RW, Prince HM. Histone deacetylase inhibitors in lymphoma and solid malignancies. Expert Rev Anticancer Ther 2014; 8:413-32. [DOI: 10.1586/14737140.8.3.413] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta Rev Cancer 2013; 1845:84-9. [PMID: 24361676 DOI: 10.1016/j.bbcan.2013.12.002] [Citation(s) in RCA: 357] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 11/16/2013] [Accepted: 12/10/2013] [Indexed: 11/23/2022]
Abstract
Doxorubicin is one of the most important anti-cancer chemotherapeutic drugs, being widely used for the treatment of solid tumors and acute leukemias. The action of doxorubicin and other anthracycline drugs has been intensively investigated during the last several decades, but the mechanisms that have been proposed for cell killing remain disparate and controversial. In this review, we examine the proposed models for doxorubicin action from the perspective of the chromatin landscape, which is altered in many types of cancer due to recurrent mutations in chromatin modifiers. We highlight recent evidence for effects of anthracyclines on DNA torsion and chromatin dynamics that may underlie basic mechanisms of doxorubicin-mediated cell death and suggest new therapeutic strategies for cancer treatment.
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50
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The discovery and optimization of novel dual inhibitors of topoisomerase ii and histone deacetylase. Bioorg Med Chem 2013; 21:6981-95. [DOI: 10.1016/j.bmc.2013.09.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 09/07/2013] [Accepted: 09/07/2013] [Indexed: 11/22/2022]
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