Abstract
O6-Methylguanine-DNA-methyltransferase (MGMT) is an antimutagenic DNA repair protein highly expressed in human brain tumors. Because MGMT repairs the mutagenic, carcinogenic and cytotoxic O6-alkylguanine adducts, including those generated by the clinically used anticancer alkylating agents, it has emerged as a central and rational target for overcoming tumor resistance to alkylating agents. Although the pseudosubstrates for MGMT [O6-benzylguanine, O6-(4- bromothenyl)guanine] have gained attention as powerful and clinically-relevant inhibitors, bone marrow suppression due to excessive alkylation damage has diminished this strategy. Our laboratory has been working on various posttranslational modifications of MGMT that affect its protein stability, DNA repair activity and response to oxidative stress. While these modifications greatly impact the physiological regulation of MGMT, they also highlight the opportunities for inactivating DNA repair and new drug discovery in this specific area. This review briefly describes the newer aspects of MGMT posttranslational regulation by ubiquitination, sumoylation and glutathionylation and reveals how the reactivity of the active site Cys145 can be exploited for potent inhibition and depletion of MGMT by thiol-reacting drugs such as the disulfiram and various dithiocarbamate derivatives. The possible repurposing of these nontoxic and safe drugs for improved therapy of pediatric and adult brain tumors is discussed.
Keywords: Alkylating agents, DNA repair, Drug repurposing, gliomas, Protein glutathionylation, Reactive cysteines.
Mini-Reviews in Medicinal Chemistry
Title:Posttranslational Regulation of O6-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers
Volume: 16 Issue: 6
Author(s): Kalkunte S. Srivenugopal, Amit Rawat, Suryakant K. Niture, Ameya Paranjpe, Chinavenmani Velu, Sanjay N. Venugopal, Hanumantha Rao Madala, Debasish Basak and Surendra R. Punganuru
Affiliation:
Keywords: Alkylating agents, DNA repair, Drug repurposing, gliomas, Protein glutathionylation, Reactive cysteines.
Abstract: O6-Methylguanine-DNA-methyltransferase (MGMT) is an antimutagenic DNA repair protein highly expressed in human brain tumors. Because MGMT repairs the mutagenic, carcinogenic and cytotoxic O6-alkylguanine adducts, including those generated by the clinically used anticancer alkylating agents, it has emerged as a central and rational target for overcoming tumor resistance to alkylating agents. Although the pseudosubstrates for MGMT [O6-benzylguanine, O6-(4- bromothenyl)guanine] have gained attention as powerful and clinically-relevant inhibitors, bone marrow suppression due to excessive alkylation damage has diminished this strategy. Our laboratory has been working on various posttranslational modifications of MGMT that affect its protein stability, DNA repair activity and response to oxidative stress. While these modifications greatly impact the physiological regulation of MGMT, they also highlight the opportunities for inactivating DNA repair and new drug discovery in this specific area. This review briefly describes the newer aspects of MGMT posttranslational regulation by ubiquitination, sumoylation and glutathionylation and reveals how the reactivity of the active site Cys145 can be exploited for potent inhibition and depletion of MGMT by thiol-reacting drugs such as the disulfiram and various dithiocarbamate derivatives. The possible repurposing of these nontoxic and safe drugs for improved therapy of pediatric and adult brain tumors is discussed.
Export Options
About this article
Cite this article as:
Srivenugopal S. Kalkunte, Rawat Amit, Niture K. Suryakant, Paranjpe Ameya, Velu Chinavenmani, Venugopal N. Sanjay, Madala Rao Hanumantha, Basak Debasish and Punganuru R. Surendra, Posttranslational Regulation of O6-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers, Mini-Reviews in Medicinal Chemistry 2016; 16 (6) . https://dx.doi.org/10.2174/1389557515666150722101046
DOI https://dx.doi.org/10.2174/1389557515666150722101046 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Mitochondria as a Therapeutic Target in Metabolic Disorders
Mitochondria are the primary site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, these organelles are an important source of reactive oxygen and nitrogen species in virtually any nucleated cell type. The modulation of a myriad of cellular signaling pathways depends on the mitochondrial physiology. Mitochondrial dysfunction is observed ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...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
-
Monofunctional Platinum (PtII) Compounds – Shifting the Paradigm in Designing New Pt-based Anticancer Agents
Current Medicinal Chemistry VEGF in Tumor Progression and Targeted Therapy
Current Cancer Drug Targets Review of and Perspectives on the Toxicology of Graphene-based Materials
Current Drug Metabolism Blockade of Neoangiogenesis, a New and Promising Technique to Control the Growth of Malignant Tumors and their Metastases
Current Vascular Pharmacology Mitochondrial Drug Targets in Cell Death and Cancer
Current Pharmaceutical Design Mechanism of Action of Volatile Anesthetics: Involvement of Intracellular Calcium Signaling
Current Drug Targets - CNS & Neurological Disorders Glutathione-Triggered Drug Release from Nanostructures
Current Topics in Medicinal Chemistry Lipoprotein-Related and Apolipoprotein-Mediated Delivery Systems for Drug Targeting and Imaging
Current Medicinal Chemistry Fluorescence Imaging of Human Cells with a Novel Conjugate of the Antifungal Nystatin
Medicinal Chemistry Structure of the Epidermal Growth Factor Receptor Gene and Intron Recombination in Human Gliomas
Current Genomics Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients’ Outcome
Current Cancer Drug Targets Techniques to Investigate Neuronal Mitochondrial Function and its Pharmacological Modulation
Current Drug Targets Role of Tumor Microenvironment in Cancer Stem Cells Resistance to Radiotherapy
Current Cancer Drug Targets Recent Advances in Superparamagnetic Iron Oxide Nanoparticles for Cellular Imaging and Targeted Therapy Research
Current Pharmaceutical Design A Novel Lily-of-the-Valley Fragrance Contrast Agent for Magnetic Resonance and Fluorescence Imaging of Prostate Cancer Cells
Current Pharmaceutical Biotechnology EMT Blockage Strategies: Targeting Akt Dependent Mechanisms for Breast Cancer Metastatic Behaviour Modulation
Current Gene Therapy Novel Therapeutic Strategies for Dementia
CNS & Neurological Disorders - Drug Targets Aneurysm of the Communicating Vein Between the Left Renal Vein and Left Ascending Lumbar Vein Mimicking Retroperitoneal Lymphadenopathy: A Case Report
Current Medical Imaging An Integrative Informatics Approach to Explain the Mechanism of Action of N1-(Anthraquinon-2-yl) Amidrazones as BCR/ABL Inhibitors
Current Computer-Aided Drug Design Changes in the Apoptotic and Survival Signaling in Cancer Cells and Their Potential Therapeutic Implications
Current Cancer Drug Targets