Abstract
Pancreatic ductal adenocarcinoma (PDAC) is quite resistant to conventional treatments, and gemcitabine, the standard chemotherapeutic agent, offers only a small benefit. Development and progression of PDAC are complex processes involving dysregulation of multiple signal transduction pathways arising from not only genetic but also epigenetic alterations. This makes the epigenetic approach to the treatment of PDAC of great interest. Histone deacetylases, a family of enzymes that, by removal of acetyl groups from a variety of histone and nonhistone proteins, play an important role in the epigenetic regulation of gene expression, are frequently dysregulated in PDAC. In particular, overexpression of class I histone deacetylases has been related to higher tumor grade, poor prognosis and development of chemoresistance. Histone deacetylase inhibitors (HDACIs), a novel class of agents endowed with pleiotropic antitumor effects, appear promising either for their preferential toxicity towards transformed as compared to normal cells and their ability to synergistically enhance the anticancer activity of radiotherapy and many chemotherapeutic agents. Many HDACIs have been shown to increase the antiproliferative and proapoptotic effects of gemcitabine, 5-fluorouracil and bortezomib, a new proteasome inhibitor, in vitro and in vivo PDAC xenograft models. MGCD0103, romidepsin, panobinostat, vorinostat and valproic acid, are currently being tested in association with radiotherapy or chemotherapy (gemcitabine, fluoropyrimidines, proteasome inhibitors) in phase I-II clinical trials in patients with locally advanced or metastatic PDAC.
Keywords: Cancer therapy, epigenetic, histone deacetylase, histone deacetylase inhibitor, molecular targeted therapy, pancreatic ductal adenocarcinoma, HDACs IN PDAC, 10-epoxy-decanoyl, gemcitabine, interleukin-13 Receptor 2, non-homologous end-joining, reactive oxygen species, radiation therapy
Current Cancer Drug Targets
Title:An Epigenetic Approach to Pancreatic Cancer Treatment: The Prospective Role of Histone Deacetylase Inhibitors
Volume: 12 Issue: 4
Author(s): Nicola Tinari, Michele De Tursi, Antonino Grassadonia, Marinella Zilli, Liborio Stuppia, Stefano Iacobelli and Clara Natoli
Affiliation:
Keywords: Cancer therapy, epigenetic, histone deacetylase, histone deacetylase inhibitor, molecular targeted therapy, pancreatic ductal adenocarcinoma, HDACs IN PDAC, 10-epoxy-decanoyl, gemcitabine, interleukin-13 Receptor 2, non-homologous end-joining, reactive oxygen species, radiation therapy
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is quite resistant to conventional treatments, and gemcitabine, the standard chemotherapeutic agent, offers only a small benefit. Development and progression of PDAC are complex processes involving dysregulation of multiple signal transduction pathways arising from not only genetic but also epigenetic alterations. This makes the epigenetic approach to the treatment of PDAC of great interest. Histone deacetylases, a family of enzymes that, by removal of acetyl groups from a variety of histone and nonhistone proteins, play an important role in the epigenetic regulation of gene expression, are frequently dysregulated in PDAC. In particular, overexpression of class I histone deacetylases has been related to higher tumor grade, poor prognosis and development of chemoresistance. Histone deacetylase inhibitors (HDACIs), a novel class of agents endowed with pleiotropic antitumor effects, appear promising either for their preferential toxicity towards transformed as compared to normal cells and their ability to synergistically enhance the anticancer activity of radiotherapy and many chemotherapeutic agents. Many HDACIs have been shown to increase the antiproliferative and proapoptotic effects of gemcitabine, 5-fluorouracil and bortezomib, a new proteasome inhibitor, in vitro and in vivo PDAC xenograft models. MGCD0103, romidepsin, panobinostat, vorinostat and valproic acid, are currently being tested in association with radiotherapy or chemotherapy (gemcitabine, fluoropyrimidines, proteasome inhibitors) in phase I-II clinical trials in patients with locally advanced or metastatic PDAC.
Export Options
About this article
Cite this article as:
Tinari Nicola, De Tursi Michele, Grassadonia Antonino, Zilli Marinella, Stuppia Liborio, Iacobelli Stefano and Natoli Clara, An Epigenetic Approach to Pancreatic Cancer Treatment: The Prospective Role of Histone Deacetylase Inhibitors, Current Cancer Drug Targets 2012; 12 (4) . https://dx.doi.org/10.2174/156800912800190884
DOI https://dx.doi.org/10.2174/156800912800190884 |
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
-
Exosomes: A Promising Factor Involved in Cancer Hypoxic Microenvironments
Current Medicinal Chemistry The Novel Functions of cGMP-Specific Phosphodiesterase 5 and its Inhibitors in Carcinoma Cells and Pulmonary/Cardiovascular Vessels
Current Topics in Medicinal Chemistry The Induction and Repair of DNA Interstrand Crosslinks and Implications in Cancer Chemotherapy
Anti-Cancer Agents in Medicinal Chemistry Molecular Mechanisms of Pancreatic Cancer Dissemination: The Role of the Chemokine System
Current Pharmaceutical Design Overview of Molecular Signal Transduction of Malignant Gliomas and Correlation with Responses to Targeted Therapy Recent advances in Molecular Characterization of Glioblastoma
Current Signal Transduction Therapy Gene Therapy Targeting in the Central Nervous System
Current Gene Therapy PET Molecular Imaging of Hypoxia in Ischemic Stroke: An Update
Current Vascular Pharmacology Gene Therapy and Cell Reprogramming For the Aging Brain: Achievements and Promise
Current Gene Therapy Critical Role of IL-8 Targeting in Gliomas
Current Medicinal Chemistry Antioxidant Effect of a Nitrated Cyclic Nucleotide Functioning as an Endogenous Electrophile
Current Topics in Medicinal Chemistry Novel Therapeutic Approaches Targeting Vascular Endothelial Growth Factor and its Receptors in Haematological Malignancies
Current Cancer Drug Targets Perfusion MRI of Brain Neoplams
Current Medical Imaging Inhibitor at the Gates, Inhibitor in the Chamber: Allosteric and Competitive Inhibitors of the Proteasome as Prospective Drugs
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Hydrolyzed Rutin Decreases Worsening of Anaplasia in Glioblastoma Relapse
CNS & Neurological Disorders - Drug Targets A QSAR Study on Novel Series of Carbonic Anhydrase Inhibitors hCA IX—Tumor-Associated (Hypoxia)
Medicinal Chemistry Human Galectin-3 Selective and High Affinity Inhibitors. Present State and Future Perspectives
Current Medicinal Chemistry MicroRNA-mediated Regulation of Angiogenesis
Current Angiogenesis (Discontinued) Chemoinformatics in Multi-target Drug Discovery for Anti-cancer Therapy: In Silico Design of Potent and Versatile Anti-brain Tumor Agents
Anti-Cancer Agents in Medicinal Chemistry Role of C1QBP/p32 and its Therapeutic Potential in Breast Carcinoma and other Cancers
Current Medicinal Chemistry Signal Transduction in HIV Protein-Treated Astrocytes
Current Signal Transduction Therapy