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1.
Redox Biol ; 26: 101237, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31276937

RESUMO

Extracellular vesicles (EVs) generated from redox active anticancer drugs are released into the extracellular environment. These EVs contain oxidized molecules and trigger inflammatory responses by macrophages. Using a mouse model of doxorubicin (DOX)-induced tissue injury, we previously found that the major sources of circulating EVs are from heart and liver, organs that are differentially affected by DOX. Here, we investigated the effects of EVs from cardiomyocytes and those from hepatocytes on macrophage activation. EVs from H9c2 rat cardiomyocytes (H9c2 EVs) and EVs from FL83b mouse hepatocytes (FL83 b EVs) have different levels of protein-bound 4-hydroxynonenal and thus different immunostimulatory effects on mouse RAW264.7 macrophages. H9c2 EVs but not FL83 b EVs induced both pro-inflammatory and anti-inflammatory macrophage activation, mediated by NFκB and Nrf-2 pathways, respectively. DOX enhanced the effects of H9c2 EVs but not FL83 b EVs. While EVs from DOX-treated H9c2 cells (H9c2 DOXEVs) suppressed mitochondrial respiration and increased glycolysis of macrophages, EVs from DOX-treated FL83b cells (FL83b DOXEVs) enhanced mitochondrial reserve capacity. Mechanistically, the different immunostimulatory functions of H9c2 EVs and FL83 b EVs are regulated, in part, by the redox status of the cytoplasmic thioredoxin 1 (Trx1) of macrophages. H9c2 DOXEVs lowered the level of reduced Trx1 in cytoplasm while FL83b DOXEVs did the opposite. Trx1 overexpression alleviated the effect of H9c2 DOXEVs on NFκB and Nrf-2 activation and prevented the upregulation of their target genes. Our findings identify EVs as a novel Trx1-mediated redox mediator of immune response, which greatly enhances our understanding of innate immune responses during cancer therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Vesículas Extracelulares/imunologia , Hepatócitos/química , Miócitos Cardíacos/química , Tiorredoxinas/imunologia , Aldeídos/imunologia , Aldeídos/metabolismo , Aldeídos/farmacologia , Animais , Linhagem Celular , Meios de Cultivo Condicionados/química , Vesículas Extracelulares/química , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Hepatócitos/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Oxirredução , Células RAW 264.7 , Ratos , Tiorredoxinas/genética
2.
J Biol Chem ; 294(17): 6831-6842, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30858178

RESUMO

Mitochondria are major sites of energy metabolism that influence numerous cellular events, including immunity and cancer development. Previously, we reported that the mitochondrion-specific antioxidant enzyme, manganese-containing superoxide dismutase (MnSOD), has dual roles in early- and late-carcinogenesis stages. However, how defective MnSOD impacts the chain of events that lead to cell transformation in pathologically normal epidermal cells that have been exposed to carcinogens is unknown. Here, we show that UVB radiation causes nitration and inactivation of MnSOD leading to mitochondrial injury and mitophagy. In keratinocytes, exposure to UVB radiation decreased mitochondrial oxidative phosphorylation, increased glycolysis and the expression of autophagy-related genes, and enhanced AKT Ser/Thr kinase (AKT) phosphorylation and cell growth. Interestingly, UVB initiated a prosurvival mitophagy response by mitochondria-mediated reactive oxygen species (ROS) signaling via the mammalian target of the mTOR complex 2 (mTORC2) pathway. Knockdown of rictor but not raptor abrogated UVB-induced mitophagy responses. Furthermore, fractionation and proximity-ligation assays reveal that ROS-mediated mTOC2 activation in mitochondria is necessary for UVB-induced mitophagy. Importantly, pretreatment with the MnSOD mimic MnTnBuOE-2-PyP5+ (MnP) attenuates mTORC2 activation and suppresses UVB-induced mitophagy. UVB radiation exposure also increased cell growth as assessed by soft-agar colony survival and cell growth assays, and pretreatment with MnP or the known autophagy inhibitor 3-methyladenine abrogated UVB-induced cell growth. These results indicate that MnSOD is a major redox regulator that maintains mitochondrial health and show that UVB-mediated MnSOD inactivation promotes mitophagy and thereby prevents accumulation of damaged mitochondria.


Assuntos
Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/antagonistas & inibidores , Raios Ultravioleta , Animais , Autofagia/fisiologia , Linhagem Celular , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Nitratos/metabolismo , Oxirredução , Proteína Companheira de mTOR Insensível à Rapamicina/fisiologia , Proteína Regulatória Associada a mTOR/fisiologia
3.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1088-1097, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30759363

RESUMO

Increasing numbers of cancer patients survive and live longer than five years after therapy, but very often side effects of cancer treatment arise at same time. One of the side effects, chemotherapy-induced cognitive impairment (CICI), also called "chemobrain" or "chemofog" by patients, brings enormous challenges to cancer survivors following successful chemotherapeutic treatment. Decreased abilities of learning, memory, attention, executive function and processing speed in cancer survivors with CICI, are some of the challenges that greatly impair survivors' quality of life. The molecular mechanisms of CICI involve very complicated processes, which have been the subject of investigation over the past decades. Many mechanistic candidates have been studied including disruption of the blood-brain barrier (BBB), DNA damage, telomere shortening, oxidative stress and associated inflammatory response, gene polymorphism of neural repair, altered neurotransmission, and hormone changes. Oxidative stress is considered as a vital mechanism, since over 50% of FDA-approved anti-cancer drugs can generate reactive oxygen species (ROS) or reactive nitrogen species (RNS), which lead to neuronal death. In this review paper, we discuss these important candidate mechanisms, in particular oxidative stress and the cytokine, TNF-alpha and their potential roles in CICI.


Assuntos
Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Sobreviventes de Câncer/estatística & dados numéricos , Disfunção Cognitiva/fisiopatologia , Neoplasias/fisiopatologia , Qualidade de Vida , Antineoplásicos/uso terapêutico , Encéfalo/patologia , Encéfalo/fisiopatologia , Sobreviventes de Câncer/psicologia , Disfunção Cognitiva/induzido quimicamente , Humanos , Memória/efeitos dos fármacos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Estresse Oxidativo/efeitos dos fármacos
4.
Cell Chem Biol ; 26(3): 366-377.e12, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30661989

RESUMO

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Glutarredoxinas/metabolismo , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutarredoxinas/antagonistas & inibidores , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Nus , Naftoquinonas/química , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peroxirredoxinas/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
5.
Free Radic Biol Med ; 134: 1-8, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30593843

RESUMO

Cancer treatments are developing fast and the number of cancer survivors could arise to 20 million in United State by 2025. However, a large fraction of cancer survivors demonstrate cognitive dysfunction and associated decreased quality of life both shortly, and often long-term, after chemotherapy treatment. The etiologies of chemotherapy induced cognitive impairment (CICI) are complicated, made more so by the fact that many anti-cancer drugs cannot cross the blood-brain barrier (BBB). Multiple related factors and confounders lead to difficulties in determining the underlying mechanisms. Chemotherapy induced, oxidative stress-mediated tumor necrosis factor-alpha (TNF-α) elevation was considered as one of the main candidate mechanisms underlying CICI. Doxorubicin (Dox) is a prototypical reactive oxygen species (ROS)-generating chemotherapeutic agent used to treat solid tumors and lymphomas as part of multi-drug chemotherapeutic regimens. We previously reported that peripheral Dox-administration leads to plasma protein damage and elevation of TNF-α in plasma and brain of mice. In the present study, we used TNF-α null (TNFKO) mice to investigate the role of TNF-α in Dox-induced, oxidative stress-mediated alterations in brain. We report that Dox-induced oxidative stress in brain is ameliorated and brain mitochondrial function assessed by the Seahorse-determined oxygen consumption rate (OCR) is preserved in brains of TNFKO mice. Further, we show that Dox-decreased the level of hippocampal choline-containing compounds and brain phospholipases activity are partially protected in TNFKO group in MRS study. Our results provide strong evidence that Dox-targeted mitochondrial damage and levels of brain choline-containing metabolites, as well as phospholipases changes decreased in the CNS are associated with oxidative stress mediated by TNF-α. These results are consistent with the notion that oxidative stress and elevated TNF-α in brain underlie the damage to mitochondria and other pathological changes that lead to CICI. The results are discussed with reference to our identifying a potential therapeutic target to protect against cognitive problems after chemotherapy.

6.
Oncogene ; 37(48): 6225-6242, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30038268

RESUMO

Autophagy is a highly regulated evolutionarily conserved metabolic process induced by stress and energy deprivation. Here, we show that DNA polymerase gamma (Polγ) deficiency activates a selective prosurvival autophagic response via mitochondria-mediated reactive oxygen species (ROS) signaling and the mammalian target of rapamycin complex 2 (mTORC2) activities. In keratinocytes, Polγ deficiency causes metabolic adaptation that triggers cytosolic sensing of energy demand for survival. Knockdown of Polγ causes mitochondrial stress, decreases mitochondrial energy production, increases glycolysis, increases the expression of autophagy-associated genes, and enhances AKT phosphorylation and cell proliferation. Deficiency of Polγ preferentially activates mTORC2 formation to increase autophagy and cell proliferation, and knocking down Rictor abrogates these responses. Overexpression of Rictor, but not Raptor, reactivates autophagy in Polγ-deficient cells. Importantly, inhibition of ROS by a mitochondria-selective ROS scavenger abolishes autophagy and cell proliferation. These results identify Rictor as a critical link between mitochondrial stress, ROS, and autophagy. They represent a major shift in our understanding of the prosurvival role of the mTOR complexes and highlight mitochondria-mediated ROS as a prosurvival autophagy regulator during cancer development.


Assuntos
Autofagia/fisiologia , Polimerase do DNA Mitocondrial/deficiência , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Glicólise/fisiologia , Humanos , Queratinócitos/metabolismo , Camundongos , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
Free Radic Biol Med ; 117: 99-109, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29421238

RESUMO

AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2•- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. CONCLUSION: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Neoplasias da Próstata/patologia , Superóxido Dismutase/metabolismo , Microambiente Tumoral/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Oxirredução , Neoplasias da Próstata/metabolismo
8.
Antioxid Redox Signal ; 29(13): 1237-1272, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325444

RESUMO

SIGNIFICANCE: Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies. CRITICAL ISSUES: The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment. FUTURE DIRECTIONS: Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
9.
Clin Cancer Res ; 24(7): 1644-1653, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29070527

RESUMO

Purpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EV) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury.Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content.Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EV) compared with saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury.Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury. Clin Cancer Res; 24(7); 1644-53. ©2017 AACRSee related commentary by Zhu and Gius, p. 1516.


Assuntos
Biomarcadores/metabolismo , Doxorrubicina/farmacologia , Vesículas Extracelulares/metabolismo , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Aldeídos/metabolismo , Animais , Encéfalo/metabolismo , Cardiotoxicidade/metabolismo , Modelos Animais de Doenças , Cinética , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Proteoma/metabolismo , Proteômica/métodos , Superóxido Dismutase/metabolismo
10.
Antioxid Redox Signal ; 29(16): 1612-1632, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29084438

RESUMO

SIGNIFICANCE: The long-term hematopoietic stem cell (LT-HSC) demonstrates characteristics of self-renewal and the ability to manage expansion of the hematopoietic compartment while maintaining the capacity for differentiation into hematopoietic stem/progenitor cell (HSPC) and terminal subpopulations. Deregulation of the HSPC redox environment results in loss of signaling that normally controls HSPC fate, leading to a loss of HSPC function and exhaustion. The characteristics of HSPC exhaustion via redox stress closely mirror phenotypic traits of hematopoietic malignancies and the leukemic stem cell (LSC). These facets elucidate the HSC/LSC redox environment as a druggable target and a growing area of cancer research. Recent Advances: Although myelosuppression and exhaustion of the hematopoietic niche are detrimental side effects of classical chemotherapies, new agents that modify the HSPC/LSC redox environment have demonstrated the potential for protection of normal HSPC function while inducing cytotoxicity within malignant populations. CRITICAL ISSUES: New therapies must preserve, or only slightly disturb normal HSPC redox balance and function, while simultaneously altering the malignant cellular redox state. The cascade nature of redox damage makes this a critical and delicate line for the development of a redox-based therapeutic index. FUTURE DIRECTIONS: Recent evidence demonstrates the potential for redox-based therapies to impact metabolic and epigenetic factors that could contribute to initial LSC transformation. This is balanced by the development of therapies that protect HSPC function. This pushes toward therapies that may alter the HSC/LSC redox state but lead to initiation cell fate signaling lost in malignant transformation while protecting normal HSPC function. Antioxid. Redox Signal.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Animais , Células-Tronco Hematopoéticas/metabolismo , Humanos , Oxirredução
11.
Oncotarget ; 8(44): 77436-77452, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100399

RESUMO

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS.

12.
Antioxidants (Basel) ; 6(4)2017 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-28956814

RESUMO

The short- and long-term side effects of chemotherapy limit the maximum therapeutic dose and impair quality of life of survivors. Injury to normal tissues, especially chemotherapy-induced cardiomyopathy, is an unintended outcome that presents devastating health impacts. Approximately half of the drugs approved by the Food and Drug Administration for cancer treatment are associated with the generation of reactive oxygen species, and Doxorubicin (Dox) is one of them. Dox undergoes redox cycling by involving its quinone structure in the production of superoxide free radicals, which are thought to be instrumental to the role it plays in cardiomyopathy. Dox-induced protein oxidation changes protein function, translocation, and aggregation that are toxic to cells. To maintain cellular homeostasis, oxidized proteins can be degraded intracellularly by ubiquitin-proteasome pathway or by autophagy, depending on the redox status of the cell. Alternatively, the cell can remove oxidized proteins by releasing extracellular vesicles (EVs), which can be transferred to neighboring or distant cells, thereby instigating an intercellular oxidative stress response. In this article, we discuss the role of EVs in oxidative stress response, the potential of EVs as sensitive biomarkers of oxidative stress, and the role of superoxide dismutase in attenuating EV-associated oxidative stress response resulting from chemotherapy.

13.
Handb Exp Pharmacol ; 240: 439-456, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28176043

RESUMO

Mitochondria are a major source of intracellular energy and reactive oxygen species in cells, but are also increasingly being recognized as a controller of cell death. Here, we review evidence of signal transduction control by mitochondrial superoxide generation via the nuclear factor-κB (NF-κB) and GATA signaling pathways. We have also reviewed the effects of ROS on the activation of MMP and HIF. There is significant evidence to support the hypothesis that mitochondrial superoxide can initiate signaling pathways following transport into the cytosol. In this study, we provide evidence of TATA signal transductions by mitochondrial superoxide. Oxidative phosphorylation via the electron transfer chain, glycolysis, and generation of superoxide from mitochondria could be important factors in regulating signal transduction, cellular homeostasis, and cell death.


Assuntos
Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , NF-kappa B/fisiologia
14.
Cancer Res ; 77(6): 1345-1356, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108513

RESUMO

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings. Cancer Res; 77(6); 1345-56. ©2017 AACR.


Assuntos
Ácido Ascórbico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Radiossensibilizantes/farmacologia , Fator de Transcrição RelB/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Nus , Estresse Oxidativo/efeitos da radiação , Próstata/citologia , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Pharmacol Res ; 117: 267-273, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28063894

RESUMO

One of the major complaints patients who survive cancer often make is chemotherapy induced cognitive impairment (CICI), which survivors often call "chemo brain." CICI is a side effect of chemotherapy due to the cytotoxicity and neurotoxicity of anti-cancer drugs causing structural and functional changes in brain, even when drugs that do not cross the blood brain barrier (BBB) are used. Diminished cognitive functions including diminution of learning and memory, concentration and attention, processing speed and executive functions that reduce quality of life and ability to work are common signs and symptoms of CICI. There still is not a clarified and complete mechanism for CICI, but researchers have pointed to several biochemical candidates. Chemotherapy-induced, cytokine-mediated involvement in CICI will be mainly discussed in this review paper with emphasis on different types of cytokines, correlated with BBB and epigenetic changes. Mechanisms of ROS-generating, anti-cancer drugs and their relation to cytokine-mediated CICI will be emphasized.


Assuntos
Antineoplásicos/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Citocinas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Humanos , Neoplasias/tratamento farmacológico
16.
PLoS One ; 12(1): e0169767, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28081176

RESUMO

An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis-p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA) nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies.


Assuntos
Apoptose/efeitos da radiação , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Radiação Ionizante , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos da radiação , Células Cultivadas , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Proteína 1 de Resposta de Crescimento Precoce/genética , Histonas/genética , Histonas/metabolismo , Camundongos , Microscopia de Fluorescência , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Tíbia/citologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos da radiação , Irradiação Corporal Total
17.
J Cell Sci ; 130(1): 190-202, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27656113

RESUMO

Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor κB (NF-κB) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is a crucial regulator that links cell polarity and ROS generation. We also linked monocyte infiltration with disruption of polarized acinar structure using a 3D co-culture system. Gain- and loss-of-function experiments demonstrated that increased ROS in non-polarized cells is necessary and sufficient to enhance monocyte recruitment. ROS also induced cytokine expression and NF-κB activity. These results suggest that increased ROS production in mammary epithelial cell leads to disruption of cell polarity and promotes monocyte infiltration.


Assuntos
Técnicas de Cultura de Células/métodos , Polaridade Celular , Células Epiteliais/citologia , Glândulas Mamárias Humanas/citologia , Monócitos/citologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular , Citocinas/metabolismo , Células Epiteliais/metabolismo , Humanos , Monócitos/metabolismo , NF-kappa B/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
18.
Free Radic Biol Med ; 97: 85-94, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27212018

RESUMO

Cellular redox balance plays a significant role in the regulation of hematopoietic stem-progenitor cell (HSC/MPP) self-renewal and differentiation. Unregulated changes in cellular redox homeostasis are associated with the onset of most hematological disorders. However, accurate measurement of the redox state in stem cells is difficult because of the scarcity of HSC/MPPs. Glutathione (GSH) constitutes the most abundant pool of cellular antioxidants. Thus, GSH metabolism may play a critical role in hematological disease onset and progression. A major limitation to studying GSH metabolism in HSC/MPPs has been the inability to measure quantitatively GSH concentrations in small numbers of HSC/MPPs. Current methods used to measure GSH levels not only rely on large numbers of cells, but also rely on the chemical/structural modification or enzymatic recycling of GSH and therefore are likely to measure only total glutathione content accurately. Here, we describe the validation of a sensitive method used for the direct and simultaneous quantitation of both oxidized and reduced GSH via liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) in HSC/MPPs isolated from bone marrow. The lower limit of quantitation (LLOQ) was determined to be 5.0ng/mL for GSH and 1.0ng/mL for GSSG with lower limits of detection at 0.5ng/mL for both glutathione species. Standard addition analysis utilizing mouse bone marrow shows that this method is both sensitive and accurate with reproducible analyte recovery. This method combines a simple extraction with a platform for the high-throughput analysis, allows for efficient determination of GSH/GSSG concentrations within the HSC/MPP populations in mouse, chemotherapeutic treatment conditions within cell culture, and human normal/leukemia patient samples. The data implicate the importance of the modulation of GSH/GSSG redox couple in stem cells related diseases.


Assuntos
Cromatografia Líquida/métodos , Dissulfeto de Glutationa/isolamento & purificação , Glutationa/isolamento & purificação , Espectrometria de Massas em Tandem/métodos , Animais , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células MCF-7 , Camundongos , Oxirredução , Estresse Oxidativo
19.
Arch Biochem Biophys ; 595: 54-60, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27095216

RESUMO

Prof. Dr. Helmut Sies is a pioneer of "Oxidative Stress", and has published over 18 papers with the name of "Oxidative Stress" in the title. He has been Editor-in-Chief of the journal "Archives of Biochemistry and Biophysics" for many years, and is a former Editor-in-Chief of the journal "Free Radical Research". He has clarified our understanding of the causes of chronic developing diseases, and has studied antioxidant factors. In this article, importance of "Oxidative Stress" and our mitochondrial oxidative stress studies; roles of mitochondrial ROS, effects of vitamin E and its homologues in oxidative stress-related diseases, effects of antioxidants in vivo and in vitro, and a mitochondrial superoxide theory for oxidative stress diseases and aging are introduced, and some of our interactions with Helmut are described, congratulating and appreciating his great path.


Assuntos
Estresse Oxidativo , Envelhecimento , Antioxidantes , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Vitamina E/fisiologia
20.
Free Radic Biol Med ; 91: 68-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26689472

RESUMO

Cardiovascular complications are major side effects of many anticancer drugs. Accumulated evidence indicates that oxidative stress in mitochondria plays an important role in cardiac injury, but how mitochondrial redox mechanisms are involved in cardiac dysfunction remains unclear. Here, we demonstrate that 4-hydroxy-2-nonenal (HNE) activates the translocation of the mitochondrial apoptosis inducing factor (AIFm2) and facilitates apoptosis in heart tissue of mice and humans. Doxorubicin treatments significantly enhance cardiac levels of HNE and AIFm2. HNE adduction of AIFm2 inactivates the NADH oxidoreductase activity of AIFm2 and facilitates its translocation from mitochondria. His 174 on AIFm2 is the critical target of HNE adduction that triggers this functional switch. HNE adduction and translocation of AIFm2 from mitochondria upon Doxorubicin treatment are attenuated by superoxide dismutase mimetics. These results identify a previously unrecognized role of HNE with important consequences for mitochondrial stress signaling, heart failure, and the side effects of cancer therapy.


Assuntos
Aldeídos/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Mitocôndrias Cardíacas/metabolismo , Estresse Oxidativo , Oxirredutases/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Apoptose , Doxorrubicina/toxicidade , Cardiopatias/induzido quimicamente , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/efeitos dos fármacos , Oxirredução , Transporte Proteico , Transdução de Sinais
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