Abstract
The purpose of this study was to determine the effects of the histone deacetylase inhibitor, MS-275, on the Fas signaling pathway and susceptibility of osteosarcoma (OS) to Fas ligand (FasL)-induced cell death. OS metastasizes almost exclusively to the lungs. We have shown that Fas expression in OS cells is inversely correlated with their metastatic potential. Fas+ cells are rapidly eliminated when they enter the lungs via interaction with FasL, which is constitutively expressed in the lungs. Fas- OS cells escape this FasL-induced apoptosis and survive in the lung microenvironment. Moreover, upregulation of Fas in established OS lung metastases results in tumor regression. Therefore, agents that upregulate Fas expression or activate the Fas signaling pathway may have therapeutic potential. Treatment of Fas- metastatic OS cell lines with 2 µM MS-275 sensitized cells to FasL-induced cell death in vitro. We found that MS-275 did not alter the expression of Fas on the cell surface; rather it resulted in the downregulation of the anti-apoptotic protein, c-FLIP (cellular FLICE-inhibitory protein), by inhibiting c-FLIP mRNA. Downregulation of c- FLIP correlated with caspase activation and apoptosis induction. Treatment of nu/nu-mice with established OS lung metastases with oral MS-275 resulted in tumor regression, increased apoptosis and a significant inhibition of c-FLIP expression in tumors. Histopathological examination of mice showed no evidence of significant toxicity. Overall, these results suggest that the mechanism by which MS-275 sensitizes OS cells and lung metastases to FasL-induced cell death may be by a direct reduction in the expression of c-FLIP.
Keywords: c-FLIP, Entinostat, Fas, FasL, histone deacetylase inhibitors, MS-275, osteosarcoma.
Current Cancer Drug Targets
Title:The Histone Deacetylase Inhibitor, MS-275 (Entinostat), Downregulates c-FLIP, Sensitizes Osteosarcoma Cells to FasL, and Induces the Regression of Osteosarcoma Lung Metastases
Volume: 13 Issue: 4
Author(s): Krithi Rao-Bindal, Nadezhda V. Koshkina, John Stewart and Eugenie S. Kleinerman
Affiliation:
Keywords: c-FLIP, Entinostat, Fas, FasL, histone deacetylase inhibitors, MS-275, osteosarcoma.
Abstract: The purpose of this study was to determine the effects of the histone deacetylase inhibitor, MS-275, on the Fas signaling pathway and susceptibility of osteosarcoma (OS) to Fas ligand (FasL)-induced cell death. OS metastasizes almost exclusively to the lungs. We have shown that Fas expression in OS cells is inversely correlated with their metastatic potential. Fas+ cells are rapidly eliminated when they enter the lungs via interaction with FasL, which is constitutively expressed in the lungs. Fas- OS cells escape this FasL-induced apoptosis and survive in the lung microenvironment. Moreover, upregulation of Fas in established OS lung metastases results in tumor regression. Therefore, agents that upregulate Fas expression or activate the Fas signaling pathway may have therapeutic potential. Treatment of Fas- metastatic OS cell lines with 2 µM MS-275 sensitized cells to FasL-induced cell death in vitro. We found that MS-275 did not alter the expression of Fas on the cell surface; rather it resulted in the downregulation of the anti-apoptotic protein, c-FLIP (cellular FLICE-inhibitory protein), by inhibiting c-FLIP mRNA. Downregulation of c- FLIP correlated with caspase activation and apoptosis induction. Treatment of nu/nu-mice with established OS lung metastases with oral MS-275 resulted in tumor regression, increased apoptosis and a significant inhibition of c-FLIP expression in tumors. Histopathological examination of mice showed no evidence of significant toxicity. Overall, these results suggest that the mechanism by which MS-275 sensitizes OS cells and lung metastases to FasL-induced cell death may be by a direct reduction in the expression of c-FLIP.
Export Options
About this article
Cite this article as:
Rao-Bindal Krithi, Koshkina Nadezhda V., Stewart John and Kleinerman Eugenie S., The Histone Deacetylase Inhibitor, MS-275 (Entinostat), Downregulates c-FLIP, Sensitizes Osteosarcoma Cells to FasL, and Induces the Regression of Osteosarcoma Lung Metastases, Current Cancer Drug Targets 2013; 13 (4) . https://dx.doi.org/10.2174/1568009611313040005
DOI https://dx.doi.org/10.2174/1568009611313040005 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Antagonists of Growth Hormone-Releasing Hormone in Oncology
Combinatorial Chemistry & High Throughput Screening Inhibition of Apoptosis in Pediatric Cancer by Survivin
Current Pediatric Reviews Role of ncRNAs in Development, Diagnosis and Treatment of Human Cancer
Recent Patents on Anti-Cancer Drug Discovery Investigating ABCB1-Mediated Drug-Drug Interactions: Considerations for In vitro and In vivo Assay Design
Current Drug Metabolism Targeting MDM4 as a Novel Therapeutic Approach for Hematologic Malignancies
Current Cancer Drug Targets The Recent Progresses on The Improved Therapy of Melanoma by Novel Drug Delivery Systems
Current Drug Targets Concise Review; The Recent Methods that Enhance the Osteogenic Differentiation of Human Induced Pluripotent Stem Cells
Current Stem Cell Research & Therapy Decreased lncRNA SNHG16 Accelerates Oxidative Stress Induced Pathological Angiogenesis in Human Retinal Microvascular Endothelial Cells by Regulating miR-195/mfn2 Axis
Current Pharmaceutical Design Novel Targets for Apoptosis Modulation: BAG3 Protein and Other Co- Chaperones
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Cancer T Cell Immunotherapy with Bispecific Antibodies and Chimeric Antigen Receptors
Recent Patents on Anti-Cancer Drug Discovery Synergism of Temozolomide, Metformin, and Epigallocatechin Gallate Promotes Oxidative Stress-Induced Apoptosis in Glioma Cells
Current Drug Therapy Chemokines and Chemokine Receptors: Potential Therapeutic Targets in Multiple Sclerosis
Current Drug Targets - Inflammation & Allergy P-Glycoprotein Mediated Multidrug Resistance Reversal by Phytochemicals: A Review of SAR & Future Perspective for Drug Design
Current Topics in Medicinal Chemistry Arsenic Trioxide Exerts Anti-lung Cancer Activity by Inhibiting Angiogenesis
Current Cancer Drug Targets Biosynthetic and Metabolic Alterations in Cancer Growth
Current Angiogenesis (Discontinued) Multiple Target-Specific Molecular Agents for Detection and Image Analysis of Breast Cancer Characteristics in Mice
Current Molecular Medicine Gene Delivery by Functional Inorganic Nanocarriers
Recent Patents on DNA & Gene Sequences Harnessing the Natural Pool of Polyketide and Non-ribosomal Peptide Family: A Route Map towards Novel Drug Development
Current Molecular Pharmacology Pharmacogenetics of Drug Transporters and Its Impact on the Pharmacotherapy
Current Topics in Medicinal Chemistry High-Content Analysis of Kinase Activity in Cells
Combinatorial Chemistry & High Throughput Screening