Abstract
Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that α , β unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
Keywords: Michael reaction acceptor, acetylation, p300/CBP, Curcumin
Medicinal Chemistry
Title: Curcumin is an Inhibitor of p300 Histone Acetylatransferase
Volume: 2 Issue: 2
Author(s): Len Neckers, Jane Trepel, Sunmin Lee, Eun-Joo Chung, Min-Jung Lee, Yun-Jin Jung and Monica G. Marcu
Affiliation:
Keywords: Michael reaction acceptor, acetylation, p300/CBP, Curcumin
Abstract: Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that α , β unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
Export Options
About this article
Cite this article as:
Neckers Len, Trepel Jane, Lee Sunmin, Chung Eun-Joo, Lee Min-Jung, Jung Yun-Jin and Marcu G. Monica, Curcumin is an Inhibitor of p300 Histone Acetylatransferase, Medicinal Chemistry 2006; 2 (2) . https://dx.doi.org/10.2174/157340606776056133
DOI https://dx.doi.org/10.2174/157340606776056133 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...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
-
Magnetic Nanoparticles: Properties, Synthesis and Biomedical Applications
Current Drug Metabolism Drugs Made of RNA: Development and Application of Engineered RNAs for Gene Therapy
Mini-Reviews in Medicinal Chemistry Endogenous Factors in the Recovery of Reproductive Function After Testicular Injury and Cancer
Current Molecular Medicine Advances in Spirocyclic Hybrids: Chemistry and Medicinal Actions
Current Medicinal Chemistry Marine Derived Anticancer Drugs Targeting Microtubule
Recent Patents on Anti-Cancer Drug Discovery Phosphodiesterase 5 Inhibitors in the Treatment of Erectile Dysfunction
Current Pharmaceutical Design Meet Our Editorial Board Member
Recent Patents on Anti-Cancer Drug Discovery Recent Developments in Chimeric NSAIDs as Anticancer Agents: Teaching an Old Dog a New Trick
Mini-Reviews in Medicinal Chemistry The Role of Non-coding Genome in Cancer-associated Fibroblasts; Stateof- the-Art and Perspectives in Cancer Targeted Therapy
Current Drug Targets Angiogenesis and Angiogenesis Inhibitors: a New Potential Anticancer Therapeutic Strategy
Current Drug Targets - Immune, Endocrine & Metabolic Disorders The Role of Insulin Resistance and Hyperinsulinemia in Cancer Causation
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Toxicology of Tributyltin in Mammalian Animal Models
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Ex Vivo Liver – Directed Gene Therapy for the Treatment of Metabolic Diseases: Advances in Hepatocyte Transplantation and Retroviral Vectors
Current Gene Therapy Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder
Current Neuropharmacology Phenotypic Alteration of Bone Marrow HSC and Microenvironmental Association in Experimentally Induced Leukemia
Current Stem Cell Research & Therapy Focus on Ulcerative Colitis: Stable Gastric Pentadecapeptide BPC 157
Current Medicinal Chemistry Doing the Puzzle of Steroid Hormone Action: Biological Functions, Physiological and Clinical Significance of Plasma Membrane-Residing Glucocorticoid Recognizing Proteins
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Evaluation of Direct Effect of Testosterone on NGEP and LM O1 Expression in LNCaP Prostate Cancer Cells
Current Biomarkers (Discontinued) Pharmacological Innovations for Posttraumatic Stress Disorder and Medication- Enhanced Psychotherapy
Current Pharmaceutical Design In Silico Analysis and Molecular Docking Studies of Novel 6,7-dihydropyrano [2,3-d] pyrimidin-5-one Derivatives as Human Epidermal Growth Factor Receptor 2 (HER2) and Epidermal Growth Factor Receptor (EGFR) Inhibitors
Current Cancer Therapy Reviews