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Major sites of reactive oxygen species (ROS) production in leukemia cells. ROS are derived from different cellular compartments and enzymatic systems. The most significant source of ROS in the cell is represented by mitochondria, in which ROS are largely generated by the electron
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Myeloid leukemic cells are intrinsically under oxidative stress due to impaired reactive oxygen species (ROS) homeostasis, a common signature of several hematological malignancies. The present review focuses on the molecular mechanisms of aberrant ROS production in myeloid leukemia cells as well as on the redox-dependent signaling pathways involved...
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... in ROS metabolism are complex and linked to both enhanced ROS production and defective antioxidant defenses. Many metabolic pathways contributing to ROS production such as xanthine oxidoreductase (XOR), uncoupled nitric oxide (NO) synthase (NOS), cytochrome P450 mono-oxygenase (CYP), cyclo-oxygenase (COX) and NADPH oxidase (NOX) activities are altered in myeloid leukemia (Figure 1) [16,38,39]. The NOX family is the first enzyme system reported to produce ROS as a primary function and not just as a by-product of cell metabolism. ...
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... as representing the main cause of cellular oxidative stress, dysregulated mitochondrial metabolism plays a prominent role in many leukemia types [42][43][44]. Generation of mitochondrial ROS mainly takes place at complex I and complex III of the electron transport chain (ETC) as a consequence of undesired electron leaks that fail to reach complex IV and univalently react with oxygen to produce the superoxide radical anion (O2 − ) (Figure 1) [45]. Superoxide can also be generated during fatty acid oxidation or other mitochondrial oxidoreductase activities, including xanthine oxidase [14,[46][47][48]. ...
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... the major sites of intracellular H2O2, represent another important source of ROS in leukemia [60] (Figure 1). Several metabolic processes in these organelles generate a wide range of ROS [61]. ...
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... catalyzes thiol-disulfide exchange reactions, which form native disulfide bonds in proteins. During this process, PDI is oxidized by endoplasmic reticulum oxidoreductin-1 (Ero1), which accepts electrons from a reduced PDI and transfers them to oxygen, thereby generating H2O2 (Figure 1). PDI is also involved in H2O2 generation through interaction with two members of the NOX family, NOX1 and NOX4, that catalyze the univalent reduction of O2 to generate O2 − and are involved in H2O2 release in the ER lumen [66,67]. ...
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... in ROS metabolism are complex and linked to both enhanced ROS production and defective antioxidant defenses. Many metabolic pathways contributing to ROS production such as xanthine oxidoreductase (XOR), uncoupled nitric oxide (NO) synthase (NOS), cytochrome P450 mono-oxygenase (CYP), cyclo-oxygenase (COX) and NADPH oxidase (NOX) activities are altered in myeloid leukemia (Figure 1) [16,38,39]. The NOX family is the first enzyme system reported to produce ROS as a primary function and not just as a by-product of cell metabolism. ...
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... as representing the main cause of cellular oxidative stress, dysregulated mitochondrial metabolism plays a prominent role in many leukemia types [42][43][44]. Generation of mitochondrial ROS mainly takes place at complex I and complex III of the electron transport chain (ETC) as a consequence of undesired electron leaks that fail to reach complex IV and univalently react with oxygen to produce the superoxide radical anion (O2 − ) (Figure 1) [45]. Superoxide can also be generated during fatty acid oxidation or other mitochondrial oxidoreductase activities, including xanthine oxidase [14,[46][47][48]. ...
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... the major sites of intracellular H2O2, represent another important source of ROS in leukemia [60] (Figure 1). Several metabolic processes in these organelles generate a wide range of ROS [61]. ...
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... catalyzes thiol-disulfide exchange reactions, which form native disulfide bonds in proteins. During this process, PDI is oxidized by endoplasmic reticulum oxidoreductin-1 (Ero1), which accepts electrons from a reduced PDI and transfers them to oxygen, thereby generating H2O2 (Figure 1). PDI is also involved in H2O2 generation through interaction with two members of the NOX family, NOX1 and NOX4, that catalyze the univalent reduction of O2 to generate O2 − and are involved in H2O2 release in the ER lumen [66,67]. ...
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Citations
... LSCs depend on OXPHOS as an energy source which is ROS productive. LSCs use various mechanisms such as mitophagy, glutathione, or antioxidants to keep ROS low which is an important hallmark of stem cells [23]. Ara-c induces ROS production through inhibition of DNA polymerase gamma, and hence induces cellular stress by disruption of mitochondrial function and ROS increment [24] [25]. ...
Background: Acute myeloid leukemia (AML) has a high probability of recurrence 5 years after treatment with traditional chemotherapy. One of the factors that play a role in AML relapses is the presence of leukemia stem cells (LSCs). Many vital roles of mitochondria such as energy production, oxidation-reduction status, Reactive oxygen species (ROS) production, control of cytosolic calcium levels, and initiation of apoptosis, these organelles carry out an important role in developing LSCs. Metabolic flexibility and mitochondrial dependence are two important requirements of LSCs resistance to chemotherapy. Therefore, it would be reasonable to target mitochondria in cancer treatment.
Method and result: In this study, an acute myeloid leukemia-derived cell line i.e., KG1-a was treated with different concentrations of Cytarabine (Ara-c), 2-Deoxy-D-Glucose (2-DG), and their combination. The effects of different treatments were assessed by MTT assay and calculated synergistic index. Then, The Magnetic Antibody Cell Sorting (MACS) was used to isolate cancer CD34⁺ and CD34⁻ cells as representatives of leukemia stem-like cells and other leukemia cells, respectively. Flow cytometric dyes DCFH-da and Rhodamine 123 were used to evaluate the production of ROS and mitochondrial membrane potential (MMP) in the cells, respectively.
Conclusion: We found that 2-DG and Ara-c have synergistic effects on KG1-a, as well as their combination increases ROS production and reduces MMP, significantly. It seems that combination treatment is the best choice to target more resistant stem-like cells.
... � Gasoline station workers in India with sufficiently high exposure to benzene to significantly decrease GSH were found to have elevated levels of benzene and its metabolites in blood and urine as well as indicators for oxidative stress in blood (Uzma et al. 2010). � Roles of increased ROS and oxidative stress (OS) in bone marrow in the initiation, promotion, and progression of AML are suggested by numerous in vitro experiments and observations of human bone marrow cells from AML patients and controls (Trombetti et al. 2021). ...
Introduction:
Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define interventional probability of causation (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of causal assigned share (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed. Traditional approaches used to evaluate the preventable risk implications of epidemiological associations, including population attributable fraction (PAF) and the Bradford Hill considerations, cannot reveal whether removing a risk factor would reduce disease incidence. We argue that modern formal causal models coupled with causal artificial intelligence (CAI) and realistically partial and imperfect knowledge of underlying disease mechanisms, show great promise for determining and quantifying IPoC and CAS for exposures and diseases of practical interest.
Methods:
We briefly review key CAI concepts and terms and then apply them to define IPoC and CAS. We present steps to quantify IPoC using a fully specified causal Bayesian network (BN) model. Useful bounds for quantitative IPoC and CAS calculations are derived for a two-stage clonal expansion (TSCE) model for carcinogenesis and illustrated by applying them to benzene and formaldehyde based on available epidemiological and partial mechanistic evidence.
Results:
Causal BN models for benzene and risk of acute myeloid leukemia (AML) incorporating mechanistic, toxicological and epidemiological findings show that prolonged high-intensity exposure to benzene can increase risk of AML (IPoC of up to 7e-5, CAS of up to 54%). By contrast, no causal pathway leading from formaldehyde exposure to increased risk of AML was identified, consistent with much previous mechanistic, toxicological and epidemiological evidence; therefore, the IPoC and CAS for formaldehyde-induced AML are likely to be zero.
Conclusion:
We conclude that the IPoC approach can differentiate between likely and unlikely causal factors and can provide useful upper bounds for IPoC and CAS for some exposures and diseases of practical importance. For causal factors, IPoC can help to estimate the quantitative impacts on health risks of reducing exposures, even in situations where mechanistic evidence is realistically incomplete and individual-level exposure-response parameters are uncertain. This illustrates the strength that can be gained for causal inference by using causal models to generate testable hypotheses and then obtaining toxicological data to test the hypotheses implied by the models-and, where necessary, refine the models. This virtuous cycle provides additional insight into causal determinations that may not be available from weight-of-evidence considerations alone.
... In addition, ferroptosis is regulated by numerous tumor-related genes and signaling pathways [57,58]. Several mechanisms involved in ferroptosis, including system Xc-, GPX4, lipid peroxidation, and GSH metabolism, mediate biological processes such as oxidative stress and iron overload and appear to be dysregulated in many cancer types [59][60][61][62]. ...
... Chemotherapeutic drugs induce apoptosis by producing high levels of ROS, which suppress tumor growth [73]. Low levels of ROS, on the other hand, protect AML cells from apoptosis and increase treatment resistance, cell migration, growth, and proliferation [61,74]. AML cells are particularly sensitive to iron overload, and although there is strong evidence that transferrin is highly expressed in these cells with increased binding activity, the exact effect of transferrin on AML cells is unclear [70]. ...
Ferroptosis is a type of programmed cell death that differs from apoptosis, autophagy, and necrosis and is related to several physio-pathological processes, including tumorigenesis, neu-rodegeneration, senescence, blood diseases, kidney disorders, and ischemia-reperfusion injuries. Ferroptosis is linked to iron accumulation, eliciting dysfunction of antioxidant systems, which favor the production of lipid peroxides, cell membrane damage, and ultimately, cell death. Thus, signaling pathways evoking ferroptosis are strongly associated with those protecting cells against iron excess and/or lipid-derived ROS. Here, we discuss the interaction between the metabolic pathways of ferroptosis and antioxidant systems, with a particular focus on transcription factors implicated in the regulation of ferroptosis, either as triggers of lipid peroxidation or as ferroptosis antioxidant defense pathways.
... The shorter isoform can originate either from an alternatively spliced mRNA variant lacking exon 2 or from the use of an alternative translation initiation site (Met84) located in exon 3 (figure 1) [1][2][3]. These two isoforms have distinct roles in normal haematopoiesis: as the result of a complex interplay of transcriptional networks, GATA-1 FL promotes the terminal differentiation of megakaryocytic-erythroid lineages, whereas GATA-1 S enhances the proliferation and self-renewal of myeloid progenitors and contributes to the maintenance of the proliferative potency of haematopoietic precursors and skewing of the myeloid lineage [1][2][3][4][5][6][7][8][9]. Consequently, an imbalanced expression of GATA-1 S over GATA-1 FL has been identified as an oncogenic factor in several haematopoietic disorders including different subtypes of acute and chronic myeloid leukaemia [3,[10][11][12][13][14][15]. ...
Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1S). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1S, we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an in silico prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1S production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1S. These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1S levels.
... Mounting evidence supports the idea that increased levels of oxidative stress play a crucial role in the onset and progression of solid and lymphoid malignancies. This is achieved by inducing genomic instability, promoting cell survival, signaling for cell proliferation, and increasing resistance to treatment modalities (reviewed in [152]). Multiple mechanisms have been described for aberrant ROS generation in malignant cells, particularly of myeloid origin. ...
Simple Summary
OGG1-enabled NFκB activity can promote cancer progression via a number of key mechanisms that include phenotypic transitions of cancer and stromal cells, expression and secretion of molecules that modulate innate immunity, and alteration of the vascular network. Under oxidative stress, the supraphysiological levels of nongenotoxic 8-oxoGua, along with redox inactivation of OGG1 via cysteine oxidation and potential dimerization, provide multiple interfaces with redox-activated/modulated NFκB and other transacting factors, including Myc. This promotes not only cell proliferation, the expression of innate immune genes, and angiogenesis but also the metastatic capability of cells involving the expression of epithelial–mesenchymal transition genes. Mounting evidence supports the idea that increased levels of oxidative stress play a crucial role in the onset and progression of solid and lymphoid malignancies. This is achieved by gaining mutations and by activating signaling pathways that promote cell survival, cell proliferation, and resistance to treatment modalities.
Abstract
8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now also recognized as a modulator of gene expression. What is important for cancer is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, such as NFκB to their cognate sites, enabling the expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which hold significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. This review analyzes and discusses how these cells adapt through redox-modulated intricate connections, via interaction of OGG1 with NFκB, which provides malignant cells with alternative molecular pathways to transform their microenvironment, enabling adjustment, promoting cell proliferation, metastasis, and evading killing by therapeutic agents.
... Mounting evidence supports the idea that increased levels of oxidative stress play a crucial role in the onset and progression of solid and lymphoid malignancies. This is achieved by inducing genomic instability, promoting cell survival, signaling for cell proliferation, and increasing resistance to treatment modalities (reviewed in [144]). Multiple mechanisms are described for aberrant ROS generation in malignant cells, particularly of myeloid origin. ...
8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now known also as a modulator of gene expression. What is important for cancer, is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts the enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NFκB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which have a significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. In general, the capacity of cancer cells to adapt to oxidative stress depends on molecular systems such as the interface of OGG1 with NFκB, which bestows a cancer cell with the molecular mechanism of transformation of its microenvironment to enable adaptation and survival of malignant clones.
... These observations support the view that ELPDNVs, as well as ascorbic acid at high doses, induce an inhibitory effect on leukemic proliferation and promote leukemic cell death through a mechanism related to stimulation of ROS production. Through this action, ELPDNVs could promote a redox imbalance of leukemic cells through a mechanism conceivably related to the ascorbic acid contained in the ELPDNVs, thus also supporting leukemic cells' peculiar vulnerability to oxidative stress [12,32]. ROS are important signaling molecules, and their production is increased in myeloid leukemic cells, thus rendering these cells exposed to oxidative stress [32]. ...
... Through this action, ELPDNVs could promote a redox imbalance of leukemic cells through a mechanism conceivably related to the ascorbic acid contained in the ELPDNVs, thus also supporting leukemic cells' peculiar vulnerability to oxidative stress [12,32]. ROS are important signaling molecules, and their production is increased in myeloid leukemic cells, thus rendering these cells exposed to oxidative stress [32]. Oxidative stress and metabolic rewiring toward oxidative metabolism represent two intimately intermingled features of leukemic cells and offer new therapeutic approaches potentially capable of eradicating leukemic stem cells [33]. ...
Citrus fruits are a natural source of ascorbic acid, and exosome-like nanovesicles obtained from these fruits contain measurable levels of ascorbic acid. We tested the ability of grapefruit-derived extracellular vesicles (EVs) to inhibit the growth of human leukemic cells and leukemic patient-derived bone marrow blasts. Transmission electron microscopy and nanoparticle tracking analysis (NTA) showed that the obtained EVs were homogeneous exosomes, defined as exosome-like plant-derived nanovesicles (ELPDNVs). The analysis of their content has shown measurable amounts of several molecules with potent antioxidant activity. ELPDNVs showed a time-dependent antiproliferative effect in both U937 and K562 leukemic cell lines, comparable with the effect of high-dosage ascorbic acid (2 mM). This result was confirmed by a clear decrease in the number of AML blasts induced by ELPDNVs, which did not affect the number of normal cells. ELPDNVs increased the ROS levels in both AML blast cells and U937 without affecting ROS storage in normal cells, and this effect was comparable to ascorbic acid (2 mM). With our study, we propose ELPDNVs from grapefruits as a combination/supporting therapy for human leukemias with the aim to improve the effectiveness of the current therapies.
... GATA-1 is a key transcriptional regulator of hematopoiesis-related genes. A balanced expression of its two isoforms, the full-length GATA-1 FL and the shorter variant GATA-1 S , contributes to controlling hematopoiesis, whereas their dysregulation alters the differentiation/proliferation potential of hematopoietic precursors with aberrant expression of GATA-1 S, representing an adverse prognostic factor in myeloid leukemia [10]. In our previous studies, we showed that GATA-1 S promotes cell survival and enhances apoptosis resistance in myeloid cells by modulating oxidative metabolism and cellular redox states [11,12]. ...
... This coordinated enzymatic activity relies on the interdependence of XO and XDH, thereby contributing to the generation of ROS in the peroxisomal environment. Following its involvement in purine catabolism, XDH plays a pivotal role by catalyzing the oxidation of hypoxanthine to xanthine, and subsequently, the conversion of xanthine to uric acid [49]. Furthermore, the peroxisome may also serve as a site for the generation of superoxide radicals, which could potentially arise from the short electron chain associated with the NADH/NADPH-driven peroxisomal membrane [50]. ...
Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment.
Graphical Abstract
... NADPH oxidases (Nox), Nox1, Nox2, and Nox3, were also elevated in Gpr44 −/− AML cells ( Figure S6H), perhaps contributing to oxidative stress to favor leukemia. 32 Cell-cycle analysis indicated that most of the Gpr44 −/− AML cells were in S and G2/M phases, showing a higher proliferation than WT AML cells ( Figure S6I). In addition, increased expression of Pdl1 and Pd1 ( Figure S6J) and their associated gene signatures ( Figure S6K) and increased expression of Yes1-associated transcriptional regulator (Yap1), a key cell-cycle regulatory gene ( Figure S6L), may partly explain the aggressiveness of Gpr44 −/− AML cells. ...
Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44-/- LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.
