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Wilson H Miller - One of the best experts on this subject based on the ideXlab platform.
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abstract 491 selective killing of oncogenically transformed cells by arsenic trioxide and Trolox
Cancer Research, 2014Co-Authors: Genevieve G J Redstone, Koren K Mann, Jessica N Nichol, Brandon Faubert, Russell G Jones, Wilson H MillerAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: A major disadvantage of cytotoxic chemotherapy is the difficulty in selectively targeting tumor cells. Although arsenic trioxide (ATO) is an effective therapy in acute promyelocytic leukemia (APL), its use in solid tumors is limited by the toxicity observed at concentrations required to induce apoptosis in non-APL cells. We previously found that Trolox, a vitamin E derivative, enhances ATO-induced apoptosis in APL cells, while simultaneously protecting normal cells. The objective of the current study is to understand the mechanism(s) by which Trolox switches from cytoprotective to cytotoxic upon the oncogenic transformation of cells. Materials and methods: This study was conducted using two isogenic models: mouse embryonic fibroblast (MEFs) and MEFs stably-transfected with either E6/E7 or E1A/Ras oncogenes. Apoptosis was assessed via staining with Propidium Iodide (Cell Signaling) followed by FACS analysis. Cells were treated with various concentrations of ATO alone or in combination with 100μM Trolox for 48 hours. SubG0 cell population results were obtained by staining the cells with PI, followed by analysis using CellQuest software. Mitochondrial ROS levels were measured with MitoSox (Life Technologies), followed by FACS analysis. Cells were treated with 5μM ATO alone or in combination with 100μM Trolox for 18 hours. Mitochondrial fluorescence was examined by staining the cells with MitoSOX (Life Technologies). For the visualization and enumeration of mitochondria, cells were examined with Transmission Electron Microscopy (TEM). Intracellular pictures were taken with TEM at FEMR, McGill University. Changes in cellular metabolism were measured with an XF96 Extracellular Flux Analyzer (Seahorse Bioscience). Results: In both the E6/E7 and E1A/Ras models, Trolox enhances ATO-induced death. In contrast, Trolox has a protective effect from ATO toxicity in their untransformed counterparts. In the transformed cell lines, cell death correlates with enhanced formation of mitochondrial superoxide when treated with arsenic in combination with Trolox. The functionality of mitochondria is closely linked to their structure. Preliminary analysis of TEM images indicates that mitochondrial structural integrity in transformed cells deteriorates when treated with ATO in combination with Trolox. Finally, these results are supported by changes in cellular metabolisms in the transformed cell lines. Conclusion: Transformed cells are more sensitive to cytotoxicity induced by arsenic trioxide in combination with Trolox than their wild-type counterparts. We hypothesize that the predominant mechanism of action by which transformed cells are sensitized to the actions of Trolox and ATO is due to a dysfunction of mitochondrial activity. The results of this study will provide a means to expand the therapeutic spectrum of ATO beyond APL by enhancing tumor selectivity and protecting normal tissue from toxicity. Citation Format: Genevieve G. J. Redstone, Jessica N. Nichol, Brandon Faubert, Russell G. Jones, Koren K. Mann, Wilson H. Miller. Selective killing of oncogenically transformed cells by arsenic trioxide and Trolox. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2014-491
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Trolox improves the sensitivity of multiple myeloma to arsenic trioxide in vitro and in vivo
Blood, 2009Co-Authors: Michael Sebag, Wilson H Miller, Xianfang Huang, Nicolas Garnier, Koren K MannAbstract:Abstract 4920 Arsenic trioxide (ATO) induces apoptosis and promotes differentiation of acute promyelocytic leukemia (APL) cells, but has less activity in other types of cancers. One factor that may impede ATO success outside of APL is its toxicity profile, which limits in vivo concentrations and therefore, therapeutic benefit. We have reported that Trolox, an analogue of alpha tocopherol, can augment ATO sensitivity in a variety of malignant cells, while protecting non-malignant cells from ATO toxicity. In this current study, we have focused on Multiple Myeloma (MM), a plasma cell malignancy that often shows resistance to apoptosis, drug inhibition and remains incurable despite tremendous recent advances. Although ATO has activity against MM cells in vitro , clinical trials of ATO, given as a solo agent, in MM have shown limited promise. To see if the addition of Trolox could augment ATO toxicity, a panel of human myeloma cell lines (HMCLs, n=9) representing the genetic diversity seen in this disease, were treated with increasing concentration of ATO with and without 100uM Trolox. Cell growth was assessed by MTT viability assays and virtually all cell lines were sensitive to varying doses of ATO. Four cell lines (U266, KMS11, MM1R, MM1S) showed profound inhibition of cell growth with very low concentrations of ATO (<1uM). Trolox (100uM) alone had no effect on cell growth, but in concert with ATO further decreased cell growth by up to 50% as compared to the same dose of ATO alone in virtually all cell lines. To further elucidate the mechanism of growth inhibition, annexin V assays were performed by flow cytometry to measure apoptosis. In all cell lines (n=9), a clear increase in the apoptotic fraction was noted when Trolox was added to varying doses of arsenic. To test whether oxidative stress plays a role in ATO-mediated apoptosis of myeloma cells, we looked at the induction of a stress response protein (HO-1), a marker of oxidative stress induced by ATO. Western blot analysis revealed that in all myeloma cells tested, HO-1 was dramatically and quickly induced by ATO and further induced by the addition of Trolox, indicating a pro-oxidant activity of Trolox in the malignant cells. While the mechanism of Trolox enhancement of ATO function remains largely unknown, intracellular concentrations of ATO in MM cells, as measured by inductively coupled plasma mass spectrometry, suggest that Trolox does not work by augmenting ATO import or intracellular accumulation. To test the efficacy of ATO with Trolox in vivo , we used a novel transgenic mouse model of MM that has been shown to faithfully mimic the human disease and its response to treatment (Chesi et al, Cancer Cell 2008 Feb;13(2):167-80). We first treated MM afflicted mice with a low dose of ATO (5.0mg/kg) and Trolox (50mg/kg) to assess for toxicity and tolerability. This dose was well tolerated in all mice when given for 10 days with no obvious toxic effects. Serum protein electrophoresis performed at the end of the 10 day treatment period revealed that even at this low starting dose, one of three mice showed a 30% reduction in its paraprotein peak, while the others remained stable. Further studies with higher ATO concentrations in the same mouse model are underway. In conclusion, these data support the role of ATO plus Trolox, as a promising anti-myeloma therapy. Disclosures No relevant conflicts of interest to declare.
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Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in malignant cell lines
Cancer Research, 2005Co-Authors: Zuanel Diaz, Myrian Colombo, Koren K Mann, Haixiang Su, Kamilah N Smith, Hyman M Schipper, D. Scott Bohle, Wilson H MillerAbstract:1716 Arsenic trioxide (As2O3) has its major clinical activity in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in most non-APL tumor cells. We looked for agents that would synergize with As2O3 to induce apoptosis in malignant cells, but not in normal cells. We found that Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a hydrophilic analogue of α-tocopherol with increased antioxidant capacity and cell permeability, enhances As2O3-mediated apoptosis in APL, CML, lymphoma, myeloma and breast cancer cells. α-tocopherol partially protected these cells from As2O3-mediated apoptosis, possibly due to its partitions into the lipid bilayer matrix of membranes. Treatment with As2O3 and Trolox increased intracellular oxidative stress, as evidenced by HO-1 protein levels, JNK activation, and protein and lipid oxidation. The synergistic effects of Trolox may be specific to As2O3, as Trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of Trolox radicals when Trolox was combined with As2O3, but not with doxorubicin. Importantly, Trolox protected non-malignant cells from As2O3-mediated cytotoxicity. Our data provide the first evidence that Trolox may extend the therapeutic spectrum of As2O3. Furthermore, the combination of As2O3 and Trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As2O3 monotherapy in vivo.
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Trolox selectively enhances arsenic mediated oxidative stress and apoptosis in apl and other malignant cell lines
Blood, 2005Co-Authors: Zuanel Diaz, Myrian Colombo, Koren K Mann, Haixiang Su, Kamilah N Smith, Scott D Bohle, Hyman M Schipper, Wilson H MillerAbstract:Although arsenic trioxide (As 2 O 3 ) is an effective therapy in acute promyelocytic leukemia (APL), its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in non-APL tumor cells. We looked for agents that would synergize with As 2 O 3 to induce apoptosis in malignant cells, but not in normal cells. We found that Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a widely known antioxidant, enhances As 2 O 3 -mediated apoptosis in APL, myeloma, and breast cancer cells. Treatment with As 2 O 3 and Trolox increased intracellular oxidative stress, as evidenced by heme oxygenase-1 (HO-1) protein levels, c-Jun terminal kinase (JNK) activation, and protein and lipid oxidation. The synergistic effects of Trolox may be specific to As 2 O 3 , as Trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of Trolox radicals when Trolox was combined with As 2 O 3 , but not with doxorubicin. Importantly, Trolox protected nonmalignant cells from As 2 O 3 -mediated cytotoxicity. Our data provide the first evidence that Trolox may extend the therapeutic spectrum of As 2 O 3 . Furthermore, the combination of As 2 O 3 and Trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As 2 O 3 monotherapy in vivo.
Koren K Mann - One of the best experts on this subject based on the ideXlab platform.
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abstract 491 selective killing of oncogenically transformed cells by arsenic trioxide and Trolox
Cancer Research, 2014Co-Authors: Genevieve G J Redstone, Koren K Mann, Jessica N Nichol, Brandon Faubert, Russell G Jones, Wilson H MillerAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: A major disadvantage of cytotoxic chemotherapy is the difficulty in selectively targeting tumor cells. Although arsenic trioxide (ATO) is an effective therapy in acute promyelocytic leukemia (APL), its use in solid tumors is limited by the toxicity observed at concentrations required to induce apoptosis in non-APL cells. We previously found that Trolox, a vitamin E derivative, enhances ATO-induced apoptosis in APL cells, while simultaneously protecting normal cells. The objective of the current study is to understand the mechanism(s) by which Trolox switches from cytoprotective to cytotoxic upon the oncogenic transformation of cells. Materials and methods: This study was conducted using two isogenic models: mouse embryonic fibroblast (MEFs) and MEFs stably-transfected with either E6/E7 or E1A/Ras oncogenes. Apoptosis was assessed via staining with Propidium Iodide (Cell Signaling) followed by FACS analysis. Cells were treated with various concentrations of ATO alone or in combination with 100μM Trolox for 48 hours. SubG0 cell population results were obtained by staining the cells with PI, followed by analysis using CellQuest software. Mitochondrial ROS levels were measured with MitoSox (Life Technologies), followed by FACS analysis. Cells were treated with 5μM ATO alone or in combination with 100μM Trolox for 18 hours. Mitochondrial fluorescence was examined by staining the cells with MitoSOX (Life Technologies). For the visualization and enumeration of mitochondria, cells were examined with Transmission Electron Microscopy (TEM). Intracellular pictures were taken with TEM at FEMR, McGill University. Changes in cellular metabolism were measured with an XF96 Extracellular Flux Analyzer (Seahorse Bioscience). Results: In both the E6/E7 and E1A/Ras models, Trolox enhances ATO-induced death. In contrast, Trolox has a protective effect from ATO toxicity in their untransformed counterparts. In the transformed cell lines, cell death correlates with enhanced formation of mitochondrial superoxide when treated with arsenic in combination with Trolox. The functionality of mitochondria is closely linked to their structure. Preliminary analysis of TEM images indicates that mitochondrial structural integrity in transformed cells deteriorates when treated with ATO in combination with Trolox. Finally, these results are supported by changes in cellular metabolisms in the transformed cell lines. Conclusion: Transformed cells are more sensitive to cytotoxicity induced by arsenic trioxide in combination with Trolox than their wild-type counterparts. We hypothesize that the predominant mechanism of action by which transformed cells are sensitized to the actions of Trolox and ATO is due to a dysfunction of mitochondrial activity. The results of this study will provide a means to expand the therapeutic spectrum of ATO beyond APL by enhancing tumor selectivity and protecting normal tissue from toxicity. Citation Format: Genevieve G. J. Redstone, Jessica N. Nichol, Brandon Faubert, Russell G. Jones, Koren K. Mann, Wilson H. Miller. Selective killing of oncogenically transformed cells by arsenic trioxide and Trolox. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2014-491
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Trolox improves the sensitivity of multiple myeloma to arsenic trioxide in vitro and in vivo
Blood, 2009Co-Authors: Michael Sebag, Wilson H Miller, Xianfang Huang, Nicolas Garnier, Koren K MannAbstract:Abstract 4920 Arsenic trioxide (ATO) induces apoptosis and promotes differentiation of acute promyelocytic leukemia (APL) cells, but has less activity in other types of cancers. One factor that may impede ATO success outside of APL is its toxicity profile, which limits in vivo concentrations and therefore, therapeutic benefit. We have reported that Trolox, an analogue of alpha tocopherol, can augment ATO sensitivity in a variety of malignant cells, while protecting non-malignant cells from ATO toxicity. In this current study, we have focused on Multiple Myeloma (MM), a plasma cell malignancy that often shows resistance to apoptosis, drug inhibition and remains incurable despite tremendous recent advances. Although ATO has activity against MM cells in vitro , clinical trials of ATO, given as a solo agent, in MM have shown limited promise. To see if the addition of Trolox could augment ATO toxicity, a panel of human myeloma cell lines (HMCLs, n=9) representing the genetic diversity seen in this disease, were treated with increasing concentration of ATO with and without 100uM Trolox. Cell growth was assessed by MTT viability assays and virtually all cell lines were sensitive to varying doses of ATO. Four cell lines (U266, KMS11, MM1R, MM1S) showed profound inhibition of cell growth with very low concentrations of ATO (<1uM). Trolox (100uM) alone had no effect on cell growth, but in concert with ATO further decreased cell growth by up to 50% as compared to the same dose of ATO alone in virtually all cell lines. To further elucidate the mechanism of growth inhibition, annexin V assays were performed by flow cytometry to measure apoptosis. In all cell lines (n=9), a clear increase in the apoptotic fraction was noted when Trolox was added to varying doses of arsenic. To test whether oxidative stress plays a role in ATO-mediated apoptosis of myeloma cells, we looked at the induction of a stress response protein (HO-1), a marker of oxidative stress induced by ATO. Western blot analysis revealed that in all myeloma cells tested, HO-1 was dramatically and quickly induced by ATO and further induced by the addition of Trolox, indicating a pro-oxidant activity of Trolox in the malignant cells. While the mechanism of Trolox enhancement of ATO function remains largely unknown, intracellular concentrations of ATO in MM cells, as measured by inductively coupled plasma mass spectrometry, suggest that Trolox does not work by augmenting ATO import or intracellular accumulation. To test the efficacy of ATO with Trolox in vivo , we used a novel transgenic mouse model of MM that has been shown to faithfully mimic the human disease and its response to treatment (Chesi et al, Cancer Cell 2008 Feb;13(2):167-80). We first treated MM afflicted mice with a low dose of ATO (5.0mg/kg) and Trolox (50mg/kg) to assess for toxicity and tolerability. This dose was well tolerated in all mice when given for 10 days with no obvious toxic effects. Serum protein electrophoresis performed at the end of the 10 day treatment period revealed that even at this low starting dose, one of three mice showed a 30% reduction in its paraprotein peak, while the others remained stable. Further studies with higher ATO concentrations in the same mouse model are underway. In conclusion, these data support the role of ATO plus Trolox, as a promising anti-myeloma therapy. Disclosures No relevant conflicts of interest to declare.
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Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in malignant cell lines
Cancer Research, 2005Co-Authors: Zuanel Diaz, Myrian Colombo, Koren K Mann, Haixiang Su, Kamilah N Smith, Hyman M Schipper, D. Scott Bohle, Wilson H MillerAbstract:1716 Arsenic trioxide (As2O3) has its major clinical activity in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in most non-APL tumor cells. We looked for agents that would synergize with As2O3 to induce apoptosis in malignant cells, but not in normal cells. We found that Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a hydrophilic analogue of α-tocopherol with increased antioxidant capacity and cell permeability, enhances As2O3-mediated apoptosis in APL, CML, lymphoma, myeloma and breast cancer cells. α-tocopherol partially protected these cells from As2O3-mediated apoptosis, possibly due to its partitions into the lipid bilayer matrix of membranes. Treatment with As2O3 and Trolox increased intracellular oxidative stress, as evidenced by HO-1 protein levels, JNK activation, and protein and lipid oxidation. The synergistic effects of Trolox may be specific to As2O3, as Trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of Trolox radicals when Trolox was combined with As2O3, but not with doxorubicin. Importantly, Trolox protected non-malignant cells from As2O3-mediated cytotoxicity. Our data provide the first evidence that Trolox may extend the therapeutic spectrum of As2O3. Furthermore, the combination of As2O3 and Trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As2O3 monotherapy in vivo.
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Trolox selectively enhances arsenic mediated oxidative stress and apoptosis in apl and other malignant cell lines
Blood, 2005Co-Authors: Zuanel Diaz, Myrian Colombo, Koren K Mann, Haixiang Su, Kamilah N Smith, Scott D Bohle, Hyman M Schipper, Wilson H MillerAbstract:Although arsenic trioxide (As 2 O 3 ) is an effective therapy in acute promyelocytic leukemia (APL), its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in non-APL tumor cells. We looked for agents that would synergize with As 2 O 3 to induce apoptosis in malignant cells, but not in normal cells. We found that Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a widely known antioxidant, enhances As 2 O 3 -mediated apoptosis in APL, myeloma, and breast cancer cells. Treatment with As 2 O 3 and Trolox increased intracellular oxidative stress, as evidenced by heme oxygenase-1 (HO-1) protein levels, c-Jun terminal kinase (JNK) activation, and protein and lipid oxidation. The synergistic effects of Trolox may be specific to As 2 O 3 , as Trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of Trolox radicals when Trolox was combined with As 2 O 3 , but not with doxorubicin. Importantly, Trolox protected nonmalignant cells from As 2 O 3 -mediated cytotoxicity. Our data provide the first evidence that Trolox may extend the therapeutic spectrum of As 2 O 3 . Furthermore, the combination of As 2 O 3 and Trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As 2 O 3 monotherapy in vivo.
Borut Poljsak - One of the best experts on this subject based on the ideXlab platform.
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The antioxidant and pro‐oxidant activity of vitamin C and Trolox in vitro: a comparative study
Journal of Applied Toxicology, 2020Co-Authors: Borut Poljsak, Peter RasporAbstract:The antioxidant and pro-oxidant properties of ascorbic acid (vitamin C) and the water-soluble analogue of α-tocopherol (Trolox) were compared. Trolox has advantages over α-tocopherol, the latter being only lipid-soluble due to the presence of a carboxyl group in lieu of a phytol chain which imparts Trolox with water solubility. Trolox is used as a standard antioxidant in biochemical studies against which the antioxidant capacity of compounds is compared. Although ascorbic acid and tocopherols possess strong antioxidant properties, they might also exhibit pro-oxidant properties in the presence of free transition metals. Thus, reactions detailed in this study were performed in the presence of Cr(VI) in an effort to investigate the potential of ascorbic acid and Trolox to generate hydroxyl radicals in a Fenton-like reaction. Results obtained were derived from reactions containing the same concentration of ascorbic acid and Trolox under identical experimental conditions. Hydroxyl radical formation was observed in the reaction of Cr(VI) with ascorbic acid resulting from ascorbic acid auto-oxidation and H2O2 formation. Hydroxyl radical formation was only detected in the reaction mixture containing Cr(VI) and Trolox following the addition of H2O2. Copyright © 2007 John Wiley & Sons, Ltd.
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the antioxidant and pro oxidant activity of vitamin c and Trolox in vitro a comparative study
Journal of Applied Toxicology, 2008Co-Authors: Borut Poljsak, Peter RasporAbstract:The antioxidant and pro-oxidant properties of ascorbic acid (vitamin C) and the water-soluble analogue of α-tocopherol (Trolox) were compared. Trolox has advantages over α-tocopherol, the latter being only lipid-soluble due to the presence of a carboxyl group in lieu of a phytol chain which imparts Trolox with water solubility. Trolox is used as a standard antioxidant in biochemical studies against which the antioxidant capacity of compounds is compared. Although ascorbic acid and tocopherols possess strong antioxidant properties, they might also exhibit pro-oxidant properties in the presence of free transition metals. Thus, reactions detailed in this study were performed in the presence of Cr(VI) in an effort to investigate the potential of ascorbic acid and Trolox to generate hydroxyl radicals in a Fenton-like reaction. Results obtained were derived from reactions containing the same concentration of ascorbic acid and Trolox under identical experimental conditions. Hydroxyl radical formation was observed in the reaction of Cr(VI) with ascorbic acid resulting from ascorbic acid auto-oxidation and H2O2 formation. Hydroxyl radical formation was only detected in the reaction mixture containing Cr(VI) and Trolox following the addition of H2O2. Copyright © 2007 John Wiley & Sons, Ltd.
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Pro-oxidative versus antioxidative reactions between Trolox and Cr(VI): The role of H2O2
Environmental Toxicology and Pharmacology, 2006Co-Authors: Borut Poljsak, S Plesnicar, Zoltan Gazdag, Miklos Pesti, Spela Jenko-brinovec, Joseph Belagyi, Peter RasporAbstract:Abstract The effect of the Vitamin E model compound Trolox in reactions with Cr(VI) in the presence or absence of hydrogen peroxide was investigated. The aim of this study was to establish and discuss potential Trolox-mediated pro-oxidative reactions. The importance of the Trolox:Cr(VI) ratio in the Cr(VI) reduction process was determined from the EPR spectra and DNA cleavage reactions. In the absence of hydrogen peroxide, reduction of Cr(VI) occurred with concomitant oxidation of Trolox to the phenoxyl radical. In the presence of hydrogen peroxide, Cr(V), produced by the reduction of Cr(VI), reduced hydrogen peroxide to the hydroxyl radical. The latter was detected by spin-trapping the methyl radical following reaction with N -methyl sulfoxide. During Cr(VI) reduction with Trolox, DNA single- or double-strand breaks due to Trolox radical formation were not observed. Relaxed DNA appeared only when H 2 O 2 was added to Trolox/Cr(VI) mixtures most probably due to hydroxyl radical formation during the redox cycling of Cr(V/IV)-species. Fenton-like reactions do not play a significant role in the Trolox/Cr(VI) system in the absence of added H 2 O 2 .
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prevention of intracellular oxidation in yeast the role of vitamin e analogue Trolox 6 hydroxy 2 5 7 8 tetramethylkroman 2 carboxyl acid
Cell Biology International, 2005Co-Authors: Peter Raspor, S Plesnicar, Zoltan Gazdag, Miklos Pesti, M Miklavcic, R Logarmarinsek, Borut PoljsakAbstract:Abstract Reactive oxygen species (ROS) are not only generated in conditions of cellular stress but are also constitutively produced in most cell types by specific metabolic processes. This research focused on a potential antioxidant Trolox (model compound for α-tocopherol), with the aim to establish exact mechanisms of Trolox intracellular oxidation prevention on model organism Saccharomyces cerevisiae . Measuring intracellular oxidation of Trolox-treated yeast cells revealed that Trolox decreased intracellular oxidation during normal metabolism. Trolox treatment decreased cyto- and geno-toxicity of treated yeast cells in MES buffer, lowered intracellular oxidation, decreased intracellular peroxides formation, and increased H 2 O 2 degradation and superoxide quenching yeast extract ability. This study suggests that Trolox treatment provides prevention against intracellular ROS formation. Trolox application as therapeutic agent against intracellular ROS formation would be worth considering. Additionally, results indicate that yeasts are good model organisms for studying intracellular oxidation and oxidative stress. The obtained results on yeast cells might be useful to direct further human-related search for the Trolox evaluation as a human supplement used for protecting cells against intracellular free radical formation.
Guler Temizkan - One of the best experts on this subject based on the ideXlab platform.
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intracellular scavenging activity of Trolox 6 hydroxy 2 5 7 8 tetramethylchromane 2 carboxylic acid in the fission yeast schizosaccharomyces pombe
Journal of natural science biology and medicine, 2010Co-Authors: Ismail Hamad, Nazli Arda, Murat Pekmez, Semian Karaer, Guler TemizkanAbstract:The ability of Trolox (6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid), a water-soluble vitamin E analogue, to prevent oxidative damages is well characterized, but the mechanisms underlying it remain unclear. The protective effect of Trolox pre-treatment on H 2 O 2 -induced toxicity might be attributed to the decreased cellular permeability to H 2 O 2 or in vitro scavenging activity of Trolox, induction of antioxidant enzymes or the direct scavenging activity of Trolox. The results obtained rule out the first and second possibilities and intracellular scavenging activity was found to be the mechanism whereby Trolox confers protection. This was confirmed by measuring protein oxidation (levels), and the observed decrease in proteasomal activity indicated that the decrease in protein carbonyls was due to Trolox scavenging activity rather than proteasome activation. In conclusion, the intracellular scavenging activity of Trolox is a key protective mechanism against H 2 O 2 . These findings obtained in Schizosaccharomyces pombe, a good model organism for eukaryotic cells, can be used as standard protocols for investigating the antioxidant activity of pure or complex potential antioxidants.
Peter Raspor - One of the best experts on this subject based on the ideXlab platform.
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The antioxidant and pro‐oxidant activity of vitamin C and Trolox in vitro: a comparative study
Journal of Applied Toxicology, 2020Co-Authors: Borut Poljsak, Peter RasporAbstract:The antioxidant and pro-oxidant properties of ascorbic acid (vitamin C) and the water-soluble analogue of α-tocopherol (Trolox) were compared. Trolox has advantages over α-tocopherol, the latter being only lipid-soluble due to the presence of a carboxyl group in lieu of a phytol chain which imparts Trolox with water solubility. Trolox is used as a standard antioxidant in biochemical studies against which the antioxidant capacity of compounds is compared. Although ascorbic acid and tocopherols possess strong antioxidant properties, they might also exhibit pro-oxidant properties in the presence of free transition metals. Thus, reactions detailed in this study were performed in the presence of Cr(VI) in an effort to investigate the potential of ascorbic acid and Trolox to generate hydroxyl radicals in a Fenton-like reaction. Results obtained were derived from reactions containing the same concentration of ascorbic acid and Trolox under identical experimental conditions. Hydroxyl radical formation was observed in the reaction of Cr(VI) with ascorbic acid resulting from ascorbic acid auto-oxidation and H2O2 formation. Hydroxyl radical formation was only detected in the reaction mixture containing Cr(VI) and Trolox following the addition of H2O2. Copyright © 2007 John Wiley & Sons, Ltd.
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the antioxidant and pro oxidant activity of vitamin c and Trolox in vitro a comparative study
Journal of Applied Toxicology, 2008Co-Authors: Borut Poljsak, Peter RasporAbstract:The antioxidant and pro-oxidant properties of ascorbic acid (vitamin C) and the water-soluble analogue of α-tocopherol (Trolox) were compared. Trolox has advantages over α-tocopherol, the latter being only lipid-soluble due to the presence of a carboxyl group in lieu of a phytol chain which imparts Trolox with water solubility. Trolox is used as a standard antioxidant in biochemical studies against which the antioxidant capacity of compounds is compared. Although ascorbic acid and tocopherols possess strong antioxidant properties, they might also exhibit pro-oxidant properties in the presence of free transition metals. Thus, reactions detailed in this study were performed in the presence of Cr(VI) in an effort to investigate the potential of ascorbic acid and Trolox to generate hydroxyl radicals in a Fenton-like reaction. Results obtained were derived from reactions containing the same concentration of ascorbic acid and Trolox under identical experimental conditions. Hydroxyl radical formation was observed in the reaction of Cr(VI) with ascorbic acid resulting from ascorbic acid auto-oxidation and H2O2 formation. Hydroxyl radical formation was only detected in the reaction mixture containing Cr(VI) and Trolox following the addition of H2O2. Copyright © 2007 John Wiley & Sons, Ltd.
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Pro-oxidative versus antioxidative reactions between Trolox and Cr(VI): The role of H2O2
Environmental Toxicology and Pharmacology, 2006Co-Authors: Borut Poljsak, S Plesnicar, Zoltan Gazdag, Miklos Pesti, Spela Jenko-brinovec, Joseph Belagyi, Peter RasporAbstract:Abstract The effect of the Vitamin E model compound Trolox in reactions with Cr(VI) in the presence or absence of hydrogen peroxide was investigated. The aim of this study was to establish and discuss potential Trolox-mediated pro-oxidative reactions. The importance of the Trolox:Cr(VI) ratio in the Cr(VI) reduction process was determined from the EPR spectra and DNA cleavage reactions. In the absence of hydrogen peroxide, reduction of Cr(VI) occurred with concomitant oxidation of Trolox to the phenoxyl radical. In the presence of hydrogen peroxide, Cr(V), produced by the reduction of Cr(VI), reduced hydrogen peroxide to the hydroxyl radical. The latter was detected by spin-trapping the methyl radical following reaction with N -methyl sulfoxide. During Cr(VI) reduction with Trolox, DNA single- or double-strand breaks due to Trolox radical formation were not observed. Relaxed DNA appeared only when H 2 O 2 was added to Trolox/Cr(VI) mixtures most probably due to hydroxyl radical formation during the redox cycling of Cr(V/IV)-species. Fenton-like reactions do not play a significant role in the Trolox/Cr(VI) system in the absence of added H 2 O 2 .
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prevention of intracellular oxidation in yeast the role of vitamin e analogue Trolox 6 hydroxy 2 5 7 8 tetramethylkroman 2 carboxyl acid
Cell Biology International, 2005Co-Authors: Peter Raspor, S Plesnicar, Zoltan Gazdag, Miklos Pesti, M Miklavcic, R Logarmarinsek, Borut PoljsakAbstract:Abstract Reactive oxygen species (ROS) are not only generated in conditions of cellular stress but are also constitutively produced in most cell types by specific metabolic processes. This research focused on a potential antioxidant Trolox (model compound for α-tocopherol), with the aim to establish exact mechanisms of Trolox intracellular oxidation prevention on model organism Saccharomyces cerevisiae . Measuring intracellular oxidation of Trolox-treated yeast cells revealed that Trolox decreased intracellular oxidation during normal metabolism. Trolox treatment decreased cyto- and geno-toxicity of treated yeast cells in MES buffer, lowered intracellular oxidation, decreased intracellular peroxides formation, and increased H 2 O 2 degradation and superoxide quenching yeast extract ability. This study suggests that Trolox treatment provides prevention against intracellular ROS formation. Trolox application as therapeutic agent against intracellular ROS formation would be worth considering. Additionally, results indicate that yeasts are good model organisms for studying intracellular oxidation and oxidative stress. The obtained results on yeast cells might be useful to direct further human-related search for the Trolox evaluation as a human supplement used for protecting cells against intracellular free radical formation.
