Abstract
Resveratrol derivatives bearing an O-linked mitochondria-targeting 4-triphenylphosphoniumbutyl group at either position 3 or position 4’ are prooxidant and cytotoxic for cultured cells, selectively killing fast-growing cells when supplied in the low μM range. Resveratrol is essentially without effect under these experimental conditions, while the cytotoxicity of the mitochondriotropic derivatives increases if they are methylated on the remaining hydroxyls. Experiments with Bax-/-/Bak-/- cells and a pan-caspase inhibitor show that cell death is mostly of the necrotic type. Cytotoxicity is due to ROS produced upon accumulation of the compounds into mitochondria, and specifically to H2O2, since externally added membrane-permeant catalase largely prevents cell death while superoxide dismutase potentiates toxicity. The mitochondriotropic compounds cause ROS-independent depolarization of in situ mitochondria. Effectiveness is increased if resveratrol hydroxyls are acetylated or methylated; this excludes the involvement of autooxidation of the polyphenolic nucleus and a protonophoric cycle as the causes of ROS generation and of depolarization, respectively. Resveratrol-triphenylphosphonium conjugates may thus represent a new class of chemotherapeutic agents, redox-active “mitocans”, whose mechanisms of action and in vivo activity are worthy of further investigation.
Keywords: Resveratrol, mitochondria, mitocans, cancer, reactive oxygen species.
Current Pharmaceutical Design
Title:Mitochondria-targeted Resveratrol Derivatives Act as Cytotoxic Pro-oxidants
Volume: 20 Issue: 2
Author(s): Nicola Sassi, Andrea Mattarei, Michele Azzolini, Paolo Bernardi, Ildiko' Szabo', Cristina Paradisi, Mario Zoratti and Lucia Biasutto
Affiliation:
Keywords: Resveratrol, mitochondria, mitocans, cancer, reactive oxygen species.
Abstract: Resveratrol derivatives bearing an O-linked mitochondria-targeting 4-triphenylphosphoniumbutyl group at either position 3 or position 4’ are prooxidant and cytotoxic for cultured cells, selectively killing fast-growing cells when supplied in the low μM range. Resveratrol is essentially without effect under these experimental conditions, while the cytotoxicity of the mitochondriotropic derivatives increases if they are methylated on the remaining hydroxyls. Experiments with Bax-/-/Bak-/- cells and a pan-caspase inhibitor show that cell death is mostly of the necrotic type. Cytotoxicity is due to ROS produced upon accumulation of the compounds into mitochondria, and specifically to H2O2, since externally added membrane-permeant catalase largely prevents cell death while superoxide dismutase potentiates toxicity. The mitochondriotropic compounds cause ROS-independent depolarization of in situ mitochondria. Effectiveness is increased if resveratrol hydroxyls are acetylated or methylated; this excludes the involvement of autooxidation of the polyphenolic nucleus and a protonophoric cycle as the causes of ROS generation and of depolarization, respectively. Resveratrol-triphenylphosphonium conjugates may thus represent a new class of chemotherapeutic agents, redox-active “mitocans”, whose mechanisms of action and in vivo activity are worthy of further investigation.
Export Options
About this article
Cite this article as:
Sassi Nicola, Mattarei Andrea, Azzolini Michele, Bernardi Paolo, Szabo' Ildiko', Paradisi Cristina, Zoratti Mario and Biasutto Lucia, Mitochondria-targeted Resveratrol Derivatives Act as Cytotoxic Pro-oxidants, Current Pharmaceutical Design 2014; 20 (2) . https://dx.doi.org/10.2174/13816128113199990034
DOI https://dx.doi.org/10.2174/13816128113199990034 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
- Announcements
Related Articles
-
The Effect of Lipoic Acid on Macro and Trace Metal Levels in Living Tissues Exposed to Oxidative Stress
Anti-Cancer Agents in Medicinal Chemistry New Horizons in Diabetes Therapy
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Evaluation of Pharmacological Treatment Strategies in Traumatic Brain Injury
Current Pharmaceutical Design Advanced Glycation End Products in Chinese Medicine Mediated Aging Diseases: A Review
Current Vascular Pharmacology Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders
Current Medicinal Chemistry Ryanodine Receptor Patents
Recent Patents on Biotechnology Endothelial Dysfunction: Methods of Assessment and Application to Hypertension
Current Pharmaceutical Design Metabolic Enzyme System and Transport Pathways in Chronic Kidney Diseases
Current Drug Metabolism Mechanisms of Neutrophil-mediated Disease: Innovative Therapeutic Interventions
Current Pharmaceutical Design Dose-dependent Effects of Esmolol-epinephrine Combination Therapy in Myocardial Ischemia and Reperfusion Injury
Current Pharmaceutical Design Redox mechanisms in pathological angiogenesis in the retina: roles for NADPH oxidase
Current Pharmaceutical Design Cerebrovascular and Blood-Brain Barrier Morphology in Spontaneously Hypertensive Rats: Effect of Treatment with Choline Alphoscerate
CNS & Neurological Disorders - Drug Targets Effect of Inhibitors of Nitric Oxide in Animal Models and Future Directions for Therapy in Inflammatory Disorders
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Rho as a Target to Promote Repair: Translation to Clinical Studies with Cethrin
Current Pharmaceutical Design The Neuropeptide Systems and their Potential Role in the Treatment of Mammalian Retinal Ischemia: A Developing Story
Current Neuropharmacology Up-Regulation of TLR-4 in the Brain After Ischemic Kidney-Induced Encephalopathy in the Rat
CNS & Neurological Disorders - Drug Targets The Cellular Protective Effects of Rosmarinic Acid: From Bench to Bedside
Current Neurovascular Research Functional Genomics of Cardioprotection by Ischemic Conditioning and the Influence of Comorbid Conditions: Implications in Target Identification
Current Drug Targets Modulation of Neutrophil Function by Hormones
Current Immunology Reviews (Discontinued) Patent Selections
Recent Patents on Anti-Infective Drug Discovery