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16 pages, 4834 KiB

Open AccessArticle

Deuterium Oxide (D₂O) Induces Early Stress Response Gene Expression and Impairs Growth and Metastasis of Experimental Malignant Melanoma

by Jana Jandova, Anh B. Hua, Jocelyn Fimbres and Georg T. Wondrak

Cancers 2021, 13(4), 605; https://doi.org/10.3390/cancers13040605 - 3 Feb 2021

Cited by 9 | Viewed by 4902

Abstract

There are two stable isotopes of hydrogen, protium (¹H) and deuterium (²H; D). Cellular stress response dysregulation in cancer represents both a major pathological driving force and a promising therapeutic target, but the molecular consequences and potential therapeutic impact [...] Read more.

There are two stable isotopes of hydrogen, protium (¹H) and deuterium (²H; D). Cellular stress response dysregulation in cancer represents both a major pathological driving force and a promising therapeutic target, but the molecular consequences and potential therapeutic impact of deuterium (²H)-stress on cancer cells remain largely unexplored. We have examined the anti-proliferative and apoptogenic effects of deuterium oxide (D₂O; ‘heavy water’) together with stress response gene expression profiling in panels of malignant melanoma (A375^V600E, A375^NRAS, G361, LOX-IMVI), and pancreatic ductal adenocarcinoma (PANC-1, Capan-2, or MIA PaCa-2) cells with inclusion of human diploid Hs27 skin fibroblasts. Moreover, we have examined the efficacy of D₂O-based pharmacological intervention in murine models of human melanoma tumor growth and metastasis. D₂O-induction of apoptosis was substantiated by AV-PI flow cytometry, immunodetection of PARP-1, and pro-caspase 3 cleavage, and rescue by pan-caspase inhibition. Differential array analysis revealed early modulation of stress response gene expression in both A375 melanoma and PANC-1 adenocarcinoma cells elicited by D₂O (90%; ≤6 h) (upregulated: CDKN1A, DDIT3, EGR1, GADD45A, HMOX1, NFKBIA, or SOD2 (up to 9-fold; p < 0.01)) confirmed by independent RT-qPCR analysis. Immunoblot analysis revealed rapid onset of D₂O-induced stress response phospho-protein activation (p-ERK, p-JNK, p-eIF2α, or p-H2AX) or attenuation (p-AKT). Feasibility of D₂O-based chemotherapeutic intervention (drinking water (30% w/w)) was demonstrated in a severe combined immunodeficiency (SCID) mouse melanoma metastasis model using luciferase-expressing A375-Luc2 cells. Lung tumor burden (visualized by bioluminescence imaging) was attenuated by D₂O, and inhibition of invasiveness was also confirmed in an in vitro Matrigel transwell invasion assay. D₂O supplementation also suppressed tumor growth in a murine xenograft model of human melanoma, and median survival was significantly increased without causing adverse effects. These data demonstrate for the first time that systemic D₂O administration impairs growth and metastasis of malignant melanoma through the pharmacological induction of deuterium (²H)-stress. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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19 pages, 7359 KiB

Open AccessArticle

Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

by Suzanne Bakewell, Isabel Conde, Yassi Fallah, Mathew McCoy, Lu Jin and Ayesha N. Shajahan-Haq

Cancers 2020, 12(9), 2647; https://doi.org/10.3390/cancers12092647 - 16 Sep 2020

Cited by 29 | Viewed by 5723

Abstract

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. [...] Read more.

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 μM, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER−) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER− breast cancer. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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18 pages, 5139 KiB

Open AccessArticle

Quercetin–Resveratrol Combination for Prostate Cancer Management in TRAMP Mice

by Chandra K. Singh, Gagan Chhabra, Mary A. Ndiaye, Imtiaz A. Siddiqui, Jennifer E. Panackal, Charlotte A. Mintie and Nihal Ahmad

Cancers 2020, 12(8), 2141; https://doi.org/10.3390/cancers12082141 - 2 Aug 2020

Cited by 34 | Viewed by 6772

Abstract

Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa [...] Read more.

Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-model in prevention and intervention settings. We found resveratrol alone and in combination significantly inhibited prostate tumorigenesis in prevention setting, while the same was seen only in combination after intervention. The observed effects were associated with marked inhibition in proliferation, oxidative stress, and tumor survival markers, and induced apoptosis markers. Utilizing PCa PCR array analysis with prevention tumor tissues, we identified that quercetin–resveratrol modulates genes involved in promoter methylation, cell cycle, apoptosis, fatty acid metabolism, transcription factors, androgen response, PI3K/AKT and PTEN signaling. Ingenuity Pathway Analysis (IPA) identified IGF1 and BCL2 as central players in two gene networks. Functional annotation predicted increased apoptosis and inhibited cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis with dual treatment. Furthermore, IPA predicted upstream inhibition of major PCa signaling VEGF, Ca²⁺, PI3K, CSF2, PTH). Based on PCR array, we identified decreased levels of EGFR, EGR3, and IL6, and increased levels of IGFBP7 and NKX3.1, overall supporting anti-PCa effects of quercetin–resveratrol. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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20 pages, 4202 KiB

Open AccessArticle

Pro-Oxidant Enzymes, Redox Balance and Oxidative Damage to Proteins, Lipids and DNA in Colorectal Cancer Tissue. Is Oxidative Stress Dependent on Tumour Budding and Inflammatory Infiltration?

by Justyna Zińczuk, Mateusz Maciejczyk, Konrad Zaręba, Anna Pryczynicz, Violetta Dymicka-Piekarska, Joanna Kamińska, Olga Koper-Lenkiewicz, Joanna Matowicka-Karna, Bogusław Kędra, Anna Zalewska and Katarzyna Guzińska-Ustymowicz

Cancers 2020, 12(6), 1636; https://doi.org/10.3390/cancers12061636 - 20 Jun 2020

Cited by 52 | Viewed by 3715

Abstract

This study is the first to assess redox homeostasis in patients with colorectal cancer (CRC) in respect to histopathological parameters associated with the tumour microenvironment such as tumour budding and inflammatory infiltration. Pro-oxidant enzymes (NADPH oxidase (NOX), xanthine oxidase (XO)), antioxidant barrier (Cu,Zn-superoxide [...] Read more.

This study is the first to assess redox homeostasis in patients with colorectal cancer (CRC) in respect to histopathological parameters associated with the tumour microenvironment such as tumour budding and inflammatory infiltration. Pro-oxidant enzymes (NADPH oxidase (NOX), xanthine oxidase (XO)), antioxidant barrier (Cu,Zn-superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced glutathione (GSH)), redox status (total antioxidant (TAC)/oxidant status (TOS)) and oxidative damage products (advanced glycation end products (AGE), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG)) were determined in both the normal and cancerous tissue of 29 CRC patients. The activity of NOX (p < 0.01) and XO (p = 0.01), as well as SOD (p < 0.0001), CAT (p < 0.0001) and TAC level (p < 0.01) were significantly higher in tumour tissue than in normal colon mucosa. Oxidative damage products (AGE—p < 0.01, AOPP—p < 0.001, MDA—p < 0.001, 8-OHdG—p < 0.0001) were also higher in cancerous colon tissue. Furthermore, we observed that CAT (p < 0.05) and XO (p < 0.05) activity depends on the intensity of inflammatory infiltration. Oxidative stress index (OSI) (p < 0.05) and MDA (p < 0.01) values were significantly higher in patients with tumour budding (TB) > 5 versus cases with TB < 5. However, OSI level did not differ significantly between cancer and normal tissue. Our results confirm that CRC is associated with enzymatic/non-enzymatic redox imbalance and increased oxidative damage to proteins, lipids and DNA. The determination of these biomarkers could be useful for the evaluation of the tumour progression. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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19 pages, 36559 KiB

Open AccessArticle

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

by Jana Jandova, Jessica Perer, Anh Hua, Jeremy A. Snell and Georg T. Wondrak

Cancers 2020, 12(6), 1369; https://doi.org/10.3390/cancers12061369 - 26 May 2020

Cited by 12 | Viewed by 4501

Abstract

Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. [...] Read more.

Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. However, the specific role of GLO1 in melanomagenesis remains largely unexplored. Here, using genetic target modulation, we report the identification of GLO1 as a novel molecular determinant of invasion and metastasis in malignant melanoma. First, A375 human malignant melanoma cells with GLO1 deletion (A375-GLO1_KO) were engineered using CRISPR/Cas9, and genetic rescue clones were generated by stable transfection of KO clones employing a CMV-driven GLO1 construct (A375-GLO1_R). After confirming GLO1 target modulation at the mRNA and protein levels (RT-qPCR, immunodetection, enzymatic activity), phenotypic characterization indicated that deletion of GLO1 does not impact proliferative capacity while causing significant sensitization to methylglyoxal-, chemotherapy-, and starvation-induced cytotoxic stress. Employing differential gene expression array analysis (A375-GLO1_KO versus A375-GLO1_WT), pronounced modulation of epithelial mesenchymal transition (EMT)-related genes [upregulated: CDH1, OCLN, IL1RN, PDGFRB, SNAI3; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05)] was observed—all of which are consistent with EMT suppression as a result of GLO1 deletion. Importantly, these expression changes were largely reversed upon genetic rescue employing A375-GLO1_R cells. Differential expression of MMP9 as a function of GLO1 status was further substantiated by enzymatic activity and ELISA analysis; phenotypic assessment revealed the pronounced attenuation of morphological potential, transwell migration, and matrigel 3D-invasion capacity displayed by A375-GLO1_KO cells, reversed again in genetic rescue clones. Strikingly, in a SCID mouse metastasis model, lung tumor burden imposed by A375-GLO1_KO cells was strongly attenuated as compared to A375-GLO1_WT cells. Taken together, these prototype data provide evidence in support of a novel function of GLO1 in melanoma cell invasiveness and metastasis, and ongoing investigations explore the function and therapeutic potential of GLO1 as a novel melanoma target. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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18 pages, 4414 KiB

Open AccessArticle

Dysregulation of Redox Status in Urinary Bladder Cancer Patients

by Edyta Reszka, Monika Lesicka, Edyta Wieczorek, Ewa Jabłońska, Beata Janasik, Maciej Stępnik, Tomasz Konecki and Zbigniew Jabłonowski

Cancers 2020, 12(5), 1296; https://doi.org/10.3390/cancers12051296 - 21 May 2020

Cited by 10 | Viewed by 3973

Abstract

The alteration of redox homeostasis constitutes an important etiological feature of common human malignancies. We investigated DNA damage, selenium (Se) levels and the expression of cytoprotective genes involved in (1) the KEAP1/NRF2/ARE pathway, (2) selenoprotein synthesis, and (3) DNA methylation and histone deacetylation [...] Read more.

The alteration of redox homeostasis constitutes an important etiological feature of common human malignancies. We investigated DNA damage, selenium (Se) levels and the expression of cytoprotective genes involved in (1) the KEAP1/NRF2/ARE pathway, (2) selenoprotein synthesis, and (3) DNA methylation and histone deacetylation as putative key players in redox status dysregulation in the blood of urinary bladder cancer (UBC) patients. The study involved 122 patients and 115 control individuals. The majority of patients presented Ta and T1 stages. UBC recurrence occurred within 0.13 to 29.02 months. DNA damage and oxidative DNA damage were significantly higher in the patients compared to the controls, while plasma Se levels were significantly reduced in the cases compared to the controls. Of the 25 investigated genes, elevated expression in the peripheral blood leukocytes in patients was observed for NRF2, GCLC, MMP9 and SEP15, while down-regulation was found for KEAP1, GSR, HMOX1, NQO1, OGG1, SEPW1, DNMT1, DNMT3A and SIRT1. After Bonferroni correction, an association was found with KEAP1, OGG1, SEPW1 and DNMT1. Early recurrence was associated with the down-regulation of PRDX1 and SRXN1 at the time of diagnosis. Peripheral redox status is significantly dysregulated in the blood of UBC patients. DNA strand breaks and PRDX1 and SRXN1 expression may provide significant predictors of UBC recurrence. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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15 pages, 1778 KiB

Open AccessArticle

Statin Use Decreases the Incidence of Hepatocellular Carcinoma: An Updated Meta-Analysis

by Antonio Facciorusso, Mohamed A Abd El Aziz, Siddharth Singh, Sara Pusceddu, Massimo Milione, Luca Giacomelli and Rodolfo Sacco

Cancers 2020, 12(4), 874; https://doi.org/10.3390/cancers12040874 - 3 Apr 2020

Cited by 67 | Viewed by 3432

Abstract

Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means [...] Read more.

Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means of the DerSimonian and Laird test. Primary endpoint was the time-dependent correlation between statin use and HCC incidence expressed as hazard ratio (HR), both crude and adjusted. The crude and adjusted odds ratios (OR) for HCC occurrence between statin users and non-users were analyzed. Twenty-five studies with 1,925,964 patients were included. Crude OR for HCC incidence was 0.59 (95% CI: 0.47–0.74), confirmed in adjusted analysis (OR: 0.74, 95% CI: 0.70–0.78). Adjusted HR was 0.73 (95% CI: 0.69–0.76). This effect was more pronounced in HBV patients (HR: 0.46, 95% CI: 0.36–0.60) and with a cumulative daily dose beyond 365 (HR: 0.27, 95% CI: 0.11–0.67). Lipophilic statins were associated with reduced HCC incidence (HR: 0.49, 95% CI: 0.39–0.62). Atorvastatin determined the greater magnitude of effect (HR: 0.43, 95% CI: 0.28–0.65). This meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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23 pages, 5361 KiB

Open AccessArticle

ALDH3A1 Overexpression in Melanoma and Lung Tumors Drives Cancer Stem Cell Expansion, Impairing Immune Surveillance through Enhanced PD-L1 Output

by Erika Terzuoli, Cristiana Bellan, Sara Aversa, Valerio Ciccone, Lucia Morbidelli, Antonio Giachetti, Sandra Donnini and Marina Ziche

Cancers 2019, 11(12), 1963; https://doi.org/10.3390/cancers11121963 - 6 Dec 2019

Cited by 37 | Viewed by 4606

Abstract

Melanoma and non-small-cell lung carcinoma (NSCLC) cell lines are characterized by an intrinsic population of cancer stem-like cells (CSC), and high expression of detoxifying isozymes, the aldehyde dehydrogenases (ALDHs), regulating the redox state. In this study, using melanoma and NSCLC cells, we demonstrate [...] Read more.

Melanoma and non-small-cell lung carcinoma (NSCLC) cell lines are characterized by an intrinsic population of cancer stem-like cells (CSC), and high expression of detoxifying isozymes, the aldehyde dehydrogenases (ALDHs), regulating the redox state. In this study, using melanoma and NSCLC cells, we demonstrate that ALDH3A1 isozyme overexpression and activity is closely associated with a highly aggressive mesenchymal and immunosuppressive profile. The contribution of ALDH3A1 to the stemness and immunogenic status of melanoma and NSCLC cells was evaluated by their ability to grow in 3D forming tumorspheres, and by the expression of markers for stemness, epithelial to mesenchymal transition (EMT), and inflammation. Furthermore, in specimens from melanoma and NSCLC patients, we investigated the expression of ALDH3A1, PD-L1, and cyclooxygenase-2 (COX-2) by immunohistochemistry. We show that cells engineered to overexpress the ALDH3A1 enzyme enriched the CSCs population in melanoma and NSCLC cultures, changing their transcriptome. In fact, we found increased expression of EMT markers, such as vimentin, fibronectin, and Zeb1, and of pro-inflammatory and immunosuppressive mediators, such as NFkB, prostaglandin E2, and interleukin-6 and -13. ALDH3A1 overexpression enhanced PD-L1 output in tumor cells and resulted in reduced proliferation of peripheral blood mononuclear cells when co-cultured with tumor cells. Furthermore, in tumor specimens from melanoma and NSCLC patients, ALDH3A1 expression was invariably correlated with PD-L1 and the pro-inflammatory marker COX-2. These findings link ALDH3A1 expression to tumor stemness, EMT and PD-L1 expression, and suggest that aldehyde detoxification is a redox metabolic pathway that tunes the immunological output of tumors. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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22 pages, 9038 KiB

Open AccessArticle

Salivary Gland Function, Antioxidant Defence and Oxidative Damage in the Saliva of Patients with Breast Cancer: Does the BRCA1 Mutation Disturb the Salivary Redox Profile?

by Beata Sawczuk, Mateusz Maciejczyk, Magdalena Sawczuk-Siemieniuk, Renata Posmyk, Anna Zalewska and Halina Car

Cancers 2019, 11(10), 1501; https://doi.org/10.3390/cancers11101501 - 8 Oct 2019

Cited by 36 | Viewed by 3586

Abstract

: Oxidative stress plays a key role in breast cancer progression. However, little is still known about the relationship between the BRCA1 mutation, the incidence of breast cancer and oral homeostasis. This is the first study to evaluate the secretory function of salivary [...] Read more.

: Oxidative stress plays a key role in breast cancer progression. However, little is still known about the relationship between the BRCA1 mutation, the incidence of breast cancer and oral homeostasis. This is the first study to evaluate the secretory function of salivary glands, biomarkers of redox balance, and oxidative damage to proteins and lipids in the saliva of subjects with the BRCA1 mutation. Ninety eight women were enrolled in the study and allocated to four groups based on molecular DNA testing: generally healthy patients without the BRCA1 mutation, patients with breast cancer but without the BRCA1 mutation, generally healthy patients with the BRCA1 mutation, and patients with both breast cancer and the BRCA1 mutation. We demonstrated that saliva from breast cancer patients with the BRCA1 mutation is characterized by enhanced antioxidant capacity and a higher degree of oxidative damage to proteins and lipids. The BRCA1 mutation can cause a predisposition to early salivary gland dysfunction, both in patients with breast cancer and in healthy individuals, leading to a decrease in salivary proteins. Using cluster analysis, we showed that salivary peroxidase, advanced glycation end-products (AGE), total antioxidant status (TAS) and malondialdehyde (MDA) may have particular clinical significance in non-invasive diagnostics of breast cancer. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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Review

Jump to: Research

20 pages, 1425 KiB

Open AccessReview

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

by Caroline Chang, Beth L. Worley, Rébécca Phaëton and Nadine Hempel

Cancers 2020, 12(8), 2197; https://doi.org/10.3390/cancers12082197 - 6 Aug 2020

Cited by 125 | Viewed by 11475

Abstract

Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, [...] Read more.

Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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18 pages, 2043 KiB

Open AccessReview

Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts

by Dong-Hoon Hyun

Cancers 2020, 12(7), 1822; https://doi.org/10.3390/cancers12071822 - 7 Jul 2020

Cited by 36 | Viewed by 5273

Abstract

Modest levels of reactive oxygen species (ROS) are necessary for intracellular signaling, cell division, and enzyme activation. These ROS are later eliminated by the body’s antioxidant defense system. High amounts of ROS cause carcinogenesis by altering the signaling pathways associated with metabolism, proliferation, [...] Read more.

Modest levels of reactive oxygen species (ROS) are necessary for intracellular signaling, cell division, and enzyme activation. These ROS are later eliminated by the body’s antioxidant defense system. High amounts of ROS cause carcinogenesis by altering the signaling pathways associated with metabolism, proliferation, metastasis, and cell survival. Cancer cells exhibit enhanced ATP production and high ROS levels, which allow them to maintain elevated proliferation through metabolic reprograming. In order to prevent further ROS generation, cancer cells rely on more glycolysis to produce ATP and on the pentose phosphate pathway to provide NADPH. Pro-oxidant therapy can induce more ROS generation beyond the physiologic thresholds in cancer cells. Alternatively, antioxidant therapy can protect normal cells by activating cell survival signaling cascades, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in response to radio- and chemotherapeutic drugs. Nrf2 is a key regulator that protects cells from oxidative stress. Under normal conditions, Nrf2 is tightly bound to Keap1 and is ubiquitinated and degraded by the proteasome. However, under oxidative stress, or when treated with Nrf2 activators, Nrf2 is liberated from the Nrf2-Keap1 complex, translocated into the nucleus, and bound to the antioxidant response element in association with other factors. This cascade results in the expression of detoxifying enzymes, including NADH-quinone oxidoreductase 1 (NQO1) and heme oxygenase 1. NQO1 and cytochrome b5 reductase can neutralize ROS in the plasma membrane and induce a high NAD⁺/NADH ratio, which then activates SIRT1 and mitochondrial bioenergetics. NQO1 can also stabilize the tumor suppressor p53. Given their roles in cancer pathogenesis, redox homeostasis and the metabolic shift from glycolysis to oxidative phosphorylation (through activation of Nrf2 and NQO1) seem to be good targets for cancer therapy. Therefore, Nrf2 modulation and NQO1 stimulation could be important therapeutic targets for cancer prevention and treatment. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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16 pages, 1428 KiB

Open AccessReview

Reactive Oxygen Species and Antitumor Immunity—From Surveillance to Evasion

by Andromachi Kotsafti, Marco Scarpa, Ignazio Castagliuolo and Melania Scarpa

Cancers 2020, 12(7), 1748; https://doi.org/10.3390/cancers12071748 - 1 Jul 2020

Cited by 90 | Viewed by 5549

Abstract

The immune system is a crucial regulator of tumor biology with the capacity to support or inhibit cancer development, growth, invasion and metastasis. Emerging evidence show that reactive oxygen species (ROS) are not only mediators of oxidative stress but also players of immune [...] Read more.

The immune system is a crucial regulator of tumor biology with the capacity to support or inhibit cancer development, growth, invasion and metastasis. Emerging evidence show that reactive oxygen species (ROS) are not only mediators of oxidative stress but also players of immune regulation in tumor development. This review intends to discuss the mechanism by which ROS can affect the anti-tumor immune response, with particular emphasis on their role on cancer antigenicity, immunogenicity and shaping of the tumor immune microenvironment. Given the complex role that ROS play in the dynamics of cancer-immune cell interaction, further investigation is needed for the development of effective strategies combining ROS manipulation and immunotherapies for cancer treatment. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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31 pages, 1737 KiB

Open AccessReview

Targeting the Redox Landscape in Cancer Therapy

by Dilip Narayanan, Sana Ma and Dennis Özcelik

Cancers 2020, 12(7), 1706; https://doi.org/10.3390/cancers12071706 - 27 Jun 2020

Cited by 32 | Viewed by 6062

Abstract

Reactive oxygen species (ROS) are produced predominantly by the mitochondrial electron transport chain and by NADPH oxidases in peroxisomes and in the endoplasmic reticulum. The antioxidative defense counters overproduction of ROS with detoxifying enzymes and molecular scavengers, for instance, superoxide dismutase and glutathione, [...] Read more.

Reactive oxygen species (ROS) are produced predominantly by the mitochondrial electron transport chain and by NADPH oxidases in peroxisomes and in the endoplasmic reticulum. The antioxidative defense counters overproduction of ROS with detoxifying enzymes and molecular scavengers, for instance, superoxide dismutase and glutathione, in order to restore redox homeostasis. Mutations in the redox landscape can induce carcinogenesis, whereas increased ROS production can perpetuate cancer development. Moreover, cancer cells can increase production of antioxidants, leading to resistance against chemo- or radiotherapy. Research has been developing pharmaceuticals to target the redox landscape in cancer. For instance, inhibition of key players in the redox landscape aims to modulate ROS production in order to prevent tumor development or to sensitize cancer cells in radiotherapy. Besides the redox landscape of a single cell, alternative strategies take aim at the multi-cellular level. Extracellular vesicles, such as exosomes, are crucial for the development of the hypoxic tumor microenvironment, and hence are explored as target and as drug delivery systems in cancer therapy. This review summarizes the current pharmaceutical and experimental interventions of the cancer redox landscape. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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30 pages, 2024 KiB

Open AccessReview

Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies

by Monica Mossenta, Davide Busato, Michele Dal Bo and Giuseppe Toffoli

Cancers 2020, 12(6), 1668; https://doi.org/10.3390/cancers12061668 - 23 Jun 2020

Cited by 60 | Viewed by 6639

Abstract

Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further [...] Read more.

Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid–lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed. Full article

(This article belongs to the Special Issue Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities)

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Redox Dysregulation and Oxidative Stress in Cancer: Therapeutic Targets and Opportunities

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