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Chan SPY, Yeo CPX, Hong BH, Tan EMC, Beh CY, Yeo ELL, Poon DJJ, Chu PL, Soo KC, Chua MLK, Chow EKH. Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer. Exp Hematol Oncol 2025; 14:5. [PMID: 39800760 PMCID: PMC11727331 DOI: 10.1186/s40164-024-00590-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 12/07/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurrences are limited and often suboptimal, partly owing to divergent tumor and microenvironmental factors underpinning radioresistance. In this study, we utilized a combinatorial functionomics approach, the Quadratic Phenotypic Optimization Platform (QPOP), to rationally design drug pairings that exploit the molecular fingerprint and vulnerability of established in vitro isogenic radioresistant (RR)-HNC models. METHODS A QPOP-specific protocol was applied to RR-HNC models to rank and compare all possible drug combinations from a 12-drug set comprising standard chemotherapy, small molecule inhibitors and targeted therapies specific to HNC. Drug combination efficacy was evaluated by computing combination index scores, and by measuring apoptotic response. Drug targeting was validated by western blot analyses, and the Comet assay was used to quantify DNA damage. Enhanced histone deacetylase inhibitor (HDACi) efficacy in RR models was further examined by in vivo studies, and genetic and chemical inhibition of major Class I/II HDACs. Regulatory roles of HDAC6/SP1 axis were investigated using immunoprecipitation, gel shift and ChIP-qPCR assays. Comparative transcriptomic analyses were employed to determine the prognostic significance of targeting HDAC6. RESULTS We report the therapeutic potential of combining panobinostat (pan-HDAC inhibitor) with AZD7762 (CHK1/2 inhibitor; AstraZeneca) or ionizing radiation (IR) to re-sensitize RR-HNC cells and showed increased DNA damage underlying enhanced synergy. We further refined this RR-specific drug combination and prioritized HDAC6 as a targetable dependency in reversing radioresistance. We provide mechanistic insights into HDAC6-mediated regulation via a crosstalk involving SP1 and oncogenic and repair genes. From two independent patient cohorts, we identified a four-gene signature that may have discriminative ability to predict for radioresistance and amenable to HDAC6 inhibition. CONCLUSION We have uncovered HDAC6 as a promising molecular vulnerability that should be explored to treat RR-HNC.
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Affiliation(s)
- Sharon Pei Yi Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Celestia Pei Xuan Yeo
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Boon Hao Hong
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Evelyn Mui Cheng Tan
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Chaw Yee Beh
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Eugenia Li Ling Yeo
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Dennis Jun Jie Poon
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Pek Lim Chu
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, Cancer and Stem Cell Biology Programme, Singapore, Singapore
| | - Khee Chee Soo
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Melvin Lee Kiang Chua
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
- Duke-NUS Medical School, Oncology Academic Programme, Singapore, Singapore.
- Department of Head and Neck and Thoracic Cancers, Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore.
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Xu M, Hou Y, Li N, Yu W, Chen L. Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets. J Transl Med 2024; 22:418. [PMID: 38702756 PMCID: PMC11067317 DOI: 10.1186/s12967-024-05169-9] [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: 12/27/2023] [Accepted: 04/05/2024] [Indexed: 05/06/2024] Open
Abstract
The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.
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Affiliation(s)
- Mengchen Xu
- Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Shandong Provincial Clinical Research Center for Oral Diseases, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yiming Hou
- Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Shandong Provincial Clinical Research Center for Oral Diseases, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Na Li
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250022, Shandong, China
- Center of Clinical Laboratory, Shandong Second Provincial General Hospital, Jinan, 250022, Shandong, China
| | - Wenqian Yu
- Research Center of Translational Medicine, Department of Cardiac Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, People's Republic of China
| | - Lei Chen
- Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Shandong Provincial Clinical Research Center for Oral Diseases, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
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3
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Korovina I, Elser M, Borodins O, Seifert M, Willers H, Cordes N. β1 integrin mediates unresponsiveness to PI3Kα inhibition for radiochemosensitization of 3D HNSCC models. Biomed Pharmacother 2024; 171:116217. [PMID: 38286037 PMCID: PMC11627550 DOI: 10.1016/j.biopha.2024.116217] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/10/2024] [Accepted: 01/22/2024] [Indexed: 01/31/2024] Open
Abstract
Phosphoinositide 3-kinase (PI3K)-α represents a key intracellular signal transducer involved in the regulation of key cell functions such as cell survival and proliferation. Excessive activation of PI3Kα is considered one of the major determinants of cancer therapy resistance. Despite preclinical and clinical evaluation of PI3Kα inhibitors in various tumor entities, including head and neck squamous cell carcinoma (HNSCC), it remains elusive how conventional radiochemotherapy can be enhanced by concurrent PI3K inhibitors and how PI3K deactivation mechanistically exerts its effects. Here, we investigated the radiochemosensitizing potential and adaptation mechanisms of four PI3K inhibitors, Alpelisib, Copanlisib, AZD8186, and Idelalisib in eight HNSCC models grown under physiological, three-dimensional matrix conditions. We demonstrate that Alpelisib, Copanlisib and AZD8186 but not Idelalisib enhance radio- and radiochemosensitivity in the majority of HNSCC cell models (= responders) in a manner independent of PIK3CA mutation status. However, Alpelisib promotes MAPK signaling in non-responders compared to responders without profound impact on Akt, NFκB, TGFβ, JAK/STAT signaling and DNA repair. Bioinformatic analyses identified unique gene mutations associated with extracellular matrix to be more frequent in non-responder cell models than in responders. Finally, we demonstrate that targeting of the cell adhesion molecule β1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel β1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.
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Affiliation(s)
- Irina Korovina
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Marc Elser
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Olegs Borodins
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Michael Seifert
- Institute for Medical Informatics and Biometry (IMB), Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Henning Willers
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Nils Cordes
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
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Ling R, Wang J, Fang Y, Yu Y, Su Y, Sun W, Li X, Tang X. HDAC-an important target for improving tumor radiotherapy resistance. Front Oncol 2023; 13:1193637. [PMID: 37503317 PMCID: PMC10368992 DOI: 10.3389/fonc.2023.1193637] [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: 03/25/2023] [Accepted: 06/28/2023] [Indexed: 07/29/2023] Open
Abstract
Radiotherapy is an important means of tumor treatment, but radiotherapy resistance has been a difficult problem in the comprehensive treatment of clinical tumors. The mechanisms of radiotherapy resistance include the repair of sublethal damage and potentially lethal damage of tumor cells, cell repopulation, cell cycle redistribution, and reoxygenation. These processes are closely related to the regulation of epigenetic modifications. Histone deacetylases (HDACs), as important regulators of the epigenetic structure of cancer, are widely involved in the formation of tumor radiotherapy resistance by participating in DNA damage repair, cell cycle regulation, cell apoptosis, and other mechanisms. Although the important role of HDACs and their related inhibitors in tumor therapy has been reviewed, the relationship between HDACs and radiotherapy has not been systematically studied. This article systematically expounds for the first time the specific mechanism by which HDACs promote tumor radiotherapy resistance in vivo and in vitro and the clinical application prospects of HDAC inhibitors, aiming to provide a reference for HDAC-related drug development and guide the future research direction of HDAC inhibitors that improve tumor radiotherapy resistance.
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Affiliation(s)
- Rui Ling
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jingzhi Wang
- Department of Radiotherapy Oncology, Affiliated Yancheng First Hospital of Nanjing University Medical School, First People’s Hospital of Yancheng, Yancheng, China
| | - Yuan Fang
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yunpeng Yu
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yuting Su
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Wen Sun
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiaoqin Li
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiang Tang
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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5
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Moran B, Davern M, Reynolds JV, Donlon NE, Lysaght J. The impact of histone deacetylase inhibitors on immune cells and implications for cancer therapy. Cancer Lett 2023; 559:216121. [PMID: 36893893 DOI: 10.1016/j.canlet.2023.216121] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/27/2023] [Accepted: 03/07/2023] [Indexed: 03/09/2023]
Abstract
Many cancers possess the ability to suppress the immune response to malignant cells, thus facilitating tumour growth and invasion, and this has fuelled research to reverse these mechanisms and re-activate the immune system with consequent important therapeutic benefit. One such approach is to use histone deacetylase inhibitors (HDACi), a novel class of targeted therapies, which manipulate the immune response to cancer through epigenetic modification. Four HDACi have recently been approved for clinical use in malignancies including multiple myeloma and T-cell lymphoma. Most research in this context has focussed on HDACi and tumour cells, however, little is known about their impact on the cells of the immune system. Additionally, HDACi have been shown to impact the mechanisms by which other anti-cancer therapies exert their effects by, for example, increasing accessibility to exposed DNA through chromatin relaxation, impairing DNA damage repair pathways and increasing immune checkpoint receptor expression. This review details the effects of HDACi on immune cells, highlights the variability in these effects depending on experimental design, and provides an overview of clinical trials investigating the combination of HDACi with chemotherapy, radiotherapy, immunotherapy and multimodal regimens.
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Affiliation(s)
- Brendan Moran
- Cancer Immunology and Immunotherapy Group, Trinity St. James's Cancer Institute, Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland; Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Maria Davern
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | | | - Noel E Donlon
- Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Trinity St. James's Cancer Institute, Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland.
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6
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Huang J, Zhang J, Xu W, Wu Q, Zeng R, Liu Z, Tao W, Chen Q, Wang Y, Zhu WG. Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity. J Med Chem 2023; 66:1186-1209. [PMID: 36516047 DOI: 10.1021/acs.jmedchem.2c00739] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inducing protein degradation by proteolysis targeting chimeras has gained tremendous momentum as a promising novel therapeutic strategy. Here, we report the design, synthesis, and biological characterization of highly potent proteolysis targeting chimeric small molecules targeting the epigenetic regulator histone deacetylase 8 (HDAC8). We developed potent and effective HDAC8 degraders, as exemplified by SZUH280 (16e), which effectively induced HDAC8 protein degradation and inhibited cancer cell growth even at low micromolar concentrations. Our preliminary mechanistic studies revealed that SZUH280 hampers DNA damage repair in cancer cells, promoting cellular radiosensitization. In mice, a single SZUH280 dose induced rapid and prolonged HDAC8 protein degradation in xenograft tumor tissues. Moreover, SZUH280 alone or in combination with irradiation resulted in long-lasting tumor regression in an A549 tumor mouse model. Our findings qualify a new chemical tool for HDAC8 knockdown and may lead to the development of a new class of cancer therapeutics.
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Affiliation(s)
- Jinbo Huang
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
| | - Jun Zhang
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
| | - Wenchao Xu
- Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen 518055, China
| | - Qiong Wu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
| | - Rongsheng Zeng
- Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen 518055, China
| | - Zhichao Liu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
| | - Wenhui Tao
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
| | - Qian Chen
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
| | - Yongqing Wang
- Division of Rheumatology and Immunology, University of Toledo Medical Center, 3120 Glendale Avenue, Toledo 43614, Ohio, United States
| | - Wei-Guo Zhu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.,Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.,Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen 518055, China.,Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen 518055, China.,Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
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7
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Xiang XS, Li PC, Wang WQ, Liu L. Histone deacetylases: A novel class of therapeutic targets for pancreatic cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188676. [PMID: 35016922 DOI: 10.1016/j.bbcan.2022.188676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is the seventh leading cause of cancer death worldwide, with a low 5-year survival rate. Novel agents are urgently necessary to treat the main pathological type, known as pancreatic ductal carcinoma (PDAC). The dysregulation of histone deacetylases (HDACs) has been identified in association with PDAC, which can be more easily targeted by small molecular inhibitors than gene mutations and may represent a therapeutic breakthrough for PDAC. However, the contributions of HDACs to PDAC remain controversial, and pharmacokinetic challenges have limited the application of HDAC inhibitors (HDACis) in PDAC. This review summarizes the mechanisms associated with success and failure of HDACis in PDAC and discusses the recent progress made in HDACi development and application, such as combination therapies designed to enhance efficacy. More precise strategies involving HDACis might eventually improve the outcomes of PDAC treatment.
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Affiliation(s)
- Xue-Song Xiang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peng-Cheng Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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8
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Zhang H, Han W. Protein Post-translational Modifications in Head and Neck Cancer. Front Oncol 2020; 10:571944. [PMID: 33117703 PMCID: PMC7561398 DOI: 10.3389/fonc.2020.571944] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 09/11/2020] [Indexed: 12/20/2022] Open
Abstract
Head and neck cancer (HNC) is one of the most common malignant tumors worldwide, and is prone to tumor recurrence and metastasis. At present, surgery combined with radiotherapy and chemotherapy is still the conventional treatment modality for patients with HNC. However, for patients with relapse or metastasis of HNC, the treatment outcome is not ideal, and the prognosis is poor. Thus, it is crucial to deepen the understand of tumor mechanisms. Post-translational modifications (PTMs) refer to covalent binding of small chemical molecular groups to amino-acid side-chain of proteins. Post-translational modification is an important regulator of protein function, and as such, a current research hotspot of epigenetics. In recent years, it has been found that tumor occurrence is often accompanied by the abnormality of PTMs. Indeed, the abnormality play an important role in tumor development, and can be used as a target for tumor diagnosis and treatment. To date, several types of protein PTMs involved in the development of HNC have been reported. This paper reviews the relationship between HNC and several major protein PTMs, including acetylation, methylation, and glycosylation, in order to provide clues for the future application about PTMs in diagnosis and treatment of HNC.
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Affiliation(s)
- Hongbo Zhang
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wei Han
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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9
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Li M, Liu D, Lee D, Kapoor S, Gibson-Corley KN, Quinn TP, Sagastume EA, Mott SL, Walsh SA, Acevedo MR, Johnson FL, Schultz MK. Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma. Mol Pharm 2019; 16:3904-3915. [PMID: 31318566 DOI: 10.1021/acs.molpharmaceut.9b00512] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAFi) and histone deacetylase inhibitors (HDACi) to enhance the delivery of MC1R-targeted radiolabeled peptide ([212Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAFV600E cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [212Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAFi and/or HDACi was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAFi and HDACi significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAFV600E and BRAFWT cells. Combining [212Pb]DOTA-MC1L with BRAFi and/or HDACi improved the tumor response by increasing the delivery of 212Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDACi and BRAFi could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.
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Affiliation(s)
| | | | | | | | | | - Thomas P Quinn
- Department of Biochemistry , University of Missouri , Columbia , Missouri 65211 , United States
| | - Edwin A Sagastume
- Viewpoint Molecular Targeting, Inc. , Coralville , Iowa 52241 , United States
| | | | | | | | - Frances L Johnson
- Viewpoint Molecular Targeting, Inc. , Coralville , Iowa 52241 , United States
| | - Michael K Schultz
- Viewpoint Molecular Targeting, Inc. , Coralville , Iowa 52241 , United States
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Arsenic Trioxide and (-)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling. Cancers (Basel) 2019; 11:cancers11030350. [PMID: 30871073 PMCID: PMC6468469 DOI: 10.3390/cancers11030350] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/28/2019] [Accepted: 03/07/2019] [Indexed: 01/08/2023] Open
Abstract
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells.
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11
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Piao J, Chen L, Quan T, Li L, Quan C, Piao Y, Jin T, Lin Z. Superior efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A against NSCLC. Oncotarget 2018; 7:60169-60180. [PMID: 27507059 PMCID: PMC5312376 DOI: 10.18632/oncotarget.11109] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 07/19/2016] [Indexed: 12/12/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. NSCLC development and progression have recently been correlated with the heightened activation of histone deacetylases (HDACs) and PI3K/Akt signaling pathways. Targeted inhibition of these proteins is promising approach for the development of novel therapeutic strategies to treat patients with advanced NSCLC. For this reason, we combined a dual PI3K and mTOR inhibitor, BEZ235 with the HDAC inhibitor Trichostatin A (TSA), to determine their combined effects on human NSCLC. In this study, we initially discovered that co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of NSCLC cell proliferation and induction of apoptosis. The combination treatment also synergistically suppressed NSCLC migration, invasion and the NSCLC epithelial-mesenchymal transition (EMT) in vitro. The synergistic effect was also evidenced by declines in xenograft growth and metastasis rates and in ki-67 protein expression in vivo. Together, these results indicated that BEZ235 and TSA combination treatment significantly increased anti-tumor activities compared with BEZ235 and TSA alone, supporting a further evaluation of combination treatment for NSCLC.
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Affiliation(s)
- Junjie Piao
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji 133002, China.,Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules (Yanbian University), Ministry of Education, Yanji 133002, China
| | - Liyan Chen
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules (Yanbian University), Ministry of Education, Yanji 133002, China
| | - Taihao Quan
- Department of Dermatology, University of Michigan Medical School, Michigan 48109-5609, USA
| | - Longshan Li
- Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8807, USA
| | - Chunji Quan
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji 133002, China
| | - Yingshi Piao
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji 133002, China
| | - Tiefeng Jin
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji 133002, China.,Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules (Yanbian University), Ministry of Education, Yanji 133002, China
| | - Zhenhua Lin
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji 133002, China
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12
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Abou-Antoun TJ, Nazarian J, Ghanem A, Vukmanovic S, Sandler AD. Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant properties: A possible explanation for radio-therapy resistance. PLoS One 2018; 13:e0189711. [PMID: 29298329 PMCID: PMC5751995 DOI: 10.1371/journal.pone.0189711] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 11/30/2017] [Indexed: 12/19/2022] Open
Abstract
Despite significant advances in cancer treatment and management, more than 60% of patients with neuroblastoma present with very poor prognosis in the form of metastatic and aggressive disease. Solid tumors including neuroblastoma are thought to be heterogeneous with a sub-population of stem-like cells that are treatment-evasive with highly malignant characteristics. We previously identified a phenomenon of reversible adaptive plasticity (RAP) between anchorage dependent (AD) cells and anchorage independent (AI) tumorspheres in neuroblastoma cell cultures. To expand our molecular characterization of the AI tumorspheres, we sought to define the comprehensive proteomic profile of murine AD and AI neuroblastoma cells. The proteomic profiles of the two phenotypic cell populations were compared to each other to determine the differential protein expression and molecular pathways of interest. We report exclusive or significant up-regulation of tumorigenic pathways expressed by the AI tumorspheres compared to the AD cancer cells. These pathways govern metastatic potential, enhanced malignancy and epithelial to mesenchymal transition. Furthermore, radio-therapy induced significant up-regulation of specific tumorigenic and proliferative proteins, namely survivin, CDC2 and the enzyme Poly [ADP-ribose] polymerase 1. Bio-functional characteristics of the AI tumorspheres were resistant to sutent inhibition of receptor tyrosine kinases (RTKs) as well as to 2.5 Gy radio-therapy as assessed by cell survival, proliferation, apoptosis and migration. Interestingly, PDGF-BB stimulation of the PDGFRβ led to transactivation of EGFR and VEGFR in AI tumorspheres more potently than in AD cells. Sutent inhibition of PDGFRβ abrogated this transactivation in both cell types. In addition, 48 h sutent treatment significantly down-regulated the protein expression of PDGFRβ, MYCN, SOX2 and Survivin in the AI tumorspheres and inhibited tumorsphere self-renewal. Radio-sensitivity in AI tumorspheres was enhanced when sutent treatment was combined with survivin knock-down. We conclude that AI tumorspheres have a differential protein expression compared to AD cancer cells that contribute to their malignant phenotype and radio-resistance. Specific targeting of both cellular phenotypes is needed to improve outcomes in neuroblastoma patients.
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Affiliation(s)
- Tamara J. Abou-Antoun
- Department of Pharmaceutical Sciences, the School of Pharmacy, Lebanese American University, Byblos, Lebanon
- The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, Washington, D.C., United States of America
- * E-mail:
| | - Javad Nazarian
- Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, D.C., United States of America
- Center for Genetic Medicine Research, Children’s National Medical Center, Washington, D.C., United States of America
| | - Anthony Ghanem
- The School of Medicine, Lebanese American University, Byblos, Lebanon
| | - Stanislav Vukmanovic
- The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, Washington, D.C., United States of America
| | - Anthony D. Sandler
- The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, Washington, D.C., United States of America
- The Joseph E. Robert Center for Surgical Care, Children's National Health System, Washington, D.C., United States of America
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13
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Terranova-Barberio M, Pecori B, Roca MS, Imbimbo S, Bruzzese F, Leone A, Muto P, Delrio P, Avallone A, Budillon A, Di Gennaro E. Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:177. [PMID: 29212503 PMCID: PMC5719792 DOI: 10.1186/s13046-017-0647-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023]
Abstract
Background Recurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy. The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells. Methods HCT-116 (p53-wild type), HCT-116 p53−/− (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5′-deoxy-5-fluorouridine (5′-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage. Results Combined treatment with equipotent doses of VPA and 5′-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53−/− cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5′-DFUR/VPA combination in p53 expressing cells. Conclusions These results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3). Electronic supplementary material The online version of this article (10.1186/s13046-017-0647-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Manuela Terranova-Barberio
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Via Mariano Semmola, 13, 80131, Naples, NA, Italy.,Division of Hematology and Oncology, University of California, San Francisco, CA, 94143, USA
| | - Biagio Pecori
- Radiotherapy Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Maria Serena Roca
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Via Mariano Semmola, 13, 80131, Naples, NA, Italy
| | - Serena Imbimbo
- Radiotherapy Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Francesca Bruzzese
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Via Mariano Semmola, 13, 80131, Naples, NA, Italy
| | - Alessandra Leone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Via Mariano Semmola, 13, 80131, Naples, NA, Italy
| | - Paolo Muto
- Radiotherapy Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Paolo Delrio
- Colorectal Cancer Surgery Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Antonio Avallone
- Abdominal Oncology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Via Mariano Semmola, 13, 80131, Naples, NA, Italy.
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Via Mariano Semmola, 13, 80131, Naples, NA, Italy
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14
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Rivera S, Leteur C, Mégnin F, Law F, Martins I, Kloos I, Depil S, Modjtahedi N, Perfettini JL, Hennequin C, Deutsch E. Time dependent modulation of tumor radiosensitivity by a pan HDAC inhibitor: abexinostat. Oncotarget 2017; 8:56210-56227. [PMID: 28915585 PMCID: PMC5593556 DOI: 10.18632/oncotarget.14813] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 11/30/2016] [Indexed: 02/06/2023] Open
Abstract
Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi). Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in vitro in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin. Altogether, our data demonstrate in vitro and in vivo anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC.
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Affiliation(s)
- Sofia Rivera
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France.,Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Céline Leteur
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France
| | - Frédérique Mégnin
- INSERM U1196/UMR9187 CMIB, Institut Curie-Recherche, Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Frédéric Law
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France
| | - Isabelle Martins
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France
| | - Ioana Kloos
- IRIS: Institut de Recherches Internationales Servier, Suresnes, France
| | - Stéphane Depil
- IRIS: Institut de Recherches Internationales Servier, Suresnes, France
| | - Nazanine Modjtahedi
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France
| | - Jean Luc Perfettini
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France
| | | | - Eric Deutsch
- Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France.,INSERM 1030 Molecular Radiotherapy, Villejuif, France.,Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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15
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Antonietti P, Linder B, Hehlgans S, Mildenberger IC, Burger MC, Fulda S, Steinbach JP, Gessler F, Rödel F, Mittelbronn M, Kögel D. Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis. Mol Cancer Ther 2016; 16:156-168. [PMID: 27777286 DOI: 10.1158/1535-7163.mct-16-0262] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 09/14/2016] [Accepted: 09/28/2016] [Indexed: 11/16/2022]
Abstract
Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here, we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101-induced cell death and reactivates effector caspase-mediated apoptosis in U251 glioma cells with high BAG3 expression, whereas these sensitizing effects were less pronounced in U343 cells expressing lower BAG3 levels. KRIBB11 decreased protein levels of HSP70, BAG3, and the antiapoptotic Bcl-2 protein Mcl-1, and both KRIBB11 and YM-1 elicited significantly increased mitochondrial dysfunction, effector caspase activity, and apoptotic cell death after combined treatment with AT-101 and ABT-737. Depletion of BAG3 also led to a pronounced loss of cell-matrix adhesion, FAK phosphorylation, and in vivo tumor growth in an orthotopic mouse glioma model. Furthermore, it reduced the plating efficiency of U251 cells in three-dimensional clonogenic assays and limited clonogenic survival after short-term treatment with AT-101. Collectively, our data suggest that the HSF1/HSP70/BAG3 pathway plays a pivotal role for overexpression of prosurvival Bcl-2 proteins and cell death resistance of glioma. They also support the hypothesis that interference with BAG3 function is an effective novel approach to prime glioma cells to anoikis. Mol Cancer Ther; 16(1); 156-68. ©2016 AACR.
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Affiliation(s)
- Patrick Antonietti
- Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany
| | - Benedikt Linder
- Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany
| | - Stephanie Hehlgans
- Radiotherapy and Oncology, Goethe University Hospital, Frankfurt am Main, Germany
| | | | | | - Simone Fulda
- Institute for Experimental Cancer Research in Pediatrics, Goethe University Hospital, Frankfurt am Main, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Joachim P Steinbach
- Dr. Senckenberg Institute of Neurooncology.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Florian Gessler
- Department of Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany
| | - Franz Rödel
- Radiotherapy and Oncology, Goethe University Hospital, Frankfurt am Main, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Michel Mittelbronn
- German Cancer Consortium (DKTK), Heidelberg, Germany.,Edinger Institute, Goethe University Hospital, Frankfurt am Main, Germany
| | - Donat Kögel
- Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany. .,German Cancer Consortium (DKTK), Heidelberg, Germany
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17
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Khan SA, Reddy D, Gupta S. Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment? World J Biol Chem 2015; 6:333-345. [PMID: 26629316 PMCID: PMC4657128 DOI: 10.4331/wjbc.v6.i4.333] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/10/2015] [Accepted: 10/08/2015] [Indexed: 02/05/2023] Open
Abstract
Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanisms such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular, covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further, histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review, we will explore and discuss how histone modifications are involved in cancer diagnosis, prognosis and treatment.
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18
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Artacho-Cordón F, Ríos-Arrabal S, Olivares-Urbano MA, Storch K, Dickreuter E, Muñoz-Gámez JA, León J, Calvente I, Torné P, Salinas MDM, Cordes N, Núñez MI. Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells. Int J Radiat Biol 2015; 91:946-56. [PMID: 26490761 DOI: 10.3109/09553002.2015.1087067] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition. MATERIAL AND METHODS Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)]. RESULTS IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA. CONCLUSION These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.
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Affiliation(s)
- Francisco Artacho-Cordón
- a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.,b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain
| | - Sandra Ríos-Arrabal
- a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.,b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.,c Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada , Armilla, Granada , Spain
| | | | - Katja Storch
- d OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.,e Department of Radiation Oncology , University Hospital Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.,f German Cancer Consortium (DKTK), Dresden, Germany.,g German Cancer Research Center (DKFZ) , Heidelberg , Germany.,h Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany
| | - Ellen Dickreuter
- d OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.,e Department of Radiation Oncology , University Hospital Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.,f German Cancer Consortium (DKTK), Dresden, Germany.,g German Cancer Research Center (DKFZ) , Heidelberg , Germany.,h Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany
| | - José Antonio Muñoz-Gámez
- b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.,i CIBER on hepatic and digestive diseases (CIBEREHD) , Spain
| | - Josefa León
- b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.,i CIBER on hepatic and digestive diseases (CIBEREHD) , Spain
| | - Irene Calvente
- a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.,b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain
| | - Pablo Torné
- j General Surgery Management Unit, San Cecilio University Hospital , Granada , Spain
| | - María del Mar Salinas
- a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain
| | - Nils Cordes
- d OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.,e Department of Radiation Oncology , University Hospital Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.,f German Cancer Consortium (DKTK), Dresden, Germany.,g German Cancer Research Center (DKFZ) , Heidelberg , Germany.,h Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany
| | - María Isabel Núñez
- a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.,b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.,c Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada , Armilla, Granada , Spain
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Juo YY, Gong XJ, Mishra A, Cui X, Baylin SB, Azad NS, Ahuja N. Epigenetic therapy for solid tumors: from bench science to clinical trials. Epigenomics 2015; 7:215-35. [PMID: 25942532 DOI: 10.2217/epi.14.73] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The cancer epigenome is characterized by global DNA methylation and chromatin changes, such as the hypermethylation of specific CpG island promoters. Epigenetic agents like DNA methyltransferase or histone deacetylase inhibitors induce phenotype changes by reactivation of epigenetically silenced tumor suppressor genes. Despite initial promise in hematologic malignancies, epigenetic agents have not shown significant efficacy as monotherapy against solid tumors. Recent trials showed that epigenetic agents exert favorable modifier effects when combined with chemotherapy, hormonal therapy, or other epigenetic agents. Due to the novel nature of their mechanism, it is important to reconsider the optimal patient selection, drug regimen, study design, and outcome measures when pursuing future trials in order to discover the full potential of this new therapeutic modality.
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Affiliation(s)
- Yen-Yi Juo
- Department of Surgery, George Washington University Medical Center, 2150 Pennsylvania Ave. NW, Suite 6B, Washington, DC 20037, USA
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21
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Targeting Chromatin-Mediated Transcriptional Control of Gene Expression in Non-Small Cell Lung Cancer Therapy: Preclinical Rationale and Clinical Results. Drugs 2015; 75:1757-71. [DOI: 10.1007/s40265-015-0461-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Rodemann HP, Bodis S. Cutting-edge research in basic and translational radiation biology/oncology reflections from the 14th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology 2015. Radiother Oncol 2015; 116:335-41. [DOI: 10.1016/j.radonc.2015.09.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 09/04/2015] [Accepted: 09/05/2015] [Indexed: 01/11/2023]
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23
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Stachelek GC, Peterson-Roth E, Liu Y, Fernandez RJ, Pike LRG, Qian JM, Abriola L, Hoyer D, Hungerford W, Merkel J, Glazer PM. YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors. Mol Cancer Res 2015; 13:1389-97. [PMID: 26116172 DOI: 10.1158/1541-7786.mcr-15-0036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 06/10/2015] [Indexed: 11/16/2022]
Abstract
UNLABELLED Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies. IMPLICATIONS We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair-deficient cell and animal models and have strong potential for clinical translation.
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Affiliation(s)
- Gregory C Stachelek
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Department of Genetics, Yale School of Medicine, New Haven, Connecticut
| | | | - Yanfeng Liu
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Rafael J Fernandez
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Luke R G Pike
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Jack M Qian
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Laura Abriola
- Yale Center for Molecular Discovery, West Haven, Connecticut
| | - Denton Hoyer
- Yale Center for Molecular Discovery, West Haven, Connecticut
| | | | - Janie Merkel
- Yale Center for Molecular Discovery, West Haven, Connecticut
| | - Peter M Glazer
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
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24
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Willers H, Gheorghiu L, Liu Q, Efstathiou JA, Wirth LJ, Krause M, von Neubeck C. DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity. Semin Radiat Oncol 2015; 25:237-50. [PMID: 26384272 DOI: 10.1016/j.semradonc.2015.05.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anticancer agents. Genomic profiling of human cancers provides us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome produces biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (ie, foci) of proteins in the DNA damage response (DDR), such as gamma-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant end points such as tumor control probability. Therefore, preclinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future.
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Affiliation(s)
- Henning Willers
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.
| | - Liliana Gheorghiu
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
| | - Qi Liu
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
| | - Jason A Efstathiou
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
| | - Lori J Wirth
- Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Mechthild Krause
- German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Germany
| | - Cläre von Neubeck
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
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25
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Radiation oncology in vitro: trends to improve radiotherapy through molecular targets. BIOMED RESEARCH INTERNATIONAL 2014; 2014:461687. [PMID: 25302298 PMCID: PMC4180203 DOI: 10.1155/2014/461687] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 07/16/2014] [Indexed: 12/17/2022]
Abstract
Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed. Beyond simple identification of resistant phenotype the discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment including radiotherapy. Alterations on transduction signaling pathway related with MAPK cascade are the main axis in cancer cellular proliferation even as cell migration and invasiveness in irradiated tumor cell lines; then, for that reason, more studies are in course focusing on, among others, DNA damage enhancement, apoptosis stimulation, and growth factors receptor blockages, showing promising in vitro results highlighting molecular targets associated with ionizing radiation as a new radiotherapy strategy to improve clinical outcome. In this review we discuss some of the main molecular targets related with tumor cell proliferation and migration as well as their potential contributions to radiation oncology improvements.
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