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To KKW, Tolu SS, Wang L, Zhang H, Cho WC, Bates SE. HDAC inhibitors: Cardiotoxicity and paradoxical cardioprotective effect in ischemia-reperfusion myocardiocyte injury. Semin Cancer Biol 2025; 113:25-38. [PMID: 40360097 DOI: 10.1016/j.semcancer.2025.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 03/18/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025]
Abstract
Histone deacetylase inhibitors (HDACIs) are epigenetic drugs that regulate the acetylation status of histones and non-histone proteins, thereby leading to chromatin remodeling and transcriptional regulation of key apoptotic and cell cycle regulatory genes. There are currently five HDACIs clinically approved by the major regulatory authorities for treating hematological cancers, primarily as monotherapy. While HDACIs have been particularly effective in T-cell lymphomas, their clinical efficacies have not yet extended to solid tumors. The development of HDACIs continues, including for the treatment of a non-malignant conditions, with givinostat recently approved by the US FDA. However, the early development of HDACIs was limited by concerns about cardiotoxicity including QT interval prolongation. Yet, paradoxically, the latest research suggests some cardioprotective effect of HDACIs in ischemic heart disease or heart failure. This review presents the latest update about the cardiotoxicity of the clinically approved HDACIs. The mechanisms leading to HDACI-induced cardiotoxic adverse events and clinical strategies for their management are discussed. We will also deliberate the potential repurposing use of HDACIs and their HDAC isoform selectivity for treating ischemia-reperfusion cardiac muscle injury, cardiac hypertrophy, and fibrosis.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
| | - Seda S Tolu
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Longling Wang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Hang Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong
| | - Susan E Bates
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
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2
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Finnegan E, Ding W, Ude Z, Terer S, McGivern T, Blümel AM, Kirwan G, Shao X, Genua F, Yin X, Kel A, Fattah S, Myer PA, Cryan SA, Prehn JHM, O'Connor DP, Brennan L, Yochum G, Marmion CJ, Das S. Complexation of histone deacetylase inhibitor belinostat to Cu(II) prevents premature metabolic inactivation in vitro and demonstrates potent anti-cancer activity in vitro and ex vivo in colon cancer. Cell Oncol (Dordr) 2024; 47:533-553. [PMID: 37934338 PMCID: PMC11090832 DOI: 10.1007/s13402-023-00882-x] [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] [Accepted: 09/19/2023] [Indexed: 11/08/2023] Open
Abstract
PURPOSE The histone deacetylase inhibitor (HDACi), belinostat, has had limited therapeutic impact in solid tumors, such as colon cancer, due to its poor metabolic stability. Here we evaluated a novel belinostat prodrug, copper-bis-belinostat (Cubisbel), in vitro and ex vivo, designed to overcome the pharmacokinetic challenges of belinostat. METHODS The in vitro metabolism of each HDACi was evaluated in human liver microsomes (HLMs) using mass spectrometry. Next, the effect of belinostat and Cubisbel on cell growth, HDAC activity, apoptosis and cell cycle was assessed in three colon cancer cell lines. Gene expression alterations induced by both HDACis were determined using RNA-Seq, followed by in silico analysis to identify master regulators (MRs) of differentially expressed genes (DEGs). The effect of both HDACis on the viability of colon cancer patient-derived tumor organoids (PDTOs) was also examined. RESULTS Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro half-life of Cubisbel was significantly longer than belinostat. Belinostat and its Cu derivative commonly dysregulated numerous signalling and metabolic pathways while genes downregulated by Cubisbel were potentially controlled by VEGFA, ERBB2 and DUSP2 MRs. Treatment of colon cancer PDTOs with the HDACis resulted in a significant reduction in cell viability and downregulation of stem cell and proliferation markers. CONCLUSIONS Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly enhances its metabolic stability in vitro and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation of HDACis to a metal ion might improve the efficacy of clinically used HDACis in patients with colon cancer.
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Affiliation(s)
- Ellen Finnegan
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Wei Ding
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA, 17036, USA
| | - Ziga Ude
- Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Sara Terer
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Tadhg McGivern
- Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Anna M Blümel
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Grainne Kirwan
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Xinxin Shao
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Flavia Genua
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Xiaofei Yin
- UCD School of Agriculture and Food Science, UCD Conway Institute, Belfield, University College Dublin, Dublin, Ireland
| | - Alexander Kel
- GeneXplain GmbH, Wolfenbuettel, Germany
- BIOSOFT.RU, LLC, Novosibirsk, Russia
- Institute of Chemical Biology and Fundamental Medicine SBRAS, Novosibirsk, Russia
| | - Sarinj Fattah
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Parvathi A Myer
- Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA
| | - Sally-Ann Cryan
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Darran P O'Connor
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Lorraine Brennan
- UCD School of Agriculture and Food Science, UCD Conway Institute, Belfield, University College Dublin, Dublin, Ireland
| | - Gregory Yochum
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA, 17036, USA
- Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA, 17036, USA
| | - Celine J Marmion
- Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
| | - Sudipto Das
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
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Orlacchio A, Muzyka S, Gonda TA. Epigenetic therapeutic strategies in pancreatic cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 383:1-40. [PMID: 38359967 DOI: 10.1016/bs.ircmb.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 8-11%. Despite significant improvements in PDAC treatment and management, therapeutic alternatives are still limited. One of the main reasons is its high degree of intra- and inter-individual tumor heterogeneity which is established and maintained through a complex network of transcription factors and epigenetic regulators. Epigenetic drugs, have shown promising preclinical results in PDAC and are currently being evaluated in clinical trials both for their ability to sensitize cancer cells to cytotoxic drugs and to counteract the immunosuppressive characteristic of PDAC tumor microenvironment. In this review, we discuss the current status of epigenetic treatment strategies to overcome molecular and cellular PDAC heterogeneity in order to improve response to therapy.
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Affiliation(s)
- Arturo Orlacchio
- Division of Gastroenterology and Hepatology, New York University, New York, NY, United States
| | - Stephen Muzyka
- Division of Gastroenterology and Hepatology, New York University, New York, NY, United States
| | - Tamas A Gonda
- Division of Gastroenterology and Hepatology, New York University, New York, NY, United States.
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4
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Zhang L, Chai R, Tai Z, Miao F, Shi X, Chen Z, Zhu Q. Noval advance of histone modification in inflammatory skin diseases and related treatment methods. Front Immunol 2024; 14:1286776. [PMID: 38235133 PMCID: PMC10792063 DOI: 10.3389/fimmu.2023.1286776] [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: 09/01/2023] [Accepted: 12/08/2023] [Indexed: 01/19/2024] Open
Abstract
Inflammatory skin diseases are a group of diseases caused by the disruption of skin tissue due to immune system disorders. Histone modification plays a pivotal role in the pathogenesis and treatment of chronic inflammatory skin diseases, encompassing a wide range of conditions, including psoriasis, atopic dermatitis, lupus, systemic sclerosis, contact dermatitis, lichen planus, and alopecia areata. Analyzing histone modification as a significant epigenetic regulatory approach holds great promise for advancing our understanding and managing these complex disorders. Additionally, therapeutic interventions targeting histone modifications have emerged as promising strategies for effectively managing inflammatory skin disorders. This comprehensive review provides an overview of the diverse types of histone modification. We discuss the intricate association between histone modification and prevalent chronic inflammatory skin diseases. We also review current and potential therapeutic approaches that revolve around modulating histone modifications. Finally, we investigated the prospects of research on histone modifications in the context of chronic inflammatory skin diseases, paving the way for innovative therapeutic interventions and improved patient outcomes.
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Affiliation(s)
- Lichen Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Rongrong Chai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Zongguang Tai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Fengze Miao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Xinwei Shi
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Quangang Zhu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
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5
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Xu L, Yan X, Wang J, Zhao Y, Liu Q, Fu J, Shi X, Su J. The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis. Int J Mol Sci 2023; 24:15066. [PMID: 37894746 PMCID: PMC10606123 DOI: 10.3390/ijms242015066] [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: 07/31/2023] [Revised: 10/01/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
Ovarian cancer is the most lethal gynecologic malignancy, and metastasis is the major cause of death in patients with ovarian cancer, which is regulated by the coordinated interplay of genetic and epigenetic mechanisms. Histone deacetylases (HDACs) are enzymes that can catalyze the deacetylation of histone and some non-histone proteins and that are involved in the regulation of a variety of biological processes via the regulation of gene transcription and the functions of non-histone proteins such as transcription factors and enzymes. Aberrant expressions of HDACs are common in ovarian cancer. Many studies have found that HDACs are involved in regulating a variety of events associated with ovarian cancer metastasis, including cell migration, invasion, and the epithelial-mesenchymal transformation. Herein, we provide a brief overview of ovarian cancer metastasis and the dysregulated expression of HDACs in ovarian cancer. In addition, we discuss the roles of HDACs in the regulation of ovarian cancer metastasis. Finally, we discuss the development of compounds that target HDACs and highlight their importance in the future of ovarian cancer therapy.
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Affiliation(s)
- Long Xu
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
- School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China
| | - Xiaoyu Yan
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
| | - Jian Wang
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
| | - Yuanxin Zhao
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
| | - Qingqing Liu
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
| | - Jiaying Fu
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
| | - Xinyi Shi
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
| | - Jing Su
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China; (L.X.); (X.Y.); (J.W.); (Y.Z.); (Q.L.); (J.F.); (X.S.)
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6
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Shafer D, Kagan AB, Rudek MA, Kmieciak M, Tombes MB, Shrader E, Bandyopadhyay D, Hudson D, Sankala H, Weir C, Lancet JE, Grant S. Phase 1 study of belinostat and adavosertib in patients with relapsed or refractory myeloid malignancies. Cancer Chemother Pharmacol 2023; 91:281-290. [PMID: 36864346 PMCID: PMC10807611 DOI: 10.1007/s00280-023-04511-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/08/2023] [Indexed: 03/04/2023]
Abstract
PURPOSE Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models. EXPERIMENTAL DESIGN This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1-5 and 8-12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy. RESULTS Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m2) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination. CONCLUSIONS The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population.
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Affiliation(s)
- Danielle Shafer
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA
- Inova Schar Cancer Center, Fairfax, VA, USA
| | - Amanda B Kagan
- Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21231, USA
| | - Michelle A Rudek
- Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21231, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD, 21231, USA
| | - Maciej Kmieciak
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Mary Beth Tombes
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Ellen Shrader
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Dipankar Bandyopadhyay
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
- Department of Statistics, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Daniel Hudson
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Heidi Sankala
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Caryn Weir
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Jeffrey E Lancet
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Steven Grant
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
- The Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
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7
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Cell-of-Origin Targeted Drug Repurposing for Triple-Negative and Inflammatory Breast Carcinoma with HDAC and HSP90 Inhibitors Combined with Niclosamide. Cancers (Basel) 2023; 15:cancers15020332. [PMID: 36672285 PMCID: PMC9856736 DOI: 10.3390/cancers15020332] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023] Open
Abstract
We recently identified a cell-of-origin-specific mRNA signature associated with metastasis and poor outcome in triple-negative carcinoma (TNBC). This TNBC cell-of-origin signature is associated with the over-expression of histone deacetylases and zinc finger protein HDAC1, HDAC7, and ZNF92, respectively. Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Additionally, we discovered that four out of five inflammatory breast carcinoma cell lines are sensitive to this combination. Significantly, the concentration of the drugs that are used in these experiments are within or below clinically achievable dose, and the synergistic activity only emerged when all three drugs were combined. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.
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Elrakaybi A, Ruess DA, Lübbert M, Quante M, Becker H. Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment. Cancers (Basel) 2022; 14:cancers14235926. [PMID: 36497404 PMCID: PMC9738647 DOI: 10.3390/cancers14235926] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/18/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with high potential of metastases and therapeutic resistance. Although genetic mutations drive PDAC initiation, they alone do not explain its aggressive nature. Epigenetic mechanisms, including aberrant DNA methylation and histone modifications, significantly contribute to inter- and intratumoral heterogeneity, disease progression and metastasis. Thus, increased understanding of the epigenetic landscape in PDAC could offer new potential biomarkers and tailored therapeutic approaches. In this review, we shed light on the role of epigenetic modifications in PDAC biology and on the potential clinical applications of epigenetic biomarkers in liquid biopsy. In addition, we provide an overview of clinical trials assessing epigenetically targeted treatments alone or in combination with other anticancer therapies to improve outcomes of patients with PDAC.
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Affiliation(s)
- Asmaa Elrakaybi
- Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Clinical Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Dietrich A. Ruess
- Department of General and Visceral Surgery, Center of Surgery, Medical Center University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79106 Freiburg, Germany
| | - Michael Lübbert
- Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79106 Freiburg, Germany
| | - Michael Quante
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79106 Freiburg, Germany
- Department of Gastroenterology and Hepatology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Heiko Becker
- Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79106 Freiburg, Germany
- Correspondence: ; Tel.: +49-761-270-36000
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9
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Guo F, Wang H. Potential of histone deacetylase inhibitors for the therapy of ovarian cancer. Front Oncol 2022; 12:1057186. [PMID: 36505774 PMCID: PMC9732372 DOI: 10.3389/fonc.2022.1057186] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/01/2022] [Indexed: 11/27/2022] Open
Abstract
Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemotherapy increase patient mortality. Accumulating evidence demonstrates that histone modifications play a key role in cancerization and progression. Histone deacetylases is associated with chromatin condensed structure and transcriptional repression and play a role in chromatin remodeling and epigenetics. Histone deacetylases are promising targets for therapeutic interventions intended to reverse aberrant epigenetic associated with cancer. Therefore, histone deacetylases inhibitors could be used as anti-cancer drugs. Preclinical studies have shown promising outcomes of histone deacetylases inhibitors in ovarian cancer while clinical trials have had mixed results and limited success as monotherapy. Therefore, combination therapy with different anticancer drugs for synergistic effects and newly selective histone deacetylases inhibitors development for lower toxicity are hot issues now. In this review, we summarize the latest studies on the classification and mechanisms of action of histone deacetylase and the clinical application of their inhibitors as monotherapy or combination therapy in ovarian cancer.
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Affiliation(s)
- Fengyi Guo
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hongjing Wang
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China,*Correspondence: Hongjing Wang,
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10
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Kawakubo K, Castillo CFD, Liss AS. Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy. J Gastroenterol 2022; 57:819-826. [PMID: 36048239 PMCID: PMC9596544 DOI: 10.1007/s00535-022-01915-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/16/2022] [Indexed: 02/04/2023]
Abstract
Pancreatic adenocarcinoma is a lethal cancer with poor response to chemotherapy and immune checkpoint inhibitors. Recent studies suggest that epigenetic alterations contribute to its aggressive biology and the tumor microenvironment which render it unresponsive to immune checkpoint blockade. Here, we review our current understandings of epigenetic dysregulation in pancreatic adenocarcinoma, its effect on the tumor immune microenvironment, and the potential for epigenetic therapy to be combined with immune checkpoint inhibitors.
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Affiliation(s)
- Kazumichi Kawakubo
- Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | | | - Andrew Scott Liss
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Lanzi C, Cassinelli G. Combinatorial strategies to potentiate the efficacy of HDAC inhibitors in fusion-positive sarcomas. Biochem Pharmacol 2022; 198:114944. [DOI: 10.1016/j.bcp.2022.114944] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
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12
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Aru B, Günay A, Demirel GY, Gürek AG, Atilla D. Evaluation of histone deacetylase inhibitor substituted zinc and indium phthalocyanines for chemo- and photodynamic therapy. RSC Adv 2021; 11:34963-34978. [PMID: 35494743 PMCID: PMC9042886 DOI: 10.1039/d1ra05404j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/14/2021] [Indexed: 01/03/2023] Open
Abstract
In this study, we synthesized and characterized 3-hydroxypyridin-2-thione (3-HPT) bearing zinc (ZnPc-1 and ZnPc-2) and indium (InPc-1 and InPc-2) phthalocyanine (Pc) derivatives, either non-peripherally or peripherally substituted as photosensitizer (PS) agents and evaluated their anti-cancer efficacy on two breast cancer cell lines, MDA-MB-231 and MCF-7 as well as a human endothelial cell line, HUVEC. Our results indicated different localization patterns between ZnPcs and InPcs in addition to enhanced effects on the mitochondrial network for InPcs. Moreover, peripheral or non-peripheral substitution of HDACi moieties altered cellular localization between ZnPc-1 and ZnPc-2, leading to increased IC50 values along with decreased anti-cancer activity for non-peripheral substitution. When considering the compounds' differential effects in vitro, our data indicates that further research is required to determine the ideal Pcs for anti-cancer PDT treatments since the core metals of the compounds have affected the cellular localization, and positioning of the chemotherapeutic residues may inhibit cellular penetrance.
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Affiliation(s)
- Başak Aru
- Faculty of Medicine, Immunology Department, Yeditepe University 34755 Ataşehir İstanbul Turkey
| | - Aysel Günay
- Department of Chemistry, Gebze Technical University 41400 Gebze Kocaeli Turkey
| | | | - Ayşe Gül Gürek
- Department of Chemistry, Gebze Technical University 41400 Gebze Kocaeli Turkey
| | - Devrim Atilla
- Department of Chemistry, Gebze Technical University 41400 Gebze Kocaeli Turkey
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13
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Thompson JK, Bednar F. Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma. EPIGENOMES 2021; 5:20. [PMID: 34968245 PMCID: PMC8715475 DOI: 10.3390/epigenomes5040020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor's intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer.
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Affiliation(s)
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
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14
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Unraveling the Epigenetic Role and Clinical Impact of Histone Deacetylases in Neoplasia. Diagnostics (Basel) 2021; 11:diagnostics11081346. [PMID: 34441281 PMCID: PMC8394077 DOI: 10.3390/diagnostics11081346] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 02/07/2023] Open
Abstract
Histone deacetylases (HDACs) have long been implicated in tumorigenesis and tumor progression demonstrating their important participation in neoplasia. Therefore, numerous studies have been performed, highlighting the mechanism of HDACs action in tumor cells and demonstrating the potential role of HDAC inhibitors in the treatment of different cancer types. The outcome of these studies further delineated and strengthened the solid role that HDACs and epigenetic modifications exert in neoplasia. These results have spread promise regarding the potential use of HDACs as prospective therapeutic targets. Nevertheless, the clinical significance of HDAC expression and their use as biomarkers in cancer has not been extensively elucidated. The aim of our study is to emphasize the clinical significance of HDAC isoforms expression in different tumor types and the correlations noted between the clinicopathological parameters of tumors and patient outcomes. We further discuss the obstacles that the next generation HDAC inhibitors need to overcome, for them to become more potent.
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15
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Hu P, Sun M, Lu F, Wang S, Hou L, Yu Y, Zhang Y, Sun L, Yao J, Yang F, Wang C, Ma Z. Polymerized vorinostat mediated photodynamic therapy using lysosomal spatiotemporal synchronized drug release complex. Colloids Surf B Biointerfaces 2021; 205:111903. [PMID: 34144323 DOI: 10.1016/j.colsurfb.2021.111903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 01/16/2023]
Abstract
A combination of photodynamic therapy (PDT) and histone deacetylase inhibitor (HDACis) could potentiate single-mode anti-tumor activity of HDACis or PDT to inhibit tumor relapse and metastasis. However, poor solubility and heterogeneity in cellular uptake and tissue distribution hamper the dual mode antitumor effect. For a controlled drug release of photosensitizers and HDACis in cytoplasm, photosensitizer pyropheophorbide-a (Pyro) encapsulated in polymer polyethylene glycol-b-poly (asparaginyl-vorinostat) (simplified as Pyro@FPPS) are fabricated to achieve their lysosomal spatiotemporal synchronized release. With HDACis modeling PDT in vitro and in vivo, it seems that polymerized Vorinostat encapsulated photosensitizers significantly inhibited the tumor proliferation and metastasis by spatiotemporal synchronized drugs release, and Pyro@FPPS reported here reveals a promising prospect to exert drugs' synergistic effect in a spatiotemporal synchronized manner and can be an effective strategy to inhibit tumor growth, recurrence and metastasis in clinic.
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Affiliation(s)
- Pengwei Hu
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; Harbin Institute of Technology (Shenzhen), School of Science, Shenzhen, People's Republic of China; Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China
| | - Miao Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Fengkun Lu
- Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China
| | - Sizhen Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Lei Hou
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China
| | - Yingjie Yu
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Yunchang Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Linhong Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Jianzhong Yao
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Feng Yang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
| | - Chen Wang
- Department of Oncology, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Zhiqiang Ma
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
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16
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Abstract
Histone deacetylases (HDACs) are part of the epigenetic machinery that regulates transcriptional processes. The current paradigm is that HDACs silence gene expression via regulation of histone protein lysine deacetylation, or by forming corepressor complexes with transcription factors. However, HDACs are more than just nuclear proteins, and they can interact and deacetylate a growing number of nonhistone proteins to regulate cellular function. Cancer-field studies have shown that deranged HDAC activity results in uncontrolled proliferation, inflammation, and fibrosis; all pathologies that also may occur in kidney disease. Over the past decade, studies have emerged suggesting that HDAC inhibitors may prevent and potentially treat various models of acute kidney injury. This review focuses on the physiology of kidney HDACs and highlights the recent advances using HDAC inhibitors to potentially treat kidney disease patients.
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Affiliation(s)
- Kelly A Hyndman
- Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
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17
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Jenke R, Reßing N, Hansen FK, Aigner A, Büch T. Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives. Cancers (Basel) 2021; 13:634. [PMID: 33562653 PMCID: PMC7915831 DOI: 10.3390/cancers13040634] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/30/2021] [Accepted: 02/02/2021] [Indexed: 12/26/2022] Open
Abstract
The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond "classic" oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).
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Affiliation(s)
- Robert Jenke
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, D-04103 Leipzig, Germany
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| | - Nina Reßing
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, Rheinische Fried-rich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; (N.R.); (F.K.H.)
| | - Finn K. Hansen
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, Rheinische Fried-rich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; (N.R.); (F.K.H.)
| | - Achim Aigner
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| | - Thomas Büch
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
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18
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Wang X, Wang Z, Wang Z, Chen X, Yin H, Jiang L, Cao J, Liu Y. Inhibition of human UDP-glucuronosyltransferase enzyme by belinostat: Implications for drug-drug interactions. Toxicol Lett 2020; 338:51-57. [PMID: 33290829 DOI: 10.1016/j.toxlet.2020.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/08/2020] [Accepted: 12/03/2020] [Indexed: 12/31/2022]
Abstract
Belinostat is a pan-histone deacetylase (HDAC) inhibitor which recently approved for the treatment of relapsed/refractory Peripheral T-cell lymphomas (PTCL). To assess drug-drug interactions (DDIs) potential of belinostat via inhibition of UDP-glucuronosyltransferases (UGTs), the effects of belinostat on UGTs activities were investigated using the non-selective probe substrate 4-methylumbelliferone (4-MU) and trifluoperazine (TFP) by UPLC-MS/MS. Belinostat exhibited a wide range of inhibition against UGTs activities, particularly a potent non-competitive inhibition against UGT1A3, and weak inhibition against UGT1A1, 1A7, 1A8, 2B4 and 2B7. Further, in vitro-in vivo extrapolation (IVIVE) approaches were used to predict the risk of DDI arising from inhibition of UGTs. Our data indicate that the intravenous infusion of belinostat at clinical available dose can contribute a significant increase to the AUC of co-administrated drugs primarily cleared by UGT1A3 or UGT1A1, which will result in potential DDIs. In contrast, oral administrated belinostat is unlikely to cause significant DDIs through inhibition of glucuronidation.
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Affiliation(s)
- Xiaoyu Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China
| | - Zhe Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China
| | - Zhen Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China
| | - Xiuyuan Chen
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, 215123, China
| | - Hang Yin
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China
| | - Lili Jiang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China
| | - Jun Cao
- Department of Occupational and Environmental Health, Dalian Medical University, Dalian, 116044, China.
| | - Yong Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China.
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Cappellacci L, Perinelli DR, Maggi F, Grifantini M, Petrelli R. Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents. Curr Med Chem 2020; 27:2449-2493. [PMID: 30332940 DOI: 10.2174/0929867325666181016163110] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 07/29/2018] [Accepted: 10/09/2018] [Indexed: 12/13/2022]
Abstract
Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.
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Affiliation(s)
- Loredana Cappellacci
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
| | - Diego R Perinelli
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
| | - Filippo Maggi
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
| | - Mario Grifantini
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
| | - Riccardo Petrelli
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
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20
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Guo C, Wang Q, Zhang X, Lu F, Sun M, Zeng P, Sun L, She L, Wang B, Zhang Y, Wang C, Ma Z, Yang F. Gelated Vorinostat with inner-lysosome triggered release for tumor-targeting chemotherapy. Colloids Surf B Biointerfaces 2020; 194:111144. [PMID: 32535244 DOI: 10.1016/j.colsurfb.2020.111144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/13/2020] [Accepted: 05/16/2020] [Indexed: 12/16/2022]
Abstract
Histonedeacetylase inhibitor (HDACi) has great potential in targeted antitumor therapy by inhibiting tumor migration, invasion, and metastasis. As one of the typical HDACis, vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) was approved as a therapeutic agent for cancer therapy, however, challenges remain due to their poor solubility, short half-life and low efficiency in cellular penetration. Considering the disadvantages of usual drug carriers, folate and vorinostat bound BSA nanogel (FVBN)was fabricated to implement higher solubility, stability, cellular uptake, and lipase-responsive release. With good dispersion and stability, FVBN significantly increased the cellular uptake of vorinostat through folate-mediated endocytosis. FVBN exhibited comparable cytotoxicity with free SAHA, and the growth of tumor cells was blocked in G1/G0 phase just like SAHA performed in cell cycle arrest tests. Moreover, FVBN not only effectively inhibited the growth of melanoma but also observably prevented pulmonary metastasis of melanoma. In the experiment against nude mice bearing solid ovarian cancer, FVBN showed excellent antitumor effect without liver damage, demonstrating the superiority of gelated and inner-lysosome triggered release strategies to the free SAHA, and it is promising to expand the scope of application of HDACi in clinical cancer therapy.
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Affiliation(s)
- Changyong Guo
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China
| | - Qirong Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Xingjie Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Fengkun Lu
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China; School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Miao Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Peiyu Zeng
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Linhong Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Lan She
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Bingkai Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Yunchang Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Chen Wang
- Department of Oncology, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Zhiqiang Ma
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
| | - Feng Yang
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China; School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
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21
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Takebe N, Beumer JH, Kummar S, Kiesel BF, Dowlati A, O'Sullivan Coyne G, Piekarz R, Rubinstein L, Fogli LK, Vaishampayan U, Goel S, O'Bryant CL, El‐Rayes BF, Chung V, Lenz H, Kim R, Belani CP, Tuscano JM, Schelman W, Moore N, Doroshow JH, Chen AP. A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction. Br J Clin Pharmacol 2019; 85:2499-2511. [PMID: 31271459 PMCID: PMC6848909 DOI: 10.1111/bcp.14054] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 06/17/2019] [Accepted: 06/25/2019] [Indexed: 12/31/2022] Open
Abstract
AIMS The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
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Affiliation(s)
- Naoko Takebe
- Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | - Jan H. Beumer
- Cancer Therapeutics ProgramUPMC Hillman Cancer CenterPittsburghPAUSA
- Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghPAUSA
- Division of Hematology‐Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Shivaani Kummar
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | - Brian F. Kiesel
- Cancer Therapeutics ProgramUPMC Hillman Cancer CenterPittsburghPAUSA
- Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghPAUSA
| | - Afshin Dowlati
- University Hospitals Seidman Cancer Center and Case Western Reserve UniversityClevelandOHUSA
| | - Geraldine O'Sullivan Coyne
- Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | - Richard Piekarz
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | - Lawrence Rubinstein
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | - Laura K. Fogli
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | | | - Sanjay Goel
- Montefiore Medical CenterAlbert Einstein College of MedicineNew YorkNYUSA
| | | | | | | | - Heinz‐Josef Lenz
- Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesCAUSA
| | - Richard Kim
- Department of Gastrointestinal OncologyMoffitt Cancer Center and Research InstituteTampaFLUSA
| | - Chandra P. Belani
- Penn State Cancer InstitutePenn State Health Milton S. Hershey Medical CenterHersheyPAUSA
| | - Joseph M. Tuscano
- Comprehensive Cancer CenterUniversity of California Davis Medical CenterSacramentoCAUSA
| | | | - Nancy Moore
- Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
| | - James H. Doroshow
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
- Center for Cancer ResearchNational Cancer InstituteBethesdaMDUSA
| | - Alice P. Chen
- Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMDUSA
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22
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Luu T, Frankel P, Beumer JH, Lim D, Cristea M, Appleman LJ, Lenz HJ, Gandara DR, Kiesel BF, Piekarz RL, Newman EM. Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. Cancer Chemother Pharmacol 2019; 84:1201-1208. [PMID: 31522242 DOI: 10.1007/s00280-019-03955-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 08/21/2019] [Indexed: 10/26/2022]
Abstract
PURPOSE The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. METHODS Belinostat was administered days 1-5 and 13-cRA days 1-14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat. RESULTS Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. CONCLUSIONS The combination of belinostat 2000 mg/m2 days 1-5 and 13-cRA 100 mg/m2 days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.
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Affiliation(s)
- Thehang Luu
- Department of Medical Oncology, City of Hope, Duarte, USA
| | - Paul Frankel
- Department of Biostatistics, City of Hope, Duarte, USA
| | | | - Dean Lim
- Department of Medical Oncology, City of Hope, Duarte, USA
| | | | | | - Heinz J Lenz
- University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA
| | - David R Gandara
- University of California Davis Cancer Center, Sacramento, CA, 95817, USA
| | | | - Richard L Piekarz
- Cancer Therapy Evaluation Program, National Cancer Institute, 9609 Medical Center Dr., MSC 9739, Bethesda, MD, 20892, USA
| | - Edward M Newman
- Beckman Research Institute City of Hope, Duarte, CA, 91010, USA.
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23
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Blanquart C, Linot C, Cartron PF, Tomaselli D, Mai A, Bertrand P. Epigenetic Metalloenzymes. Curr Med Chem 2019; 26:2748-2785. [PMID: 29984644 DOI: 10.2174/0929867325666180706105903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022]
Abstract
Epigenetics controls the expression of genes and is responsible for cellular phenotypes. The fundamental basis of these mechanisms involves in part the post-translational modifications (PTMs) of DNA and proteins, in particular, the nuclear histones. DNA can be methylated or demethylated on cytosine. Histones are marked by several modifications including acetylation and/or methylation, and of particular importance are the covalent modifications of lysine. There exists a balance between addition and removal of these PTMs, leading to three groups of enzymes involved in these processes: the writers adding marks, the erasers removing them, and the readers able to detect these marks and participating in the recruitment of transcription factors. The stimulation or the repression in the expression of genes is thus the result of a subtle equilibrium between all the possibilities coming from the combinations of these PTMs. Indeed, these mechanisms can be deregulated and then participate in the appearance, development and maintenance of various human diseases, including cancers, neurological and metabolic disorders. Some of the key players in epigenetics are metalloenzymes, belonging mostly to the group of erasers: the zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji family (JMJ or KDM) and for DNA the iron-dependent ten-eleven-translocation enzymes (TET) responsible for the oxidation of methylcytosine prior to the demethylation of DNA. This review presents these metalloenzymes, their importance in human disease and their inhibitors.
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Affiliation(s)
- Christophe Blanquart
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
| | - Camille Linot
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France
| | - Pierre-François Cartron
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
| | - Daniela Tomaselli
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.,Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
| | - Philippe Bertrand
- Réseau Epigénétique du Cancéropôle Grand Ouest, France.,Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 51106, B27, 86073, Poitiers cedex 09, France
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Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer. Int J Mol Sci 2019; 20:ijms20061291. [PMID: 30875794 PMCID: PMC6471041 DOI: 10.3390/ijms20061291] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/07/2019] [Accepted: 03/08/2019] [Indexed: 12/24/2022] Open
Abstract
Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. “Acetyl-chromatin” homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation.
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Abbott KL, Chaudhury CS, Chandran A, Vishveshwara S, Dvorak Z, Jiskrova E, Poulikova K, Vyhlidalova B, Mani S, Pondugula SR. Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression. Mol Pharmacol 2019; 95:324-334. [PMID: 30622215 PMCID: PMC6362450 DOI: 10.1124/mol.118.114587] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 01/03/2019] [Indexed: 01/26/2023] Open
Abstract
Activation of human pregnane X receptor (hPXR) has been associated with induction of chemoresistance. It has been proposed that such chemoresistance via cytochrome P450/drug transporters can be reversed with the use of antagonists that specifically abrogate agonist-mediated hPXR activation. Unfortunately, proposed antagonists lack the specificity and appropriate pharmacological characteristics that allow these features to be active in the clinic. We propose that, ideally, an hPXR antagonist would be a cancer drug itself that is part of a "cancer drug cocktail" and effective as an hPXR antagonist at therapeutic concentrations. Belinostat (BEL), a histone deacetylase inhibitor approved for the treatment of relapsed/refractory peripheral T-cell lymphoma, and often used in combination with chemotherapy, is an attractive candidate based on its hPXR ligand-like features. We sought to determine whether these features of BEL might allow it to behave as an antagonist in combination chemotherapy regimens that include hPXR activators. BEL represses agonist-activated hPXR target gene expression at its therapeutic concentrations in human primary hepatocytes and LS174T human colon cancer cells. BEL repressed rifampicin-induced gene expression of CYP3A4 and multidrug resistance protein 1, as well as their respective protein activities. BEL decreased rifampicin-induced resistance to SN-38, the active metabolite of irinotecan, in LS174T cells. This finding indicates that BEL could suppress hPXR agonist-induced chemoresistance. BEL attenuated the agonist-induced steroid receptor coactivator-1 interaction with hPXR, and, together with molecular docking studies, the study suggests that BEL directly interacts with multiple sites on hPXR. Taken together, our results suggest that BEL, at its clinically relevant therapeutic concentration, can antagonize hPXR agonist-induced gene expression and chemoresistance.
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Affiliation(s)
- Kodye L Abbott
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Chloe S Chaudhury
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Aneesh Chandran
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Saraswathi Vishveshwara
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Zdenek Dvorak
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Eva Jiskrova
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Karolina Poulikova
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Barbora Vyhlidalova
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Sridhar Mani
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
| | - Satyanarayana R Pondugula
- Department of Anatomy, Physiology and Pharmacology (K.L.A., C.S.C., S.R.P.) and Auburn University Research Initiative in Cancer (K.L.A., C.S.C., S.R.P.), Auburn University, Auburn, Alabama; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India (A.C., S.V.); Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Czech Republic (Z.D., E.J., K.P., B.V.); and Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York (S.M.)
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Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs. J Theor Biol 2018; 451:1-9. [DOI: 10.1016/j.jtbi.2018.04.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 04/22/2018] [Accepted: 04/23/2018] [Indexed: 11/17/2022]
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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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Suraweera A, O’Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol 2018; 8:92. [PMID: 29651407 PMCID: PMC5884928 DOI: 10.3389/fonc.2018.00092] [Citation(s) in RCA: 491] [Impact Index Per Article: 70.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 03/16/2018] [Indexed: 01/10/2023] Open
Abstract
Genetic and epigenetic changes in DNA are involved in cancer development and tumor progression. Histone deacetylases (HDACs) are key regulators of gene expression that act as transcriptional repressors by removing acetyl groups from histones. HDACs are dysregulated in many cancers, making them a therapeutic target for the treatment of cancer. Histone deacetylase inhibitors (HDACi), a novel class of small-molecular therapeutics, are now approved by the Food and Drug Administration as anticancer agents. While they have shown great promise, resistance to HDACi is often observed and furthermore, HDACi have shown limited success in treating solid tumors. The combination of HDACi with standard chemotherapeutic drugs has demonstrated promising anticancer effects in both preclinical and clinical studies. In this review, we summarize the research thus far on HDACi in combination therapy, with other anticancer agents and their translation into preclinical and clinical studies. We additionally highlight the side effects associated with HDACi in cancer therapy and discuss potential biomarkers to either select or predict a patient's response to these agents, in order to limit the off-target toxicity associated with HDACi.
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Affiliation(s)
- Amila Suraweera
- School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Kenneth J. O’Byrne
- School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
- Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Derek J. Richard
- School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
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Abstract
Since the identification and cloning of human histone deacetylases (HDACs) and the rapid approval of vorinostat (Zolinza®) for the treatment of cutaneous T-cell lymphoma, the field of HDAC biology has met many initial successes. However, many challenges remain due to the complexity involved in the lysine posttranslational modifications, epigenetic transcription regulation, and nonepigenetic cellular signaling cascades. In this chapter, we will: review the discovery of the first HDAC inhibitor and present discussion regarding the future of next-generation HDAC inhibitors, give an overview of different classes of HDACs and their differences in lysine deacylation activity, discuss different classes of HDAC inhibitors and their HDAC isozyme preferences, and review HDAC inhibitors' preclinical studies, their clinical trials, their pharmacokinetic challenges, and future direction. We will also discuss the likely reason for the failure of multiple HDAC inhibitor clinical trials in malignancies other than lymphoma and multiple myeloma. In addition, the potential molecular mechanism(s) that may play a key role in the efficacy and therapeutic response rate in the clinic and the likely patient population for HDAC therapy will be discussed.
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Affiliation(s)
- Jesse J McClure
- Medical University of South Carolina, College of Pharmacy, Charleston, SC, United States
| | - Xiaoyang Li
- Medical University of South Carolina, College of Pharmacy, Charleston, SC, United States
| | - C James Chou
- Medical University of South Carolina, College of Pharmacy, Charleston, SC, United States.
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30
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Yamada T, Amann JM, Tanimoto A, Taniguchi H, Shukuya T, Timmers C, Yano S, Shilo K, Carbone DP. Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring RAS Mutations. Mol Cancer Ther 2017; 17:17-25. [PMID: 29079711 DOI: 10.1158/1535-7163.mct-17-0146] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 08/24/2017] [Accepted: 10/10/2017] [Indexed: 12/21/2022]
Abstract
Non-small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell-cycle regulators p21Cip1 and p27Kip1 We now show that an HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine whether the combination of a MEK inhibitor with an HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS-mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell-cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21Cip1 and p27Kip1 These results demonstrate that control of FOXOs localization and expression is critical in RAS-driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations. Mol Cancer Ther; 17(1); 17-25. ©2017 AACR.
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Affiliation(s)
- Tadaaki Yamada
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.,Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Joseph M Amann
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Azusa Tanimoto
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Hirokazu Taniguchi
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takehito Shukuya
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Cynthia Timmers
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Konstantin Shilo
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - David P Carbone
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
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Tchio Mantho CI, Harbuzariu A, Gonzalez-Perez RR. Histone deacetylases, microRNA and leptin crosstalk in pancreatic cancer. World J Clin Oncol 2017; 8:178-189. [PMID: 28638788 PMCID: PMC5465008 DOI: 10.5306/wjco.v8.i3.178] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/06/2017] [Accepted: 04/20/2017] [Indexed: 02/06/2023] Open
Abstract
Because pancreatic cancer (PC) historically has had poor prognosis and five year survival rates, it has been intensely investigated. Analysis of PC incidence and biology has shown a link between different risk factors such as smoking, alcoholism, and obesity and disease progression. Important factors affecting PC include the epigenomic changes driven by DNA methylation and histone acetylation, and actions of microRNA inducing oncogenic or tumor suppressor effects. Studies have identified markers whose dysregulation seem to play important roles in PC progression. PC markers involve classical histone deacetylases (HDAC), PC stem cell (PCSC), and leptin. In this review, we discuss the role of several PC biomarkers, and the potential crosstalk between HDAC, microRNA, and leptin in PC progression. Dysregulated expression of these molecules can increase proliferation, survival, PCSC, resistance to chemotherapy and tumor angiogenesis. The potential relationships between these molecules are further analyzed using data from The Cancer Genome Atlas and crosstalk pathways generated by the Pathway Studio Platform (Ariadne Genomics, Inc.). Oncogenic miRNA21 and tumor suppressor miRNA200 have been previously linked to leptin signaling. Preliminary analysis of PC biopsies and signaling crosstalk suggests that the main adipokine leptin could affect the expression of microRNA and HDAC in PC. Data analysis suggests that HDAC-microRNA-leptin signaling crosstalk may be a new target for PC therapy.
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Havas AP, Rodrigues KB, Bhakta A, Demirjian JA, Hahn S, Tran J, Scavello M, Tula-Sanchez AA, Zeng Y, Schmelz M, Smith CL. Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma. Cancer Biol Ther 2016; 17:1240-1252. [PMID: 27791595 DOI: 10.1080/15384047.2016.1250046] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.
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Affiliation(s)
- Aaron P Havas
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.,b Cancer Biology Program , University of Arizona , Tucson , AZ , USA
| | - Kameron B Rodrigues
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA
| | - Anvi Bhakta
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA
| | - Joseph A Demirjian
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA
| | - Seongmin Hahn
- c Department of Pediatrics, Steele Children's Research Center, College of Medicine , University of Arizona , Tucson , AZ , USA
| | - Jack Tran
- d Department of Pathology, College of Medicine , University of Arizona , Tucson , AZ , USA
| | - Margarethakay Scavello
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.,e Biological Chemistry Program , College of Medicine, University of Arizona , Tucson , AZ , USA
| | - Ana A Tula-Sanchez
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA
| | - Yi Zeng
- c Department of Pediatrics, Steele Children's Research Center, College of Medicine , University of Arizona , Tucson , AZ , USA
| | - Monika Schmelz
- e Biological Chemistry Program , College of Medicine, University of Arizona , Tucson , AZ , USA
| | - Catharine L Smith
- a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.,b Cancer Biology Program , University of Arizona , Tucson , AZ , USA.,e Biological Chemistry Program , College of Medicine, University of Arizona , Tucson , AZ , USA
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Peer CJ, Goey AKL, Sissung TM, Erlich S, Lee MJ, Tomita Y, Trepel JB, Piekarz R, Balasubramaniam S, Bates SE, Figg WD. UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation. J Clin Pharmacol 2015; 56:450-60. [PMID: 26637161 DOI: 10.1002/jcph.627] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 08/24/2015] [Indexed: 01/30/2023]
Abstract
Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports.
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Affiliation(s)
- Cody J Peer
- Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Andrew K L Goey
- Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Tristan M Sissung
- Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Sheryl Erlich
- Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Min-Jung Lee
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Yusuke Tomita
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Jane B Trepel
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Richard Piekarz
- Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, MD, USA
| | | | - Susan E Bates
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - William D Figg
- Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.,Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA
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Abstract
SIGNIFICANCE Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. RECENT ADVANCES Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. CRITICAL ISSUES (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. FUTURE DIRECTIONS Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment.
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Affiliation(s)
- Rosaria Benedetti
- 1 Department of Biochemistry, Biophysics, and General Pathology, Seconda Università degli Studi di Napoli , Napoli, Italy
| | - Mariarosaria Conte
- 1 Department of Biochemistry, Biophysics, and General Pathology, Seconda Università degli Studi di Napoli , Napoli, Italy
| | - Lucia Altucci
- 1 Department of Biochemistry, Biophysics, and General Pathology, Seconda Università degli Studi di Napoli , Napoli, Italy .,2 Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso," Napoli, Italy
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Iyer SP, Foss FF. Romidepsin for the Treatment of Peripheral T-Cell Lymphoma. Oncologist 2015; 20:1084-91. [PMID: 26099743 DOI: 10.1634/theoncologist.2015-0043] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/13/2015] [Indexed: 11/17/2022] Open
Abstract
UNLABELLED Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis in most subtypes. Diagnosis of this rare disease by expert hematopathologists improves accuracy of subtyping, and referral to academic or specialty centers is recommended. Many patients, however, will receive treatment in the community, and knowledge of approved agents is key to optimizing therapeutic approaches for all patients. There is no current standard of care for patients with PTCL and no approved therapies for first-line treatment. Although many patients initially respond to induction chemotherapy, responses are often brief, and many patients relapse or become treatment refractory. For patients with relapsed or refractory PTCL, achievement of durable responses is challenging, and there are few treatment options. Romidepsin is a histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received one prior systemic therapy or more and patients with PTCL who have received one prior therapy or more. Approval of romidepsin for PTCL was based on a pivotal phase II study of patients with relapsed or refractory PTCL (n = 131) that demonstrated an objective response rate of 25% including 15% with complete response; responses lasted a median of >2 years. Long-term responses to romidepsin were achieved in patients regardless of baseline characteristics, including subtype, heavy pretreatment, response to prior therapy, or advanced disease. Common adverse events included hematologic abnormalities, gastrointestinal or asthenic conditions, and infections; romidepsin was not correlated with clinically meaningful QT prolongation or electrocardiogram abnormalities. IMPLICATIONS FOR PRACTICE Due to the rarity, severity, and heterogeneous nature of peripheral T-cell lymphoma (PTCL), diagnosis by expert hematopathologists is preferred, and referral to specialty centers is recommended. Many patients, however, will receive treatment in the community, and community oncologists play a key role in the recognition and treatment of PTCL. Knowledge of approved agents is key for optimizing therapeutic approaches. This review provides an overview of PTCL and an in-depth examination of romidepsin, a histone deacetylase inhibitor approved for the treatment of relapsed or refractory PTCL, and highlights difficulties of diagnosis and optimization of treatment modalities for patients with PTCL.
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Affiliation(s)
- Swaminathan P Iyer
- Houston Methodist Cancer Center, Houston, Texas, USA; Yale Cancer Center, New Haven, Connecticut, USA
| | - Francine F Foss
- Houston Methodist Cancer Center, Houston, Texas, USA; Yale Cancer Center, New Haven, Connecticut, USA
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Reimer P. New developments in the treatment of peripheral T-cell lymphoma - role of Belinostat. Cancer Manag Res 2015; 7:145-51. [PMID: 26082661 PMCID: PMC4461120 DOI: 10.2147/cmar.s85351] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of rare malignancies that with the exception of anaplastic lymphoma kinase expressing anaplastic large cell lymphoma, share a poor outcome after standard (eg, anthracycline-based) chemotherapy. Most patients are either refractory to initial therapy or eventually relapse. Randomized studies for relapsed/refractory PTCL are not available, however, recently published data show that conventional chemotherapy has very limited efficacy in the salvage setting. Thus, novel drugs are urgently needed to improve the outcome in this setting. Belinostat, a pan-histone deacetylase inhibitor, has demonstrated meaningful efficacy and a favorable toxicity profile in two single-arm Phase II trials on 153 patients with relapsed/refractory PTCL. The conclusive results led to an accelerated approval by the US Food and Drug Administration. The present review summarizes the clinical data available for belinostat, its current role, and future perspectives.
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Affiliation(s)
- Peter Reimer
- Clinic for Hematology, Medical Oncology and Stem Cell Transplantation, Evangelisches Krankenhaus Essen-Werden gGmbH, Essen, Germany
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Sager PT, Balser B, Wolfson J, Nichols J, Pilot R, Jones S, Burris HA. Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin. Cancer Med 2015; 4:1178-85. [PMID: 25914207 PMCID: PMC4559029 DOI: 10.1002/cam4.467] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/17/2015] [Accepted: 03/24/2015] [Indexed: 01/04/2023] Open
Abstract
Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T-cell lymphoma who have received prior systemic therapy. The objective of this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4-h infusions of 14 mg/m2 romidepsin on days 1, 8, and 15 of a 28-day cycle. In cycle 2, a subset of patients received 1-h infusions of 8–12 mg/m2 romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram-evaluable population, 26 patients received romidepsin at 14 mg/m2 over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT-prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate.
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Affiliation(s)
- Philip T Sager
- Stanford University School of Medicine, San Francisco, California
| | | | | | | | | | - Suzanne Jones
- Sarah Cannon Research Institute, Nashville, Tennessee
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Abstract
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net.
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Affiliation(s)
- Whitney L Piper
- Dr. Piper is a Pharmacy Practice (PGY1) Resident at Blount Memorial Hospital , Maryville, Tennessee
| | - J Aubrey Waddell
- Dr. Piper is a Pharmacy Practice (PGY1) Resident at Blount Memorial Hospital , Maryville, Tennessee
| | - Dominic A Solimando
- Dr. Piper is a Pharmacy Practice (PGY1) Resident at Blount Memorial Hospital , Maryville, Tennessee
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Histone deacetylase inhibitors in hematological malignancies and solid tumors. Arch Pharm Res 2015; 38:933-49. [PMID: 25653088 DOI: 10.1007/s12272-015-0571-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/28/2015] [Indexed: 01/23/2023]
Abstract
Histone deacetylase (HDAC) inhibitors are emerging as promising anticancer drugs. Because aberrant activity and expression of HDACs have been implicated in various cancer types, a wide range of HDAC inhibitors are being investigated as anticancer agents. Furthermore, due to the demonstrable anticancer activity in both in vitro and in vivo studies, numerous HDAC inhibitors have undergone a rapid phase of clinical development in various cancer types, either as a monotherapy or in combination with other anticancer agents. Although preclinical trials show that HDAC inhibitors have a variety of biological effects across multiple pathways, including regulation of gene expression, inducing apoptosis and cell cycle arrest, inhibiting angiogenesis, and regulation of DNA damage and repair, the mechanism by which the clinical activity is mediated remains unclear. Understanding the mechanisms of anticancer activity of HDAC inhibitors is essential not only for rational drug design for targeted therapies, but for the design of optimized clinical protocols. This paper describes the links between HDACs and cancer, and the underlying mechanisms of action of HDAC inhibitors against hematological malignancies and solid tumors. Further, this review presents the clinical outcomes of vorinostat, romidepsin, and belinostat, which are approved by the United States Food and Drug Administration for the treatment of lymphomas.
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Hainsworth JD, Daugaard G, Lesimple T, Hübner G, Greco FA, Stahl MJ, Büschenfelde CMZ, Allouache D, Penel N, Knoblauch P, Fizazi KS. Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: A randomized, phase 2 trial. Cancer 2015; 121:1654-61. [DOI: 10.1002/cncr.29229] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 11/11/2014] [Accepted: 11/12/2014] [Indexed: 01/15/2023]
Affiliation(s)
- John D. Hainsworth
- Sarah Cannon Research Institute and Tennessee Oncology PLLC; Nashville Tennessee
| | - Gedske Daugaard
- Department of Oncology, Rigshospitalet; University of Copenhagen; Denmark
| | - Thierry Lesimple
- Department of Medical Oncology; Eugene Marquis Center; Rennes France
| | - Gerdt Hübner
- Ostholstein Oncology-ohO; Oldenburg in Holstein; Germany
| | - F. Anthony Greco
- Sarah Cannon Research Institute and Tennessee Oncology PLLC; Nashville Tennessee
| | - Michael J. Stahl
- Department of Medical Oncology and Hematology; Essen Mitte Clinic; Essen Germany
| | | | - Djelila Allouache
- Department of Medical Oncology; Francois Baclesse Regional Center for the Fight Against Cancer; Caen France
| | - Nicolas Penel
- Department of General Oncology; Oscar Lambret Center; Lille France
| | - Poul Knoblauch
- Topotarget A/S; Symbion Science Park; Copenhagen Denmark
| | - Karim S. Fizazi
- Gustave Roussy Institute; University of Paris South; Villejuif France
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Foss F, Advani R, Duvic M, Hymes KB, Intragumtornchai T, Lekhakula A, Shpilberg O, Lerner A, Belt RJ, Jacobsen ED, Laurent G, Ben-Yehuda D, Beylot-Barry M, Hillen U, Knoblauch P, Bhat G, Chawla S, Allen LF, Pohlman B. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol 2014; 168:811-9. [DOI: 10.1111/bjh.13222] [Citation(s) in RCA: 141] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 09/04/2014] [Indexed: 12/22/2022]
Affiliation(s)
| | | | | | | | | | | | - Ofer Shpilberg
- Haematology; Rabin Medical Centre; Beilinson Hospital; Davidoff Cancer Centre and Sackler School of Medicine; Tel Aviv University; Petach Tikva Israel
| | | | | | | | | | - Dina Ben-Yehuda
- Division of Haematology; Hadassah-Hebrew University Medical Centre; Jerusalem Israel
| | | | - Uwe Hillen
- Universitatsklinikum Essen; Essen Germany
| | | | | | | | | | - Brad Pohlman
- Hematologic Oncology and Blood Disorders; Cleveland Clinic Taussig Cancer Institute; Cleveland OH USA
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Thomas A, Rajan A, Szabo E, Tomita Y, Carter CA, Scepura B, Lopez-Chavez A, Lee MJ, Redon CE, Frosch A, Peer CJ, Chen Y, Piekarz R, Steinberg SM, Trepel JB, Figg WD, Schrump DS, Giaccone G. A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study. Clin Cancer Res 2014; 20:5392-402. [PMID: 25189481 PMCID: PMC4216756 DOI: 10.1158/1078-0432.ccr-14-0968] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. EXPERIMENTAL DESIGN Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. RESULTS Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m(2) belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m(2) with chemotherapy (P, 50 mg/m(2) on day 2; A, 25 mg/m(2) on days 2 and 3; C, 500 mg/m(2) on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%-50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8(+) T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3(+) CD8(+) T cells were larger in responders than nonresponders (P = 0.049). CONCLUSION This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3(+) CD8(+) T cells warrant further study.
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Affiliation(s)
- Anish Thomas
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Arun Rajan
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Eva Szabo
- Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland
| | - Yusuke Tomita
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Corey A Carter
- Department of Hematology and Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Barbara Scepura
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Ariel Lopez-Chavez
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Min-Jung Lee
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Christophe E Redon
- Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland
| | - Ari Frosch
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Cody J Peer
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Yuanbin Chen
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Richard Piekarz
- Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, Maryland
| | - Seth M Steinberg
- Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, Maryland
| | - Jane B Trepel
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - William D Figg
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - David S Schrump
- Thoracic Surgery Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Giuseppe Giaccone
- Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
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Abstract
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net ; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net .
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Affiliation(s)
- Whitney L. Piper
- Pharmacy Practice (PGY1) Resident at Blount Memorial Hospital, Maryville, Tennessee
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He WL, Li YH, Hou WJ, Ke ZF, Chen XL, Lu LY, Cai SR, Song W, Zhang CH, He YL. RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer. World J Gastroenterol 2014; 20:10094-10107. [PMID: 25110436 PMCID: PMC4123338 DOI: 10.3748/wjg.v20.i29.10094] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 01/20/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the efficacy of PCI-24781, a broad-spectrum, hydroxamic acid-derived histone deacetylase inhibitor, in the treatment of gastric cancer (GC).
METHODS: With or without treatment of PCI-24781 and/or cis-diamminedichloroplatinum (CDDP), GC cell lines were subjected to functional analysis, including cell growth, apoptosis and clonogenic assays. Chromatin immunoprecipitation and luciferase reporter assays were used to determine the interacting molecules and the activity of the enzyme. An in vivo study was carried out in GC xenograft mice. Cell culture-based assays were represented as mean ± SD. ANOVA tests were used to assess differences across groups. All pairwise comparisons between tumor weights among treatment groups were made using the Tukey-Kramer method for multiple comparison adjustment to control experimental-wise type I error rates. Significance was set at P < 0.05.
RESULTS: PCI-24781 significantly reduced the growth of the GC cells, enhanced cell apoptosis and suppressed clonogenicity, and these effects synergized with the effects of CDDP. PCI-24781 modulated the cell cycle and significantly reduced the expression of RAD51, which is related to homologous recombination. Depletion of RAD51 augmented the biological functions of PCI-24781, CDDP and the combination treatment, whereas overexpressing RAD51 had the opposite effects. Increased binding of the transcription suppressor E2F4 on the RAD51 promoter appeared to play a major role in these processes. Furthermore, significant suppression of tumor growth and weight in vivo was obtained following PCI-24781 treatment, which synergized with the anticancer effect of CDDP.
CONCLUSION: These data suggest that RAD51 potentiates the synergistic effects of chemotherapy with PCI-24781 and CDDP on GC.
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Vaiopoulos AG, Athanasoula KC, Papavassiliou AG. Epigenetic modifications in colorectal cancer: Molecular insights and therapeutic challenges. Biochim Biophys Acta Mol Basis Dis 2014; 1842:971-980. [PMID: 24561654 DOI: 10.1016/j.bbadis.2014.02.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/12/2014] [Accepted: 02/15/2014] [Indexed: 12/11/2022]
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van Kampen JGM, Marijnissen-van Zanten MAJ, Simmer F, van der Graaf WTA, Ligtenberg MJL, Nagtegaal ID. Epigenetic targeting in pancreatic cancer. Cancer Treat Rev 2014; 40:656-64. [PMID: 24433955 DOI: 10.1016/j.ctrv.2013.12.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/18/2013] [Accepted: 12/21/2013] [Indexed: 12/22/2022]
Abstract
The prognosis of pancreatic cancer patients is very poor, with a 5-year survival of less than 6%. Therefore, there is an urgent need for new therapeutic options in pancreatic cancer. In the past years it became evident that deregulation of epigenetic mechanisms plays an important role in pancreatic carcinogenesis. This review focuses on the exploitation of drugs that alter histone modifications, DNA methylation and microRNA expression as options for the treatment of pancreatic cancer.
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Affiliation(s)
- Jasmijn G M van Kampen
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Urology 267, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | | | - Femke Simmer
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Winette T A van der Graaf
- Department of Medical Oncology 452, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Marjolijn J L Ligtenberg
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Human Genetics 855, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Iris D Nagtegaal
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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Abstract
Microtubule inhibitors (MTIs) such as Taxol have been used for treating various malignant tumors. Although MTIs have been known to induce cell death through mitotic arrest, other mechanisms can operate in MTI-induced cell death. Especially, the role of p53 in this process has been controversial for a long time. Here we investigated the function of p53 in Taxol-induced apoptosis using p53 wild type and p53 null cancer cell lines. p53 was upregulated upon Taxol treatment in p53 wild type cells and deletion of p53 diminished Taxol-induced apoptosis. p53 target proteins including MDM2, p21, BAX, and β-isoform of PUMA were also upregulated by Taxol in p53 wild type cells. Conversely, when the wild type p53 was re-introduced into two different p53 null cancer cell lines, Taxol-induced apoptosis was enhanced. Among post-translational modifications that affect p53 stability and function, p53 acetylation, rather than phosphorylation, increased significantly in Taxol-treated cells. When acetylation was enhanced by anti-Sirt1 siRNA or an HDAC inhibitor, Taxol-induced apoptosis was enhanced, which was not observed in p53 null cells. When an acetylation-defective mutant of p53 was re-introduced to p53 null cells, apoptosis was partially reduced compared to the re-introduction of the wild type p53. Thus, p53 plays a pro-apoptotic role in Taxol-induced apoptosis and acetylation of p53 contributes to this pro-apoptotic function in response to Taxol in several human cancer cell lines, suggesting that enhancing acetylation of p53 could have potential implication for increasing the sensitivity of cancer cells to Taxol.
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Lin SF, Lin JD, Chou TC, Huang YY, Wong RJ. Utility of a histone deacetylase inhibitor (PXD101) for thyroid cancer treatment. PLoS One 2013; 8:e77684. [PMID: 24155971 PMCID: PMC3796495 DOI: 10.1371/journal.pone.0077684] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2013] [Accepted: 09/03/2013] [Indexed: 01/08/2023] Open
Abstract
Background We evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 alone and in combination with conventional chemotherapy in treating thyroid cancer. Methodology/Principal Findings We studied eight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic and medullary). The cytotoxicity of PXD101 alone and in combination with three conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay. Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair. Apoptosis and intracellular reactive oxygen species (ROS) were measured by flow cytometry. Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intraperitoneal injection of PXD101 for 5 days per week. PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner. PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells. Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines. PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety. Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against four ATC lines invitro. Conclusions PXD101 represses thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC. These findings support clinical trials using PXD101 for patients with this dismal disease.
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Affiliation(s)
- Shu-Fu Lin
- Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Jen-Der Lin
- Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Ting-Chao Chou
- Laboratory of Preclinical Pharmacology Core, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Yu-Yao Huang
- Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC
- * E-mail: (YH); (RJW)
| | - Richard J. Wong
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
- * E-mail: (YH); (RJW)
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Grassadonia A, Cioffi P, Simiele F, Iezzi L, Zilli M, Natoli C. Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies. Cancers (Basel) 2013; 5:919-42. [PMID: 24202327 PMCID: PMC3795372 DOI: 10.3390/cancers5030919] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/03/2013] [Accepted: 07/12/2013] [Indexed: 02/06/2023] Open
Abstract
Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms.
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Affiliation(s)
- Antonino Grassadonia
- Department of Experimental and Clinical Sciences, University ’G. d’Annunzio’, I-66013 Chieti, Italy; E-Mail:
| | - Pasquale Cioffi
- Hospital Pharmacy, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (P.C.); (F.S.)
| | - Felice Simiele
- Hospital Pharmacy, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (P.C.); (F.S.)
| | - Laura Iezzi
- Oncology Department, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (L.I.); (M.Z.)
| | - Marinella Zilli
- Oncology Department, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (L.I.); (M.Z.)
| | - Clara Natoli
- Department of Experimental and Clinical Sciences, University ’G. d’Annunzio’, I-66013 Chieti, Italy; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-0871-355-6708; Fax: +39-0871-355-6732
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