scholarly journals Control of Oxidative Stress in Cancer Chemoresistance: Spotlight on Nrf2 Role

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 510
Author(s):  
Giuseppina Barrera ◽  
Marie Angele Cucci ◽  
Margherita Grattarola ◽  
Chiara Dianzani ◽  
Giuliana Muzio ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Targeted Therapy ◽  
Cancer Cells ◽  
Antioxidant Response ◽  
Redox Status ◽  
Antioxidant Systems ◽  
Drug Induced ◽  
Transcriptional Coactivators ◽  
Metabolic Remodeling

Chemoresistance represents the main obstacle to cancer treatment with both conventional and targeted therapy. Beyond specific molecular alterations, which can lead to targeted therapy, metabolic remodeling, including the control of redox status, plays an important role in cancer cell survival following therapy. Although cancer cells generally have a high basal reactive oxygen species (ROS) level, which makes them more susceptible than normal cells to a further increase of ROS, chemoresistant cancer cells become highly adapted to intrinsic or drug-induced oxidative stress by upregulating their antioxidant systems. The antioxidant response is principally mediated by the transcription factor Nrf2, which has been considered the master regulator of antioxidant and cytoprotective genes. Nrf2 expression is often increased in several types of chemoresistant cancer cells, and its expression is mediated by diverse mechanisms. In addition to Nrf2, other transcription factors and transcriptional coactivators can participate to maintain the high antioxidant levels in chemo and radio-resistant cancer cells. The control of expression and function of these molecules has been recently deepened to identify which of these could be used as a new therapeutic target in the treatment of tumors resistant to conventional therapy. In this review, we report the more recent advances in the study of Nrf2 regulation in chemoresistant cancers and the role played by other transcription factors and transcriptional coactivators in the control of antioxidant responses in chemoresistant cancer cells.

scholarly journals Albendazole Exhibits Anti-Neoplastic Actions against Gastric Cancer Cells by Affecting STAT3 and STAT5 Activation by Pleiotropic Mechanism(s)

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 362
Author(s):  
Min Hee Yang ◽  
In Jin Ha ◽  
Jae-Young Um ◽  
Kwang Seok Ahn
Keyword(s):  
Gastric Cancer ◽  
Reactive Oxygen Species ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Small Interfering Rna ◽  
Oxygen Species ◽  
Gastric Cancer Cells ◽  
Drug Induced ◽  
Cellular Apoptosis ◽  
Interfering Rna

Albendazole (ABZ) has been reported to display anti-tumoral actions against various maliganncies, but possible impact of ABZ on gastric cancer has not been deciphered. As aberrant phosphorylation of STAT3 and STAT5 proteins can regulate the growth and progression of gastric cancer, we postulated that ABZ may interrupt the activation of these oncogenic transcription factors. We found that ABZ exposure abrogated STAT3/5 activation, inhibited phosphorylation of Janus-activated kinases 1/2 and Src and enhanced the levels of SHP-1 protein. Silencing of SHP-1 gene by small interfering RNA (siRNA) reversed the ABZ-promoted attenuation of STAT3 as well as STAT5 activation and cellular apoptosis. In addition, these effects were noted to be driven by an augmented levels of reactive oxygen species caused by drug-induced GSH/GSSG imbalance. Thus, the data indicates that ABZ can modulate the activation of STAT3 and STAT5 by pleiotropic mechanisms in gastric cancer cells.

scholarly journals Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1138
Author(s):  
Martina Schiavello ◽  
Elena Gazzano ◽  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Roberta Libener ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Malignant Pleural Mesothelioma ◽  
Antioxidant Defense ◽  
Asbestos Exposure ◽  
Predictive Biomarkers ◽  
Antioxidant Systems ◽  
Pleural Mesothelioma ◽  
Related Factor ◽  
Aggressive Cancer

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.

scholarly journals Salivary Biomarkers of Oxidative Stress in Children with Chronic Kidney Disease

2018 ◽  
Vol 7 (8) ◽  
pp. 209 ◽  
Author(s):  
Mateusz Maciejczyk ◽  
Julita Szulimowska ◽  
Anna Skutnik ◽  
Katarzyna Taranta-Janusz ◽  
Anna Wasilewska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Oxidative Damage ◽  
Diagnostic Value ◽  
Redox Status ◽  
Stress Index ◽  
Antioxidant Systems ◽  
Control Group ◽  
Potential Biomarker

There are still missing non-invasive biomarkers of chronic kidney disease (CKD) in children. Therefore, the aim of the study was to evaluate oxidative stress indicators in the non-stimulated (NWS) and stimulated saliva (SWS) of CKD children (n = 25) and healthy controls (n = 25). Salivary antioxidants (catalase (CAT), peroxidase (Px), superoxide dismutase (SOD), uric acid (UA), reduced glutathione (GSH), albumin), redox status (total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI)), and oxidative damage products (advanced glycation end products (AGE), advanced oxidation protein products (AOPP), malondialdehyde (MDA)) were evaluated. We have demonstrated the significantly higher activity of SWS GPx and SOD, as well as elevated concentrations of UA and albumin in NWS and SWS of CKD children vs. the control group. TAC, TOS and OSI were significantly higher only in SWS, while oxidative damage products (AGE, AOPP and MDA) were significantly higher in both NWS and SWS of CKD children. ROC analysis showed a considerably high diagnostic value of AOPP in both NWS and SWS of CKD children compared to controls (AUC = 0.92; 0.98). CKD is responsible for disturbances in salivary antioxidant systems and oxidative damage to proteins and lipids. Salivary AOPP can be a potential biomarker of CKD in children.

scholarly journals Correlation between Oxidative Stress and Transforming Growth Factor-Beta in Cancers

2021 ◽  
Vol 22 (24) ◽  
pp. 13181
Author(s):  
Jinwook Chung ◽  
Md Nazmul Huda ◽  
Yoonhwa Shin ◽  
Sunhee Han ◽  
Salima Akter ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Antioxidant Systems ◽  
Growth Factor Beta

The downregulation of reactive oxygen species (ROS) facilitates precancerous tumor development, even though increasing the level of ROS can promote metastasis. The transforming growth factor-beta (TGF-β) signaling pathway plays an anti-tumorigenic role in the initial stages of cancer development but a pro-tumorigenic role in later stages that fosters cancer metastasis. TGF-β can regulate the production of ROS unambiguously or downregulate antioxidant systems. ROS can influence TGF-β signaling by enhancing its expression and activation. Thus, TGF-β signaling and ROS might significantly coordinate cellular processes that cancer cells employ to expedite their malignancy. In cancer cells, interplay between oxidative stress and TGF-β is critical for tumorigenesis and cancer progression. Thus, both TGF-β and ROS can develop a robust relationship in cancer cells to augment their malignancy. This review focuses on the appropriate interpretation of this crosstalk between TGF-β and oxidative stress in cancer, exposing new potential approaches in cancer biology.

scholarly journals Neuroglobin: A Novel Player in the Oxidative Stress Response of Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Marco Fiocchetti ◽  
Virginia Solar Fernandez ◽  
Emiliano Montalesi ◽  
Maria Marino
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Selective Advantage ◽  
Antioxidant Systems ◽  
Ros Production ◽  
Apoptotic Pathway ◽  
Extracellular Stimuli ◽  
Mechanisms Of Adaptation ◽  
Set Up ◽  
Endogenous Antioxidant

Reactive oxygen species (ROS) result from intracellular aerobic metabolism and/or extracellular stimuli. Although endogenous antioxidant systems exquisitely balance ROS production, an excess of ROS production, commonly found in diverse human degenerative pathologies including cancer, gives rise to the oxidative stress. Increased oxidative stress in cancer is related to the sustained proliferation and metabolism of cancer cells. However, cancer cells show an intrinsic higher antioxidant capacity with respect to the normal counterpart as well as an ability to cope with oxidative stress-induced cell death by establishing mechanisms of adaptation, which define a selective advantage against the adverse oxidative stress environment. The identification of survival factors and adaptive pathways, set up by cancer cells against oxidative stress, provides multiple targets for the therapeutic intervention against cancer. Neuroglobin (NGB), a globin primarily described in neurons as an oxidative stress sensor and cytoprotective factor against redox imbalance, has been recently recognized as a novel tumor-associated protein. In this review, the involvement of NGB in the cancer cell adaptation and resistance to oxidative stress will be discussed highlighting the globin role in the regulation of both the stress-induced apoptotic pathway and antioxidant systems activated by cancer cells.

scholarly journals TrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy

2019 ◽  
Vol 116 (23) ◽  
pp. 11408-11417 ◽  
Author(s):  
Michael R. McLoughlin ◽  
David J. Orlicky ◽  
Justin R. Prigge ◽  
Pushya Krishna ◽  
Emily A. Talago ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Standard Care ◽  
Antioxidant Systems ◽  
Null Mouse ◽  
Dependent Manner ◽  
Damage Indices ◽  
And Oxidative Stress

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr–double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.

scholarly journals Influence of Oxidative Stress Generated by Smoking during Pregnancy on Glutathione Status in Mother-Newborn Pairs

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1866
Author(s):  
Magdalena Chełchowska ◽  
Joanna Gajewska ◽  
Jadwiga Ambroszkiewicz ◽  
Joanna Mazur ◽  
Mariusz Ołtarzewski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cord Blood ◽  
Tobacco Smoke ◽  
Competitive Inhibition ◽  
Redox Status ◽  
Antioxidant Systems ◽  
Smoking During Pregnancy ◽  
Glutathione Status ◽  
Immunoassay Technique ◽  
Negative Effect

Glutathione plays a key role in maintaining a physiological balance between prooxidants and antioxidants in the human body. Therefore, we examined the influence of maternal smoking as a source of oxidative stress measured by total oxidant capacity (TOC) on reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GPx-3), and reductase (GR) amount in maternal and umbilical cord blood in 110 (45 smoking and 65 non-smoking) mother-newborn pairs. Concentrations of glutathione status markers and TOC were evaluated by competitive inhibition enzyme immunoassay technique. Plasma TOC levels were significantly higher and the GSH/GSSG ratio, which is considered an index of the cell’s redox status, were significantly lower in smoking women and their offspring than in non-smoking pairs. Decreased GR levels were found in smoking mothers and their newborns compared with similar non-smoking groups. Although plasma GPx-3 concentrations were similar in both maternal groups, in the cord blood of newborns exposed to tobacco smoke in utero they were reduced compared with the levels observed in children of tobacco abstinent mothers. Oxidative stress generated by tobacco smoke impairs glutathione homeostasis in both the mother and the newborn. The severity of oxidative processes in the mother co-existing with the reduced potential of antioxidant systems may have a negative effect on the oxidative-antioxidant balance in the newborn.

scholarly journals Peroxiredoxin II Regulates Cancer Stem Cells and Stemness-Associated Properties of Cancers

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 305 ◽  
Author(s):  
Nisansala Chandimali ◽  
Dong Jeong ◽  
Taeho Kwon
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Redox Status ◽  
Cell Phenotype ◽  
Therapeutic Effects ◽  
Cellular Functions ◽  
Unlimited Growth ◽  
Current Therapies

Cancer stem cells (CSCs) represent a sub-population of cancer cells with the ability to regulate stemness-associated properties which are specifically responsible for unlimited growth of cancers, generation of diverse cancer cells in differentiated state and resistance to existing chemotherapy and radiotherapy. Even though, current therapies destroy majority of cancer cells, it is believed to leave CSCs without eradicating which may be the conceptualization for chemoresistance and radio-resistance. Reactive oxygen species (ROS) maintain stem cells and regulate the stemness-associated properties of cancers. Beyond the maximum limit, ROS can damage cellular functions of cancers by subjecting them to oxidative stress. Thus, maintenance of ROS level plays an important role in cancers to regulate stemness-associated properties. Peroxiredoxin II (Prx II) is a member of peroxiredoxin antioxidant enzyme family which considers as a regulator of ROS in cellular environments by modulating redox status to maintain CSC phenotype and stemness properties. Prx II has cell type-dependent expression in various types of cancer cells and overexpression or silenced expression of Prx II in cancers is associated with stem cell phenotype and stemness-associated properties via activation or deactivation of various signaling pathways. In this review, we summarized available studies on Prx II expression in cancers and the mechanisms by which Prx II takes parts to regulate CSCs and stemness-associated properties. We further discussed the potential therapeutic effects of altering Prx II expression in cancers for better anticancer strategies by sensitizing cancer cells and stem cells to oxidative stress and inhibiting stemness-associated properties.

Transcriptional control of the oxidative stress response and implications of using plant derived molecules for therapeutic interventions in cancer

2021 ◽  
Vol 28 ◽  
Author(s):  
Asim Rizvi ◽  
Mohd. Farhan ◽  
Faisal Nabi ◽  
Rizwan Hasan Khan ◽  
Mohd. Adil ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Stress Response ◽  
Cancer Cells ◽  
Transcriptional Control ◽  
Regulation Of Gene Expression ◽  
Oxidative Stress Response ◽  
Therapeutic Interventions ◽  
Lead Compounds

: Oxidative stress response is critical for the malignant cells. It plays dual role by helping cancer cells survive and proliferate but also causing apoptosis and apoptosis like cell death. The oxidative stress response is characterized by a tight regulation of gene expression by a series of transcription factors (OSRts; oxidative stress response transcription factors). In this communication, we review the role of OSRts, notably NRF2 and p53 as well as other transcription factors, that modulate the response. We discuss how the oxidative stress response is hierarchal and controls ‘live or die’ signals. This is followed by a discussion on how plant derived molecules, including polyphenols, which are described both as prooxidants and antioxidants within the cancer cells, have been reported to affect the activities of OSRts. Deriving an example from preliminary data from our group, we discuss how plant derived molecules might modulate the oxidative stress response by causing structural perturbations in the proteinacious transcription factors, notably Nrf2 and p53. We look at this information in the light of understanding how plant derived molecules maybe used as lead compounds to develop modulators of the oxidative stress response.

Administration of Antioxidants in the Infertile Male: When it may have a Beneficial Effect?.

2020 ◽  
Vol 26 ◽  
Author(s):  
Zsolt Kopa ◽  
Marton Keszthelyi ◽  
Nikolaos Sofikitis
Keyword(s):  
Oxidative Stress ◽  
Male Infertility ◽  
Membrane Damage ◽  
Live Birth Rate ◽  
Redox Status ◽  
Antioxidant Systems ◽  
Sperm Function ◽  
Antioxidant Treatment ◽  
Reductive Stress ◽  
Pre Treatment

Background: Reactive Oxygen Species (ROS) are required for intact spermatogenesis and sperm function, but excessive levels will cause oxidative stress, impairing sperms and sperm function due to membrane damage and DNA fragmentation. Objective: Theoretically, antioxidant supplementation may act as a protecting system against free radicals. Since infertile males have higher levels of ROS, nutritional supplements are widely used for protecting sperms. In the recent review authors summarize the most recent data regarding the effect of antioxidant treatment and draw an attention of the limitations of antioxidant use in male infertility. Methods: The recent review gives an update of antioxidant treatment in male infertility. Results: Improvement of sperm parameters was reported in the majority of studies. Comparing different antioxidants versus placebo showed low certainty of evidence with a serious risk of bias, and there is a lack regarding certain doses, pregnancy rate, and live birth rate outcomes. Various clinical studies and randomized control trials reported even negative outcomes. Conflicting findings lead the attention to the study of biochemical features of the oxidant vs. antioxidant equilibrium. Higher exposure to antioxidants will result in „reductive stress”, which has harmful effects on sperm function, moreover can negatively influence embryo development. Reductive stress is as dangerous as oxidative stress and may act as a cause of different human pathologies. Conclusion: An intact balance of oxidant and antioxidant systems is required to normal sperm function. No guideline exists for the antioxidant dose regimen and treatment duration. Overdosing can result in reductive stress, which is also harmful to fertility and can cause several diseases. Assessment of the pre-treatment redox status can be recommended before the administration of exogenous antioxidants.

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