Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N-MC cells.

Abstract

It has been suggested that excess accumulation of reactive oxygen species, termed oxidative stress, may lead to neuronal death resulting in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In oxidative stress-induced cell death numerous transcription factors are thought to be involved. One of them is Forkhead box protein O1 (FOXO1) that governs many genes involved in oxidative stress resistance, DNA repair, cell cycle arrest, proliferation and apoptosis. Apparently, FOXO1 activity is tightly linked to post translational modifications including phosphorylation and acetylation, which are modulated by many factors such as oxidative stress. Reactive oxygen species, as the major players in oxidative stress, guide FOXO1 nuclear localization at least by simultaneous c-Jun N-terminal kinase (JNK) activation and Akt/PKB activity suppression. Here, we showed that a synthetic salen-manganese derivative (EUK-172) with strong catalase activity reduced oxidative stress evident through marked reduction in intracellular reactive oxygen species, protein carbonylation and lipid peroxidation. In addition, our results indicated that EUK-172 not only reduced the FOXO1 protein content, but also it inhibited FOXO1 nuclear translocation in H(2)O(2)-exposed SK-N-MC cells. These events attenuated caspase-3 activity and bax/Bcl-2 ratio leading to higher viability of the H(2)O(2)-treated SK-N-MC cells.

• Authors: Ali Gheysarzadeh, Razieh Yazdanparast
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 697 Issue 1-3 Pg. 47-52 (Dec 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23041154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• BAX protein, human
• Coordination Complexes
• EUK-172
• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Neuroprotective Agents
• Oxidants
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• Hydrogen Peroxide
• Proto-Oncogene Proteins c-akt
• JNK Mitogen-Activated Protein Kinases
• CASP3 protein, human
• Caspase 3

Topics

• Active Transport, Cell Nucleus (drug effects)
• Antioxidants (pharmacology)
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coordination Complexes (pharmacology)
• Cytoprotection
• Dose-Response Relationship, Drug
• Enzyme Activation
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• Humans
• Hydrogen Peroxide (toxicity)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lipid Peroxidation (drug effects)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Oxidants (toxicity)
• Oxidative Stress (drug effects)
• Protein Carbonylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• bcl-2-Associated X Protein (metabolism)