Abstract
The aim of this minireview is to recapitulate the evidence in the literature supporting a role for the aldehyde dehydrogenases (ALDH1, ALDH2 and ALDH3) in controlling the levels of 3 endogenous apoptogenic aldehydes: methional, malondialdehyde (MDA) and 4-hydroxynonenal (HNE). All 3 aldehydes are formed during the metabolism of cellular constituents. Methional is derived from the oxidative decarboxylation of 4-methylthio-2-oxobutanoate coming from the methionine salvage pathway. MDA arises from the peroxidation of lipids and also from methional subjected to attack by reactive oxygen species (ROS). HNE is formed primarily from lipid peroxidation by ROS attack. One major origin of ROS is the dysfunctional electron transport chain in the mitochondria of cancer cells. As bifunctional electrophilic compounds, HNE forms adducts with cellular nucleophiles e.g. GSH, whilst MDA acts as a potent DNA/protein cross-linking agent in vitro and in vivo. Cancer cells protect themselves from the apoptogenic effect of these aldehydes by the ALDHs that oxidize them to their non-apoptogenic carboxylic acids. Indeed, the over-expression of ALDH3 protects cells from HNE-induced apoptosis. The inhibition of ALDH1 allows methional to reach its apoptogenic threshold in BAF3bcl2 that were resistant to methionalinducible apoptosis. One member of the α,β-acetylenic N-substituted aminothiol ester family is an “active-enzyme-dependent”, competitive, irreversible inhibitor of ALDH1 in vitro, an inhibitor of ALDH1 and ALDH3 in rat and human cancer cells in culture, an irreversible apoptogen on chemoresistant bcl2+++ murine lymphoid and human epithelial cancer cells but a reversible cytostatic compound on human prostate epithelial normal cells in culture.
Keywords: Apoptogenic aldehydes, aldehyde dehydrogenases, ALDH inhibitors, cancer, bcl2, endogenous apoptogenic, aldehydes, methional, malondialdehyde (MDA), oxidative decarboxylation, 4-methylthio-2-oxobutanoate
Current Medicinal Chemistry
Title:α,β-Acetylenic Amino Thiolester Inhibitors of Aldehyde Dehydrogenases 1&3: Suppressors of Apoptogenic Aldehyde Oxidation and Activators of Apoptosis
Volume: 20 Issue: 4
Author(s): G. Fournet, G. Martin and G. Quash
Affiliation:
Keywords: Apoptogenic aldehydes, aldehyde dehydrogenases, ALDH inhibitors, cancer, bcl2, endogenous apoptogenic, aldehydes, methional, malondialdehyde (MDA), oxidative decarboxylation, 4-methylthio-2-oxobutanoate
Abstract: The aim of this minireview is to recapitulate the evidence in the literature supporting a role for the aldehyde dehydrogenases (ALDH1, ALDH2 and ALDH3) in controlling the levels of 3 endogenous apoptogenic aldehydes: methional, malondialdehyde (MDA) and 4-hydroxynonenal (HNE). All 3 aldehydes are formed during the metabolism of cellular constituents. Methional is derived from the oxidative decarboxylation of 4-methylthio-2-oxobutanoate coming from the methionine salvage pathway. MDA arises from the peroxidation of lipids and also from methional subjected to attack by reactive oxygen species (ROS). HNE is formed primarily from lipid peroxidation by ROS attack. One major origin of ROS is the dysfunctional electron transport chain in the mitochondria of cancer cells. As bifunctional electrophilic compounds, HNE forms adducts with cellular nucleophiles e.g. GSH, whilst MDA acts as a potent DNA/protein cross-linking agent in vitro and in vivo. Cancer cells protect themselves from the apoptogenic effect of these aldehydes by the ALDHs that oxidize them to their non-apoptogenic carboxylic acids. Indeed, the over-expression of ALDH3 protects cells from HNE-induced apoptosis. The inhibition of ALDH1 allows methional to reach its apoptogenic threshold in BAF3bcl2 that were resistant to methionalinducible apoptosis. One member of the α,β-acetylenic N-substituted aminothiol ester family is an “active-enzyme-dependent”, competitive, irreversible inhibitor of ALDH1 in vitro, an inhibitor of ALDH1 and ALDH3 in rat and human cancer cells in culture, an irreversible apoptogen on chemoresistant bcl2+++ murine lymphoid and human epithelial cancer cells but a reversible cytostatic compound on human prostate epithelial normal cells in culture.
Export Options
About this article
Cite this article as:
Fournet G., Martin G. and Quash G., α,β-Acetylenic Amino Thiolester Inhibitors of Aldehyde Dehydrogenases 1&3: Suppressors of Apoptogenic Aldehyde Oxidation and Activators of Apoptosis, Current Medicinal Chemistry 2013; 20 (4) . https://dx.doi.org/10.2174/0929867311320040004
DOI https://dx.doi.org/10.2174/0929867311320040004 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
- Announcements
Related Articles
-
Targeting MDM2-p53 Interaction for Cancer Therapy: Are We There Yet?
Current Medicinal Chemistry β-Aryl-ς-Hydroxy-γ-Lactones: Synthesis, Structural Analysis and Cytotoxic Activity
Current Organic Synthesis Importance of Influx and Efflux Systems and Xenobiotic Metabolizing Enzymes in Intratumoral Disposition of Anticancer Agents
Current Cancer Drug Targets MicroRNA Therapeutics: The Emerging Anticancer Strategies
Recent Patents on Anti-Cancer Drug Discovery HSV-1-Derived Recombinant and Amplicon Vectors for Gene Transfer and Gene Therapy
Current Gene Therapy Novel Targets of Vitamin D Activity in Bone: Action of the Vitamin D Receptor in Osteoblasts, Osteocytes and Osteoclasts
Current Drug Targets The Genetic Landscapes of Inflammation-Driven Gastrointestinal Tract Cancers
Current Pharmaceutical Design Diverse Roles of GADD45α in Stress Signaling
Current Protein & Peptide Science Chimeric Antigen Receptor T Cells: Self-Replicating Drugs for Cancer
Current Drug Targets Riluzole, Neuroprotection and Amyotrophic Lateral Sclerosis
Current Medicinal Chemistry Carbon Nanotubes for Biomaterials in Contact with Bone
Current Medicinal Chemistry The Current View on the Helicase Activity of RNA Helicase A and Its Role in Gene Expression
Current Protein & Peptide Science Evaluation of the Anticancer Activities of the Plant Alkaloids Sanguinarine and Chelerythrine in Human Breast Adenocarcinoma Cells
Anti-Cancer Agents in Medicinal Chemistry Drugs of Abuse: Epigenetic Mechanisms in Toxicity and Addiction
Current Medicinal Chemistry Thioethers: An Overview
Current Drug Targets Selective Thyroid Hormone Receptor Modulators
Current Topics in Medicinal Chemistry Dual Roles of Sulforaphane in Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Biocombinatorial Selection of Carbohydrate Binding Agents of Therapeutic Significance
Current Drug Discovery Technologies Multifunctional RNase MCPIP1 and its Role in Cardiovascular Diseases
Current Medicinal Chemistry Multi- and Inter-Disciplinary Science in Personalized Delivery of Stem Cells for Tissue Repair
Current Stem Cell Research & Therapy