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Oxidative stress response induced by chemotherapy in leukemia treatment

Oxidative stress response induced by chemotherapy in leukemia treatment MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 Oxidative stress response induced by chemotherapy in leukemia treatment (Review) 1* 2* 3 4 2 JIN ZHANG , WEN LEI , XIAOHUI CHEN , SHIBING WANG and WENBIN QIAN Department of Hematology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016; Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003; Department of Hematology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China Received February 6, 2017; Accepted December 6, 2017 DOI: 10.3892/mco.2018.1549 Abstract. Oxidative stress (OS) has been linked to the etiology Contents and development of leukemia as reactive oxygen species (ROS) and free radicals have been implicated in leukemogenesis. OS 1. Introduction has benec fi ial and deleterious effects in the pathogenesis and 2. OS and the generation of ROS progression of leukemia. High-dose chemotherapy, which 3. Basic ways OS causes cell injury is frequently used in leukemia treatment, is often accompa- 4. Dual role of OS in leukemogenesis nied by ROS-induced cytotoxicity. Thus, the utilization of 5. Association between OS and chemotherapy during chemotherapy in combination with antioxidants may attenuate leukemia treatment leukemia progression, particularly for cases of refractory or 6. Conclusion relapsed neoplasms. The present review focuses on exploring the roles of OS in leukemogenesis and characterizing the asso- ciations between ROS and chemotherapy. Certain examples of 1. Introduction treatment regimens wherein antioxidants are combined with chemotherapy are presented, in order to highlight the impor- Oxidative stress (OS) refers to the cellular environment condi- tance of antioxidant application in leukemia treatment, as well tions that result from an imbalance between the generation of as the conflicting opinions regarding this method of therapy. reactive oxygen species (ROS) and the response of the antioxi- Understanding the underlying mechanisms of OS generation dant defense systems (1). ROS are short-lived highly reactive will facilitate the elucidation of novel approaches to leukemia molecules and serve a critical role in the progression of OS. treatment. ROS were identie fi d as free radicals for the first time in 1954 by Gerschman (2). They are metabolites produced during normal cellular processes, which serve important roles in activities such as promoting health and longevity (3) and antimicrobial phagocytosis by cells of the innate immune system (4,5). The over-generation of ROS without an adequate response from the innate antioxidant system to maintain the homeostasis even- tually leads to OS. ROS serve a dual role in tumorigenicity, Correspondence to: Dr Shibing Wang, Clinical Research Institute, particularly in hematologic malignancies. ROS can induce the Zhejiang Provincial People's Hospital, 158 Shangtang Road, activation of cell death processes, including apoptosis, which Hangzhou, Zhejiang 310014, P.R. China provides a mechanism for cancer treatment (6); however, it can E-mail: shibwang@163.com also facilitate carcinogenesis by protecting the cell from apop- Professor Wenbin Qian, Department of Hematology, The First tosis and promoting cell survival, inducing proliferation (7), Affiliated Hospital, College of Medicine, Zhejiang University, migration (8), metastasis (9) and drug-resistance (10,11). It 79 Qingchun Road, Hangzhou, Zhejiang 310003, P.R. China has been reported that OS is involved in the development of a E-mail: qianwenb@hotmail.com number of hematologic malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodys- Contributed equally plastic syndrome (MDS) and acute lymphoblastic leukemia Key words: oxidative stress, reactive oxygen species, (ALL) (12-16). Numerous methods including the use of chemo- leukemogenesis, chemotherapy therapeutic agents and radiation are reported to generate ROS or other free radicals in patients undergoing cancer therapy. The present review focused on exploring the role of OS in leukemogenesis and determining the association between ROS ZHANG et al: OXIDATIVE STRESS RESPONSE INDUCED BY CHEMOTHERAPY IN LEUKEMIA TREATMENT and chemotherapy, as well as highlighting the importance of phosphoglycerate kinase 1 (PGK1), triosephosphate isomerase antioxidant application in leukemia treatment. Improving (TPI) and pyruvate kinase (PK), are reported to be involved current understanding of the underlying mechanisms of in cellular senescence and cancer (30-33). Besides MDA and OS generation in leukemogenesis will facilitate significant HNE, ROS-mediated protein oxidation also can be measured progress in developing novel therapeutic measures for various via the concentration of carbonyl groups, advanced oxidation types of leukemia. protein products (AOPPS), advanced glycation end products (AGE) and S-nitrosylated proteins, which are considered to be 2. OS and the generation of ROS novel markers for OS due to their long half-life and their ease of detection (34). OS is a biochemical condition that occurs when intracellular With respect to oxidative DNA damage, ROS and prod- antioxidants are unable to neutralize pro-oxidants, such as ucts of lipid peroxidation can have an effect on genomic ROS. Mitochondria are the primary sites for oxidative phos- and mitochondrial DNA, leading to various types of DNA phorylation, which produces massive highly reactive and damage (35,36). The replication of damaged DNA prior to unstable oxygen, thus oxidizing a large number of molecules repair results in DNA mutations and genomic instability, subse- to form ROS (17). ROS are generated intracellularly within quently leading to a variety of disorders and tumorigenesis. various compartments and through multiple mechanisms The molecule 8-oxoGuanine (8-OHG) and its nucleoside form (Table I). Mitochondria-derived ROS consist of singlet oxygen 8-OHdG are considered to be indicators of oxidative DNA (O ), superoxide anions (O •‑), hydrogen peroxide (H O ), nitric damage in vivo and in vitro (37,38). The presence of 8-OHG 2 2 2 2 oxide (NO•), hydroxyl radicals (OH•) and hydroxyl ions (OH‑). in the DNA caused a G-T and a C-A transversion, as 8-OHG The generation of mitochondria-derived ROS is presented as a allows the incorporation of cytosine and adenine nucleotides schematic in Fig. 1. Initially, oxygen is catalyzed to transform opposite the lesion during DNA replication (39,40). Numerous into a superoxide anion by xanthine oxidase (XO) (17,18), or studies have reported that 8-OHG/8-OHdG is involved in by mitochondrial respiratory chain complexes I (NADH dehy- carcinogenesis and altered level of them demonstrated an drogenase) and III (bc1 complex) either in the matrix or in the association with pathogenesis of aging associated disease and intermembrane space (19). Subsequently, the superoxide anion cancer (41-43). For example, Ames and colleagues have found is converted to H O by superoxide dismutase (SOD). H O the age-dependent accumulation of 8-OHdG in DNA from 2 2 2 2 can be detoxie fi d to H O and O with glutathione peroxidase, various aged rat organs (44) and increased levels of 8-OHdG 2 2 catalase (CAT) or thioredoxin peroxidase (TPx) (20). It can and OH8Gua were shown in senescent human diploid br fi o - also be transformed into an OH• and an OH‑ via the Fenton blast (45). Mitochondrial dysfunction and the lack of protective reaction (21). mechanisms mean that mitochondrial DNA can be more easily and extensively exposed to ROS than nuclear DNA, which 3. Basic ways OS causes cell injury can result in irreversible DNA damage. In general, ROS and other OS-products attack cells through a variety of intricate OS causes cell injury predominantly via the following three pathways. The lipid peroxidation of membranes, the oxida- basic pathways: Lipid peroxidation of membranes; oxidative tive modic fi ation of proteins and DNA damage are the major modic fi ation of proteins; and DNA damage (17). Lipid peroxi- known mechanisms for oxidative cell damage. Improved dation affects cell membranes and other lipid-containing understanding the molecular mechanisms associated with OS structure via a process known as the ‘chain reaction of lipid will assist in the development of novel and reliable treatments, peroxidation’. The critical intermediate products of this as well as preventive measures, for various types of cancer, reaction are hydroperoxides (LOOHs), which can disturb particularly for leukemia. the membrane structure and endanger cells (22,23). It has been reported that the direct secondary products of lipid 4. Dual role of OS in leukemogenesis peroxidation are aldehydes, malondialdehyde (MDA) and 4-hydroxynonenal/4-hydroxy-2-nonenal (HNE) (24). These Leukemia develops when hematopoietic stem cells (HSC) lose products are considered to be the markers of OS, and their the capacity to differentiate normally into mature blood cells unique property of a no-charge structure allows them to at various stages during maturation and differentiation (46). easily permeate through membranes and into the cytosol, thus Hypoxia has emerged as a key regulator of stem cell biology causing far-reaching and damaging effects inside and outside and maintains HSC quiescence with a condition of metabolic the cells, rendering them superior to ROS (25,26). There is dormancy based on anaerobic glycolysis, which causes low evidence that HNE and MDA can cause protein or nucleic acid production of ROS and high antioxidant defense (47,48). damage by modifying the amino acid residues to form stable While hematopoietic cell differentiation is accompanied by adducts or covalent adducts with nucleic acids and membrane changes in oxidative metabolism, including a decrease in lipids (27,28). anaerobic glycolysis and an increase in oxidative phosphoryla- Oxidative modic fi ation of proteins is another pathway by tion, thus producing high levels of ROS (49-51). Furthermore, which OS causes cell damage, and thus serves a critical role evidences have indicated that leukemia stem cells (LSC) are in aging and cancer (29). MDA and HNE can react with and more dependent on oxidative respiration and are more sensi- covalently modify numerous proteins, including amyloid-β tive to OS, compared with normal HSCs (16). Although OS peptide, collapsing response mediator protein-2 (CRMP2) has been linked to the etiology and development of leukemia, and heat shock protein 70 (HSP70) (17,27,28). HNE- and numerous chemotherapeutic drugs exert their biological MDA-protein adducts, including alpha-enolase (ENO1), effects via the induction of OS in affected cells. Thus OS MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 Table I. Major intracellular sources of ROS. Reactive oxygen species Intracellular sources Compartment O Fenton reaction Mitochondria Lipid peroxidation chain reactions Cytosol Haber-Weiss reaction Peroxisomes Superoxide dismutase (SOD)-mediated reaction Nucleus Catalase-mediated reaction Plasma membrane Glutathione peroxidase-mediated reaction Endoplasmic reticulum Xanthine oxidase (XO)-mediated reaction Lysosome All membranes OH• Proton‑catalyzed decomposition of peroxynitrite Mitochondria Fenton reaction Cytosol Haber-Weiss reaction Endoplasmic reticulum Decomposition of ozone (O) Lysosome Beckman-Radi-Freeman pathway H O Superoxide dismutase (SOD)-mediated reaction Mitochondria 2 2 NADPH oxidase-mediated reaction Cytosol Cytochrome P450-mediated reaction Peroxisomes Xanthine oxidase (XO)-mediated reaction Plasma membrane Monoamine oxidases (MAO)-mediated reaction Endosomes Peroxisomal fatty acid oxidation Endoplasmic reticulum Flavin adenine dinucleotide (FAD)-mediated reaction Lysosome Antibody-catalyzed water (H O) oxidation Nucleus Electron‑transfer flavoprotein pathway O •‑ Fenton reaction Mitochondria NADH/NADPH oxidase (NOX)-mediated reaction Cytosol Xanthine oxidase (XO)-mediated reaction Plasma membrane Lipoxygenase pathway Peroxisomes Cyclooxygenase pathway Nucleus Cytochrome P450 monooxygenase reaction Endoplasmic reticulum Mitochondrial oxidative phosphorylation Electron‑transfer flavoprotein reaction Hemoglobin auto-oxidation (within erythrocyte) Nitric oxide synthases (NOS)-mediated reaction HOCL, HOBr, HOI, and HOSCN Eosinophil peroxidase (EPX)-mediated reaction (within eosinophil granulocytes) Cytosol Myeloperoxidase (MPO)-dependent oxidation (within neutrophil granulocytes) Endoplasmic reticulum Lysosome ZHANG et al: OXIDATIVE STRESS RESPONSE INDUCED BY CHEMOTHERAPY IN LEUKEMIA TREATMENT Table I. Continued. Reactive oxygen species Intracellular sources Compartment Vacuole Plasma membrane Mitochondria Nucleus OH- Fenton reaction Mitochondria Haber-Weiss reaction Cytosol Hydroperoxide (ROOH) decomposition Endoplasmic reticulum Lysosome 2- O • Peroxide is unstable molecule. Hydrogen peroxide is more stable molecule Mitochondria formed as described above. Cytosol Peroxisomes Plasma membrane Endosomes Endoplasmic reticulum Lysosome Nucleus O Ozone (O ) is unstable molecule generated during antibody catalyzed Cytosol 3 3 oxidation of H O to H O Mitochondria 2 2 2 NO• Nitric oxide synthases (NOS)‑mediated nitrite (NO -) reduction Cytosol Xanthine oxidase (XO) reducing nitrates and nitrites Peroxisomes Endoplasmic reticulum Plasma membrane Nucleus ONOO- Fenton reaction Mitochondria Rapid reaction of singlet oxygen (O ) and nitric oxide radical (NO•) Cytosol The reaction of hydrogen peroxide (H O ) with nitrite (NO-) Lysosome 2 2 2 Endoplasmic reticulum Nucleus Peroxisomes ROO•/RCOO•(Peroxyl radical) Lipid peroxidation chain reactions Cytosol Synthesis of eicosanoids Plasma membrane Hydroperoxide (ROOH) decomposition induced by heat or radiation Peroxisomes ROOH reaction with transition metal ions and other oxidants capable Endoplasmic reticulum of abstracting hydrogen Mitochondria Nucleus Lysosome MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 Table I. Continued. Reactive oxygen species Intracellular sources Compartment All membranes HO Fenton reaction Mitochondria Cytosol Endoplasmic reticulum Lysosome ROOH/RCOOH Lipoxygenase-mediated reaction Cytosol Oxidation of biomolecules, including lipids, proteins and DNA Plasma membrane Cyclooxygenase reaction Nucleus Cytochrome P450 monooxygenase reaction Endoplasmic reticulum Heme-peroxidase turnover Mitochondria Peroxisomes Lysosome R•, RO•, R‑S• Hydroperoxide (ROOH) decomposition induced by heat or radiation Cytosol ROOH reaction with transition metal ions and other oxidants capable Plasma membrane of abstracting hydrogen Mitochondria Lipid peroxidation chain reactions Lysosome Peroxisomes Endoplasmic reticulum Nucleus All membranes CO3•‑ The reaction between peroxynitrite and CO Mitochondria SOD-mediated reaction Cytosol XO-mediated reaction Peroxisomes Metal-ion catalyzed decomposition of HCO - Endoplasmic reticulum Peroxisomes Lysosome Vacuole Major intracellular sources of ROS. O , singlet oxygen; OH•, hydroxyl radical; H O , hydrogen peroxide; O •‑, superoxide anion; HOCL, HOBr, HOI, HOSCN, hypochlorous acid and associated species; 2 2 2 2 2- OH-, hydroxyl ion; O • , peroxide; O ozone; NO•, nitric oxide radical; ONOO‑, peroxynitrite; ROO•/RCOO•, peroxyl radical; HOO•, hydroperoxy radical; ROOH/RCOOH,organic hydroperoxide; R•; 2 3, RO• R‑S•, Organic radicals; CO3•‑, carbonate radical; SOD, superoxide dismutase; XO, xanthine oxidase; HCO -, peroxymonocarbonate. 4 ZHANG et al: OXIDATIVE STRESS RESPONSE INDUCED BY CHEMOTHERAPY IN LEUKEMIA TREATMENT activated protein kinase (Ras/MAPK), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signal pathway and the phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT) pathway (63). Ras/MAPK cascades consisting of mitogen-activated protein kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and 14-3-3β binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) pathways (64) are involved in cytokines and growth factors signaling transmission. The latter, including tumor necrosis factor (TNF)-α, interferon gamma (IFN-γ), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), bind to their receptors under extracellular or intracellular stimuli and subsequently activate a series of MAP kinases (MAPKKK, MAPKK, MAPK). The activated MAPKs phosphorylate various substrate proteins, resulting in the Figure 1. Schematic representation of the generation of mtROS. Complex I, regulation of various cellular activities (65-67). Each of NADH dehydrogenase; II, succinate dehydrogenase; III, bc 1 complex; aforementioned processes may be a target of ROS regulation. IV, cytochrome c oxidase; V, ATP synthase; Cyto c, cytochrome c; mPTP, For example, it has been demonstrated that ROS activates the mitochondrial permeability transition pore; SOD, superoxide dismutase; GPxs, glutathione peroxidase; TPx, thioredoxin peroxidase; mtROS, mito- receptors of EGF and PDGF without corresponding ligands, chondrial derived reactive oxygen species. thus stimulating Ras and activating the ERK pathway (68,69). Furthermore, in certain cells, treatment with H O leads to the 2 2 phosphorylation and activation of phospholipase C-γ (PLC-γ), serves a dual role in leukemogenesis. ROS have a pathogenic and results in the generation of inositol trisphosphate (IP3) role in various leukemia models, including CML, MDS and and diacylglycerol (DAG). The increase of the IP3 and DAG AML (14,52). First, BCR-ABL induces ROS production, which induces the release of calcium from intracellular stores, and then contributes to malignant transformation, cell growth, activates numerous forms of Protein Kinase C (PKC), leading resistance to apoptosis and increased DNA damage (53-55). to the activation of Ras and Raf and the initiation of ERK Second, FLT3-ITD mutants induce increased production of signaling (70,71). Akt is a serine/threonine kinase, recruited ROS, which are responsible for increased DNA double-strand to the cell membrane by PI3K and activated via phosphory- breaks and repair errors (56). Third, activated mutant Ras lation. The end result of PI3K/Akt pathway activation is the (N-Ras or H-Ras) induces the production of superoxide and stimulation of growth pathways and the inhibition of apop- H O in human CD34 cells through the stimulation of NOX-1 tosis, or vice versa. ROS not only activate PI3K directly to 2 2 (NADPH oxidase 1) activity; this effect promotes the growth amplify its downstream signaling, but also concurrently factor-independent proliferation of these cells (57). inactivate its negative regulator PTEN (72). For example, it is Conversely, ROS and lipid peroxidation by-products are reported that ROS can induce the phosphorylation of PTEN reported to be involved in mitochondria-derived apoptosis and via casein kinase II, thus urging it to enter the proteolytic the induction of cell death (6). It has been reported that ROS degradation pathway (73). ROS inu fl ence the NK‑ κB pathway or lipid peroxidation by-products primarily react to cardio- mainly through inhibiting IκBα phosphorylation and degra- lipin molecules in the inner mitochondrial membrane (IMM), dation, thus activating the NK-κB pathway. In addition, IKK which disturbs the cytochrome c-cardiolipin interaction and is the primary target for ROS through S-glutathionylation of promotes the release of cytochrome c into the cytoplasm, the IKKβ on cysteine 179, resulting in the inhibition of IKKβ finally resulting in caspase activation and causing cell activity (74,75). death (58,59). It has also been demonstrated that HNE reacts with the surrounding molecules near the site of its formation, 5. Association between OS and chemotherapy during thereby stimulating chain-reactions of mitochondria-derived leukemia treatment apoptosis (60). A recent study explored the molecular mecha- nisms responsible for the leukemogenesis effect of MLL-AF9 The current therapy for leukemia primarily consists of and revealed an essential role of MEIS1 (61). MEIS1 expres- high-dose cytotoxic chemotherapy with or without allogeneic sion in these leukemia types limits the extent of OS and stem cell transplantation. However, chemotherapeutic treat- responses for leukemia cell survival, while MEIS1 knockdown ments are often accompanied by elevated ROS levels, and in MLL-AF9 leukemic cells induces ROS production and the cause drug-intolerance or resistance correspondingly (75). inhibition of leukemic cell growth. Furthermore, a prior study The underlying mechanisms may be closely associated published by our group demonstrated that increased intracel- with the aforementioned ROS-mediated signaling pathway. lular ROS levels are important for the induction of cell death Chemotherapy impairs the mitotic and metabolic process of and the downregulation of BCR-ABL (62). cancer cells, involving various signal transmission abnormali- Furthermore, ROS participate in numerous cell growth ties or sub-cellular organ damage, thus causing excess ROS pathways by interfering with the regulation of certain genes production. Angsutararux et al (75) studied doxorubicin and signal transduction pathways, including tumor protein (DOX)-induced cardiotoxicity, and proposed that DOX is p53 mutation, activator protein-1 (AP-1) activation, vascular particularly harmful to the heart due to its exceptional effects endothelial growth factor (VEGF) or rat sarcoma/mitogen on mitochondria, which are the home of ROS. Petrola et al (76) MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 performed a clinical trial to evaluate OS through detecting the by OS and causes cell death. It is difc fi ult to separate the onco - levels of MDA and nitrite in patients with CML undergoing genic properties from the tumor suppressive activity. Therefore, treatment with 1st and 2nd generation TKIs. The results an improved understanding of the association between OS and indicated that TKIs caused signic fi antly high concentration of leukemogenesis will provide more insight for leukemia treat- ROS in patients CML who were undergoing these treatments, ments. Chemotherapy is a commonly used strategy for leukemia and that oxidative damage markers could indicate resistance treatment. However, the current cytotoxic drugs available for use to TKIs. Furthermore, it has been demonstrated that anthra- in standard leukemia therapy are often accompanied by elevated cyclines, including DOX, a type of important component of ROS production, and cause drug-intolerance or resistance. Thus, current cancer treatment, generate high levels of ROS and targeting ROS levels during chemotherapy could constitute cause severe chemotherapy-associated cardiotoxicity (77-79). a novel approach for various types of leukemia, particularly Therefore, combinations of antioxidants and chemotherapeutic for those of refractory and relapsed hematological neoplasms. agents perhaps have promising synergistic effects (80). The Indeed, studies have demonstrated that antioxidant treatments role of OS in DOX-induced cardiotoxicity can be attenuated combined with chemotherapy are effective in leukemia therapy, in a transgenic mouse model containing high levels of cardiac but their concurrent negative effects have also been recorded. metallothionein, a potent antioxidant (81). Nakayama et al (82) Therefore, further studies are required to explore the synergistic conducted a systematic review of published clinical trials to effects, long-term effects and consequences of using these examine the effects of dietary antioxidants taken concurrently combination therapies. Potentially, targeted OS therapy in with chemotherapy or radiation therapy. The results indicated combination with chemotherapy or other strategies may become that glutathione (GSH), vitamin E and N-acetysteine (NAC) a clinically useful therapeutic approach for various types of were the most frequently used antioxidant supplements in hematological diseases in the near future. combination with chemotherapy or radiation therapy for kinds of cancer treatments, including leukemia. GSH combined with Acknowledgements cisplatin (CDDP)-based chemotherapy accord for 88% of all the experiments (23/26), and adding GSH to CDDP-based The present study was supported by the National Natural chemotherapy could improve the antitumor response against Science Foundation of China (grant no. 81670178, 81370645), solid tumors and hematological malignancies; some also the Hangzhou Science and Technology Bureau (grant revealed a neuroprotective effect. Another study reported no. 20140633B06) and the Special Scientific Construction a trend of longer clinical PFS and OS in patients with CML Research Funds of National Chinese Medicine Clinical when they were treated with vitamin A in combination with Research Center, SATCM (grant no. JDZX2015113). standard chemotherapy, although this trend was not statisti- cally signic fi ant ( 83). Competing interests However, there are conflicting opinions regarding the administration of antioxidants during cancer therapy. 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Oncogene 33: 1385-1394, http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular and Clinical Oncology Pubmed Central

Oxidative stress response induced by chemotherapy in leukemia treatment

Molecular and Clinical Oncology , Volume 8 (3) – Jan 10, 2018

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10.3892/mco.2018.1549
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Abstract

MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 Oxidative stress response induced by chemotherapy in leukemia treatment (Review) 1* 2* 3 4 2 JIN ZHANG , WEN LEI , XIAOHUI CHEN , SHIBING WANG and WENBIN QIAN Department of Hematology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016; Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003; Department of Hematology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China Received February 6, 2017; Accepted December 6, 2017 DOI: 10.3892/mco.2018.1549 Abstract. Oxidative stress (OS) has been linked to the etiology Contents and development of leukemia as reactive oxygen species (ROS) and free radicals have been implicated in leukemogenesis. OS 1. Introduction has benec fi ial and deleterious effects in the pathogenesis and 2. OS and the generation of ROS progression of leukemia. High-dose chemotherapy, which 3. Basic ways OS causes cell injury is frequently used in leukemia treatment, is often accompa- 4. Dual role of OS in leukemogenesis nied by ROS-induced cytotoxicity. Thus, the utilization of 5. Association between OS and chemotherapy during chemotherapy in combination with antioxidants may attenuate leukemia treatment leukemia progression, particularly for cases of refractory or 6. Conclusion relapsed neoplasms. The present review focuses on exploring the roles of OS in leukemogenesis and characterizing the asso- ciations between ROS and chemotherapy. Certain examples of 1. Introduction treatment regimens wherein antioxidants are combined with chemotherapy are presented, in order to highlight the impor- Oxidative stress (OS) refers to the cellular environment condi- tance of antioxidant application in leukemia treatment, as well tions that result from an imbalance between the generation of as the conflicting opinions regarding this method of therapy. reactive oxygen species (ROS) and the response of the antioxi- Understanding the underlying mechanisms of OS generation dant defense systems (1). ROS are short-lived highly reactive will facilitate the elucidation of novel approaches to leukemia molecules and serve a critical role in the progression of OS. treatment. ROS were identie fi d as free radicals for the first time in 1954 by Gerschman (2). They are metabolites produced during normal cellular processes, which serve important roles in activities such as promoting health and longevity (3) and antimicrobial phagocytosis by cells of the innate immune system (4,5). The over-generation of ROS without an adequate response from the innate antioxidant system to maintain the homeostasis even- tually leads to OS. ROS serve a dual role in tumorigenicity, Correspondence to: Dr Shibing Wang, Clinical Research Institute, particularly in hematologic malignancies. ROS can induce the Zhejiang Provincial People's Hospital, 158 Shangtang Road, activation of cell death processes, including apoptosis, which Hangzhou, Zhejiang 310014, P.R. China provides a mechanism for cancer treatment (6); however, it can E-mail: shibwang@163.com also facilitate carcinogenesis by protecting the cell from apop- Professor Wenbin Qian, Department of Hematology, The First tosis and promoting cell survival, inducing proliferation (7), Affiliated Hospital, College of Medicine, Zhejiang University, migration (8), metastasis (9) and drug-resistance (10,11). It 79 Qingchun Road, Hangzhou, Zhejiang 310003, P.R. China has been reported that OS is involved in the development of a E-mail: qianwenb@hotmail.com number of hematologic malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodys- Contributed equally plastic syndrome (MDS) and acute lymphoblastic leukemia Key words: oxidative stress, reactive oxygen species, (ALL) (12-16). Numerous methods including the use of chemo- leukemogenesis, chemotherapy therapeutic agents and radiation are reported to generate ROS or other free radicals in patients undergoing cancer therapy. The present review focused on exploring the role of OS in leukemogenesis and determining the association between ROS ZHANG et al: OXIDATIVE STRESS RESPONSE INDUCED BY CHEMOTHERAPY IN LEUKEMIA TREATMENT and chemotherapy, as well as highlighting the importance of phosphoglycerate kinase 1 (PGK1), triosephosphate isomerase antioxidant application in leukemia treatment. Improving (TPI) and pyruvate kinase (PK), are reported to be involved current understanding of the underlying mechanisms of in cellular senescence and cancer (30-33). Besides MDA and OS generation in leukemogenesis will facilitate significant HNE, ROS-mediated protein oxidation also can be measured progress in developing novel therapeutic measures for various via the concentration of carbonyl groups, advanced oxidation types of leukemia. protein products (AOPPS), advanced glycation end products (AGE) and S-nitrosylated proteins, which are considered to be 2. OS and the generation of ROS novel markers for OS due to their long half-life and their ease of detection (34). OS is a biochemical condition that occurs when intracellular With respect to oxidative DNA damage, ROS and prod- antioxidants are unable to neutralize pro-oxidants, such as ucts of lipid peroxidation can have an effect on genomic ROS. Mitochondria are the primary sites for oxidative phos- and mitochondrial DNA, leading to various types of DNA phorylation, which produces massive highly reactive and damage (35,36). The replication of damaged DNA prior to unstable oxygen, thus oxidizing a large number of molecules repair results in DNA mutations and genomic instability, subse- to form ROS (17). ROS are generated intracellularly within quently leading to a variety of disorders and tumorigenesis. various compartments and through multiple mechanisms The molecule 8-oxoGuanine (8-OHG) and its nucleoside form (Table I). Mitochondria-derived ROS consist of singlet oxygen 8-OHdG are considered to be indicators of oxidative DNA (O ), superoxide anions (O •‑), hydrogen peroxide (H O ), nitric damage in vivo and in vitro (37,38). The presence of 8-OHG 2 2 2 2 oxide (NO•), hydroxyl radicals (OH•) and hydroxyl ions (OH‑). in the DNA caused a G-T and a C-A transversion, as 8-OHG The generation of mitochondria-derived ROS is presented as a allows the incorporation of cytosine and adenine nucleotides schematic in Fig. 1. Initially, oxygen is catalyzed to transform opposite the lesion during DNA replication (39,40). Numerous into a superoxide anion by xanthine oxidase (XO) (17,18), or studies have reported that 8-OHG/8-OHdG is involved in by mitochondrial respiratory chain complexes I (NADH dehy- carcinogenesis and altered level of them demonstrated an drogenase) and III (bc1 complex) either in the matrix or in the association with pathogenesis of aging associated disease and intermembrane space (19). Subsequently, the superoxide anion cancer (41-43). For example, Ames and colleagues have found is converted to H O by superoxide dismutase (SOD). H O the age-dependent accumulation of 8-OHdG in DNA from 2 2 2 2 can be detoxie fi d to H O and O with glutathione peroxidase, various aged rat organs (44) and increased levels of 8-OHdG 2 2 catalase (CAT) or thioredoxin peroxidase (TPx) (20). It can and OH8Gua were shown in senescent human diploid br fi o - also be transformed into an OH• and an OH‑ via the Fenton blast (45). Mitochondrial dysfunction and the lack of protective reaction (21). mechanisms mean that mitochondrial DNA can be more easily and extensively exposed to ROS than nuclear DNA, which 3. Basic ways OS causes cell injury can result in irreversible DNA damage. In general, ROS and other OS-products attack cells through a variety of intricate OS causes cell injury predominantly via the following three pathways. The lipid peroxidation of membranes, the oxida- basic pathways: Lipid peroxidation of membranes; oxidative tive modic fi ation of proteins and DNA damage are the major modic fi ation of proteins; and DNA damage (17). Lipid peroxi- known mechanisms for oxidative cell damage. Improved dation affects cell membranes and other lipid-containing understanding the molecular mechanisms associated with OS structure via a process known as the ‘chain reaction of lipid will assist in the development of novel and reliable treatments, peroxidation’. The critical intermediate products of this as well as preventive measures, for various types of cancer, reaction are hydroperoxides (LOOHs), which can disturb particularly for leukemia. the membrane structure and endanger cells (22,23). It has been reported that the direct secondary products of lipid 4. Dual role of OS in leukemogenesis peroxidation are aldehydes, malondialdehyde (MDA) and 4-hydroxynonenal/4-hydroxy-2-nonenal (HNE) (24). These Leukemia develops when hematopoietic stem cells (HSC) lose products are considered to be the markers of OS, and their the capacity to differentiate normally into mature blood cells unique property of a no-charge structure allows them to at various stages during maturation and differentiation (46). easily permeate through membranes and into the cytosol, thus Hypoxia has emerged as a key regulator of stem cell biology causing far-reaching and damaging effects inside and outside and maintains HSC quiescence with a condition of metabolic the cells, rendering them superior to ROS (25,26). There is dormancy based on anaerobic glycolysis, which causes low evidence that HNE and MDA can cause protein or nucleic acid production of ROS and high antioxidant defense (47,48). damage by modifying the amino acid residues to form stable While hematopoietic cell differentiation is accompanied by adducts or covalent adducts with nucleic acids and membrane changes in oxidative metabolism, including a decrease in lipids (27,28). anaerobic glycolysis and an increase in oxidative phosphoryla- Oxidative modic fi ation of proteins is another pathway by tion, thus producing high levels of ROS (49-51). Furthermore, which OS causes cell damage, and thus serves a critical role evidences have indicated that leukemia stem cells (LSC) are in aging and cancer (29). MDA and HNE can react with and more dependent on oxidative respiration and are more sensi- covalently modify numerous proteins, including amyloid-β tive to OS, compared with normal HSCs (16). Although OS peptide, collapsing response mediator protein-2 (CRMP2) has been linked to the etiology and development of leukemia, and heat shock protein 70 (HSP70) (17,27,28). HNE- and numerous chemotherapeutic drugs exert their biological MDA-protein adducts, including alpha-enolase (ENO1), effects via the induction of OS in affected cells. Thus OS MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 Table I. Major intracellular sources of ROS. Reactive oxygen species Intracellular sources Compartment O Fenton reaction Mitochondria Lipid peroxidation chain reactions Cytosol Haber-Weiss reaction Peroxisomes Superoxide dismutase (SOD)-mediated reaction Nucleus Catalase-mediated reaction Plasma membrane Glutathione peroxidase-mediated reaction Endoplasmic reticulum Xanthine oxidase (XO)-mediated reaction Lysosome All membranes OH• Proton‑catalyzed decomposition of peroxynitrite Mitochondria Fenton reaction Cytosol Haber-Weiss reaction Endoplasmic reticulum Decomposition of ozone (O) Lysosome Beckman-Radi-Freeman pathway H O Superoxide dismutase (SOD)-mediated reaction Mitochondria 2 2 NADPH oxidase-mediated reaction Cytosol Cytochrome P450-mediated reaction Peroxisomes Xanthine oxidase (XO)-mediated reaction Plasma membrane Monoamine oxidases (MAO)-mediated reaction Endosomes Peroxisomal fatty acid oxidation Endoplasmic reticulum Flavin adenine dinucleotide (FAD)-mediated reaction Lysosome Antibody-catalyzed water (H O) oxidation Nucleus Electron‑transfer flavoprotein pathway O •‑ Fenton reaction Mitochondria NADH/NADPH oxidase (NOX)-mediated reaction Cytosol Xanthine oxidase (XO)-mediated reaction Plasma membrane Lipoxygenase pathway Peroxisomes Cyclooxygenase pathway Nucleus Cytochrome P450 monooxygenase reaction Endoplasmic reticulum Mitochondrial oxidative phosphorylation Electron‑transfer flavoprotein reaction Hemoglobin auto-oxidation (within erythrocyte) Nitric oxide synthases (NOS)-mediated reaction HOCL, HOBr, HOI, and HOSCN Eosinophil peroxidase (EPX)-mediated reaction (within eosinophil granulocytes) Cytosol Myeloperoxidase (MPO)-dependent oxidation (within neutrophil granulocytes) Endoplasmic reticulum Lysosome ZHANG et al: OXIDATIVE STRESS RESPONSE INDUCED BY CHEMOTHERAPY IN LEUKEMIA TREATMENT Table I. Continued. Reactive oxygen species Intracellular sources Compartment Vacuole Plasma membrane Mitochondria Nucleus OH- Fenton reaction Mitochondria Haber-Weiss reaction Cytosol Hydroperoxide (ROOH) decomposition Endoplasmic reticulum Lysosome 2- O • Peroxide is unstable molecule. Hydrogen peroxide is more stable molecule Mitochondria formed as described above. Cytosol Peroxisomes Plasma membrane Endosomes Endoplasmic reticulum Lysosome Nucleus O Ozone (O ) is unstable molecule generated during antibody catalyzed Cytosol 3 3 oxidation of H O to H O Mitochondria 2 2 2 NO• Nitric oxide synthases (NOS)‑mediated nitrite (NO -) reduction Cytosol Xanthine oxidase (XO) reducing nitrates and nitrites Peroxisomes Endoplasmic reticulum Plasma membrane Nucleus ONOO- Fenton reaction Mitochondria Rapid reaction of singlet oxygen (O ) and nitric oxide radical (NO•) Cytosol The reaction of hydrogen peroxide (H O ) with nitrite (NO-) Lysosome 2 2 2 Endoplasmic reticulum Nucleus Peroxisomes ROO•/RCOO•(Peroxyl radical) Lipid peroxidation chain reactions Cytosol Synthesis of eicosanoids Plasma membrane Hydroperoxide (ROOH) decomposition induced by heat or radiation Peroxisomes ROOH reaction with transition metal ions and other oxidants capable Endoplasmic reticulum of abstracting hydrogen Mitochondria Nucleus Lysosome MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 Table I. Continued. Reactive oxygen species Intracellular sources Compartment All membranes HO Fenton reaction Mitochondria Cytosol Endoplasmic reticulum Lysosome ROOH/RCOOH Lipoxygenase-mediated reaction Cytosol Oxidation of biomolecules, including lipids, proteins and DNA Plasma membrane Cyclooxygenase reaction Nucleus Cytochrome P450 monooxygenase reaction Endoplasmic reticulum Heme-peroxidase turnover Mitochondria Peroxisomes Lysosome R•, RO•, R‑S• Hydroperoxide (ROOH) decomposition induced by heat or radiation Cytosol ROOH reaction with transition metal ions and other oxidants capable Plasma membrane of abstracting hydrogen Mitochondria Lipid peroxidation chain reactions Lysosome Peroxisomes Endoplasmic reticulum Nucleus All membranes CO3•‑ The reaction between peroxynitrite and CO Mitochondria SOD-mediated reaction Cytosol XO-mediated reaction Peroxisomes Metal-ion catalyzed decomposition of HCO - Endoplasmic reticulum Peroxisomes Lysosome Vacuole Major intracellular sources of ROS. O , singlet oxygen; OH•, hydroxyl radical; H O , hydrogen peroxide; O •‑, superoxide anion; HOCL, HOBr, HOI, HOSCN, hypochlorous acid and associated species; 2 2 2 2 2- OH-, hydroxyl ion; O • , peroxide; O ozone; NO•, nitric oxide radical; ONOO‑, peroxynitrite; ROO•/RCOO•, peroxyl radical; HOO•, hydroperoxy radical; ROOH/RCOOH,organic hydroperoxide; R•; 2 3, RO• R‑S•, Organic radicals; CO3•‑, carbonate radical; SOD, superoxide dismutase; XO, xanthine oxidase; HCO -, peroxymonocarbonate. 4 ZHANG et al: OXIDATIVE STRESS RESPONSE INDUCED BY CHEMOTHERAPY IN LEUKEMIA TREATMENT activated protein kinase (Ras/MAPK), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signal pathway and the phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT) pathway (63). Ras/MAPK cascades consisting of mitogen-activated protein kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and 14-3-3β binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) pathways (64) are involved in cytokines and growth factors signaling transmission. The latter, including tumor necrosis factor (TNF)-α, interferon gamma (IFN-γ), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), bind to their receptors under extracellular or intracellular stimuli and subsequently activate a series of MAP kinases (MAPKKK, MAPKK, MAPK). The activated MAPKs phosphorylate various substrate proteins, resulting in the Figure 1. Schematic representation of the generation of mtROS. Complex I, regulation of various cellular activities (65-67). Each of NADH dehydrogenase; II, succinate dehydrogenase; III, bc 1 complex; aforementioned processes may be a target of ROS regulation. IV, cytochrome c oxidase; V, ATP synthase; Cyto c, cytochrome c; mPTP, For example, it has been demonstrated that ROS activates the mitochondrial permeability transition pore; SOD, superoxide dismutase; GPxs, glutathione peroxidase; TPx, thioredoxin peroxidase; mtROS, mito- receptors of EGF and PDGF without corresponding ligands, chondrial derived reactive oxygen species. thus stimulating Ras and activating the ERK pathway (68,69). Furthermore, in certain cells, treatment with H O leads to the 2 2 phosphorylation and activation of phospholipase C-γ (PLC-γ), serves a dual role in leukemogenesis. ROS have a pathogenic and results in the generation of inositol trisphosphate (IP3) role in various leukemia models, including CML, MDS and and diacylglycerol (DAG). The increase of the IP3 and DAG AML (14,52). First, BCR-ABL induces ROS production, which induces the release of calcium from intracellular stores, and then contributes to malignant transformation, cell growth, activates numerous forms of Protein Kinase C (PKC), leading resistance to apoptosis and increased DNA damage (53-55). to the activation of Ras and Raf and the initiation of ERK Second, FLT3-ITD mutants induce increased production of signaling (70,71). Akt is a serine/threonine kinase, recruited ROS, which are responsible for increased DNA double-strand to the cell membrane by PI3K and activated via phosphory- breaks and repair errors (56). Third, activated mutant Ras lation. The end result of PI3K/Akt pathway activation is the (N-Ras or H-Ras) induces the production of superoxide and stimulation of growth pathways and the inhibition of apop- H O in human CD34 cells through the stimulation of NOX-1 tosis, or vice versa. ROS not only activate PI3K directly to 2 2 (NADPH oxidase 1) activity; this effect promotes the growth amplify its downstream signaling, but also concurrently factor-independent proliferation of these cells (57). inactivate its negative regulator PTEN (72). For example, it is Conversely, ROS and lipid peroxidation by-products are reported that ROS can induce the phosphorylation of PTEN reported to be involved in mitochondria-derived apoptosis and via casein kinase II, thus urging it to enter the proteolytic the induction of cell death (6). It has been reported that ROS degradation pathway (73). ROS inu fl ence the NK‑ κB pathway or lipid peroxidation by-products primarily react to cardio- mainly through inhibiting IκBα phosphorylation and degra- lipin molecules in the inner mitochondrial membrane (IMM), dation, thus activating the NK-κB pathway. In addition, IKK which disturbs the cytochrome c-cardiolipin interaction and is the primary target for ROS through S-glutathionylation of promotes the release of cytochrome c into the cytoplasm, the IKKβ on cysteine 179, resulting in the inhibition of IKKβ finally resulting in caspase activation and causing cell activity (74,75). death (58,59). It has also been demonstrated that HNE reacts with the surrounding molecules near the site of its formation, 5. Association between OS and chemotherapy during thereby stimulating chain-reactions of mitochondria-derived leukemia treatment apoptosis (60). A recent study explored the molecular mecha- nisms responsible for the leukemogenesis effect of MLL-AF9 The current therapy for leukemia primarily consists of and revealed an essential role of MEIS1 (61). MEIS1 expres- high-dose cytotoxic chemotherapy with or without allogeneic sion in these leukemia types limits the extent of OS and stem cell transplantation. However, chemotherapeutic treat- responses for leukemia cell survival, while MEIS1 knockdown ments are often accompanied by elevated ROS levels, and in MLL-AF9 leukemic cells induces ROS production and the cause drug-intolerance or resistance correspondingly (75). inhibition of leukemic cell growth. Furthermore, a prior study The underlying mechanisms may be closely associated published by our group demonstrated that increased intracel- with the aforementioned ROS-mediated signaling pathway. lular ROS levels are important for the induction of cell death Chemotherapy impairs the mitotic and metabolic process of and the downregulation of BCR-ABL (62). cancer cells, involving various signal transmission abnormali- Furthermore, ROS participate in numerous cell growth ties or sub-cellular organ damage, thus causing excess ROS pathways by interfering with the regulation of certain genes production. Angsutararux et al (75) studied doxorubicin and signal transduction pathways, including tumor protein (DOX)-induced cardiotoxicity, and proposed that DOX is p53 mutation, activator protein-1 (AP-1) activation, vascular particularly harmful to the heart due to its exceptional effects endothelial growth factor (VEGF) or rat sarcoma/mitogen on mitochondria, which are the home of ROS. Petrola et al (76) MOLECULAR AND CLINICAL ONCOLOGY 8: 391-399, 2018 performed a clinical trial to evaluate OS through detecting the by OS and causes cell death. It is difc fi ult to separate the onco - levels of MDA and nitrite in patients with CML undergoing genic properties from the tumor suppressive activity. Therefore, treatment with 1st and 2nd generation TKIs. The results an improved understanding of the association between OS and indicated that TKIs caused signic fi antly high concentration of leukemogenesis will provide more insight for leukemia treat- ROS in patients CML who were undergoing these treatments, ments. Chemotherapy is a commonly used strategy for leukemia and that oxidative damage markers could indicate resistance treatment. However, the current cytotoxic drugs available for use to TKIs. Furthermore, it has been demonstrated that anthra- in standard leukemia therapy are often accompanied by elevated cyclines, including DOX, a type of important component of ROS production, and cause drug-intolerance or resistance. Thus, current cancer treatment, generate high levels of ROS and targeting ROS levels during chemotherapy could constitute cause severe chemotherapy-associated cardiotoxicity (77-79). a novel approach for various types of leukemia, particularly Therefore, combinations of antioxidants and chemotherapeutic for those of refractory and relapsed hematological neoplasms. agents perhaps have promising synergistic effects (80). The Indeed, studies have demonstrated that antioxidant treatments role of OS in DOX-induced cardiotoxicity can be attenuated combined with chemotherapy are effective in leukemia therapy, in a transgenic mouse model containing high levels of cardiac but their concurrent negative effects have also been recorded. metallothionein, a potent antioxidant (81). Nakayama et al (82) Therefore, further studies are required to explore the synergistic conducted a systematic review of published clinical trials to effects, long-term effects and consequences of using these examine the effects of dietary antioxidants taken concurrently combination therapies. Potentially, targeted OS therapy in with chemotherapy or radiation therapy. The results indicated combination with chemotherapy or other strategies may become that glutathione (GSH), vitamin E and N-acetysteine (NAC) a clinically useful therapeutic approach for various types of were the most frequently used antioxidant supplements in hematological diseases in the near future. combination with chemotherapy or radiation therapy for kinds of cancer treatments, including leukemia. GSH combined with Acknowledgements cisplatin (CDDP)-based chemotherapy accord for 88% of all the experiments (23/26), and adding GSH to CDDP-based The present study was supported by the National Natural chemotherapy could improve the antitumor response against Science Foundation of China (grant no. 81670178, 81370645), solid tumors and hematological malignancies; some also the Hangzhou Science and Technology Bureau (grant revealed a neuroprotective effect. Another study reported no. 20140633B06) and the Special Scientific Construction a trend of longer clinical PFS and OS in patients with CML Research Funds of National Chinese Medicine Clinical when they were treated with vitamin A in combination with Research Center, SATCM (grant no. JDZX2015113). standard chemotherapy, although this trend was not statisti- cally signic fi ant ( 83). Competing interests However, there are conflicting opinions regarding the administration of antioxidants during cancer therapy. 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