Bentham Briefs in Biomedicine and Pharmacotherapy Oxidative Stress and Natural Antioxidants E-Book
76,64 €
Mehr erfahren.
- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
Bentham Briefs in Biomedicine and Pharmacotherapy brings new trends and techniques in pharmacology and medical biochemistry to the forefront through unique volumes. Each volume provides a brief review of selected topics, written by scientific experts. The book series is essential reading for graduate students and researchers in pharmacology and life sciences as well as medical professionals seeking knowledge for research oriented projects.
The first volume, Oxidative Stress and Natural Antioxidants, is a compilation of articles about free radicals (which are extremely reactive, short-lived molecules with unpaired electron valency), and antioxidants (which are stabilizing agents of free radicals in the body). The volume presents 17 chapters on the biochemistry of free radicals and antioxidants, with contributions from over 60 scientists. Readers will understand the basic and clinical aspects of free radical biomedicine, the role of antioxidants in neutralizing free radicals through physiological homeostasis, as well as the range of natural compounds which can be used to combat oxidative stress. The chapters also cover special topics such as recent advances in preparation methods of antioxidants, and industrial applications of antioxidants. The range of topics in this volume provide a consolidated reference for a broad set of readers on the subject.
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 936
Veröffentlichungsjahr: 2021
Ähnliche
BENTHAM SCIENCE PUBLISHERS LTD.
End User License Agreement (for non-institutional, personal use)
This is an agreement between you and Bentham Science Publishers Ltd. Please read this License Agreement carefully before using the book/echapter/ejournal (“Work”). Your use of the Work constitutes your agreement to the terms and conditions set forth in this License Agreement. If you do not agree to these terms and conditions then you should not use the Work.
Bentham Science Publishers agrees to grant you a non-exclusive, non-transferable limited license to use the Work subject to and in accordance with the following terms and conditions. This License Agreement is for non-library, personal use only. For a library / institutional / multi user license in respect of the Work, please contact: [email protected].
Usage Rules:
All rights reserved: The Work is the subject of copyright and Bentham Science Publishers either owns the Work (and the copyright in it) or is licensed to distribute the Work. You shall not copy, reproduce, modify, remove, delete, augment, add to, publish, transmit, sell, resell, create derivative works from, or in any way exploit the Work or make the Work available for others to do any of the same, in any form or by any means, in whole or in part, in each case without the prior written permission of Bentham Science Publishers, unless stated otherwise in this License Agreement.You may download a copy of the Work on one occasion to one personal computer (including tablet, laptop, desktop, or other such devices). You may make one back-up copy of the Work to avoid losing it.The unauthorised use or distribution of copyrighted or other proprietary content is illegal and could subject you to liability for substantial money damages. You will be liable for any damage resulting from your misuse of the Work or any violation of this License Agreement, including any infringement by you of copyrights or proprietary rights.Disclaimer:
Bentham Science Publishers does not guarantee that the information in the Work is error-free, or warrant that it will meet your requirements or that access to the Work will be uninterrupted or error-free. The Work is provided "as is" without warranty of any kind, either express or implied or statutory, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. The entire risk as to the results and performance of the Work is assumed by you. No responsibility is assumed by Bentham Science Publishers, its staff, editors and/or authors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products instruction, advertisements or ideas contained in the Work.
Limitation of Liability:
In no event will Bentham Science Publishers, its staff, editors and/or authors, be liable for any damages, including, without limitation, special, incidental and/or consequential damages and/or damages for lost data and/or profits arising out of (whether directly or indirectly) the use or inability to use the Work. The entire liability of Bentham Science Publishers shall be limited to the amount actually paid by you for the Work.
General:
Any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims) will be governed by and construed in accordance with the laws of Singapore. Each party agrees that the courts of the state of Singapore shall have exclusive jurisdiction to settle any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims).Your rights under this License Agreement will automatically terminate without notice and without the need for a court order if at any point you breach any terms of this License Agreement. In no event will any delay or failure by Bentham Science Publishers in enforcing your compliance with this License Agreement constitute a waiver of any of its rights.You acknowledge that you have read this License Agreement, and agree to be bound by its terms and conditions. To the extent that any other terms and conditions presented on any website of Bentham Science Publishers conflict with, or are inconsistent with, the terms and conditions set out in this License Agreement, you acknowledge that the terms and conditions set out in this License Agreement shall prevail.Bentham Science Publishers Pte. Ltd. 80 Robinson Road #02-00 Singapore 068898 Singapore Email: [email protected]
FOREWORD
I am pleased to write this foreword for the e-book entitled ‘Oxidative Stress and Natural Antioxidants’. This outstanding endeavor by the co-editors represents a multi-disciplinary coverage of all aspects of oxidative stress and the role of anti-oxidants in this fundamental phenomenon. This e-book represents an effective compilation of chapters on the fundamentals of oxidative stress and the role of anti-oxidants in health and disease. The authors deserve credit for their time and effort to contribute excellent chapters relevant to their individual expertise. These chapters include excellent discussions on oxidative stress in human physiology, redox homeostasis, functions of free radicals and intrinsic cellular mechanisms for naturally occurring anti-oxidants. I am confident that this book will be a valuable addition to the bookshelves of teaching faculty, established investigators and young graduate students. I wish all, the success for the launch of this book.
PREFACE
“Oxidative Stress and Natural Antioxidants” presents the one pot solution for the interested readers ranging from an understanding of oxidative stress, recent advances in preparation methods, characterization, and applications of antioxidants. Taken altogether, the gathered information in this volume will cover an array of topics highlighting the importance of natural antioxidants in various oxidative stress associated diseases.
The scientific framework of this e-book contains chapters by eminent experts with in-depth knowledge of antioxidants and oxidative stress. The chapters comprise the role of reactive oxygen species and environmental contaminants in redox homeostasis with cellular mechanisms in oxidative stress that trigger the development and progression of many diseases. The literature includes the extraction, profiling, and characterization of antioxidants via different procedures and screening assays. Further, the chapters deliberate the role of antioxidants in human physiology, redox homeostasis, intrinsic cellular mechanisms, and their therapeutic potential with industrial prospects. Authors whose names appear on the chapters have remarkably contributed to the scientific work in this ebook and are responsible and accountable for any scientific queries or questions.
We believe that the chapters published in this volume will enrich the understanding of interdisciplinary domains of natural products as well as offer insights into emerging avenues in drug discovery trends.
List of Contributors
Level of Oxidative Stress: A Fate-Determiner of Carcinogenesis and Anti-Carcinogenesis
Suchisnigdha Datta1,Priyanka Saha1,Dona Sinha1,*Abstract
Molecular oxygen, a double-edged sword, is both a boon and a curse for the existence of life. Oxidative stress is the disequilibrium between reactive oxygen (ROS)-generation and elimination that inflicts cellular damage. Living cells can adapt to the ever-changing internal or external stresses. However, they gradually lose their radical-scavenging adaptability with persistent stress, which further increases during neoplasia. Cancer cells, well adapted in pro-oxidative milieu, drive metabolic and genomic reprogramming, which further escalates the oxidative load. This vicious cycle promotes further carcinogenic alterations. Contrastingly, the same ROS is essential for the oxidative-burst mediated anticancer host-defense. To sustain this redox pressure, cancer cells hijack the intracellular antioxidants. Therefore, redox reorientation towards enhanced responsiveness may selectively target malignant cells by ROS-enhancement beyond tolerance leading to mortality. Carcinogenesis, a multistep process, requires ROS during initiation, promotion and progression. However, supraphysiological ROS may induce apoptosis in unmanageable malignancies. Interestingly cells possess an evolutionary-conserved nature to get hormetically pre-conditioned by a transient ultra-low exposure of a stressor, which in higher dose may show the opposite effect. Antioxidants are excellent chemopreventives and chemotherapeutics. Here, we have condensed the possible anticancer modulation of oxidative stress by phytochemicals, aiming at an insight for future strategies in cancer management.
OXIDATIVE STRESS: ORIGIN, DEFINITION AND FEATURES
Oxygen, which is indispensable for existence of all aerobic life forms, becomes lethal when in excess. ROS are oxygen-containing highly reactive species that are produced due to cellular metabolism or environmental stress and can damage nucleic acids, lipids, and proteins structurally and functionally (Jelic et al. 2019). ROS are a broad class of chemicals that includes partially oxidized radicals with unpaired electrons, such as superoxide ion (O2•-) and hydroxyl radical (OH•), and non-radicals, such as singlet oxygen (1O2), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl).
The origin and evolution of aerobic life on Earth was accompanied by ROS and oxidative stress, which has emerged as a concept in redox biology in the past 60-odd years. Oxidative stress was defined by Jones as “an imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage” (Sies 2017). The endogenous sources of oxidants are inflammatory cells, mitochondria, and peroxisomes which produce mostly H2O2 and O2•- as ROS molecules (Jelic et al. 2019). Exposomes, which include all the exogenous sources, can be direct environmental oxidants such as pollution, cigarette smoke, microbes, allergens, pesticides and ionizing or solar (UV, visible, infrared-A) radiations. Oxidative stress can be stratified according to intensity ranging from physiological oxidative stress (eustress) essential for redox signaling to supraphysiological oxidative burden (distress), which damages biomolecules (Sies 2017).
Oxidative stress markers can be divided into three categories (Valadez-Vega et al. 2013):
Modified molecules (nucleotide, protein, lipid) formed by the action of free radicalsAntioxidant molecules or enzymesSecond messengers and transcription factorsWhen the ROS production or accumulation exceeds the antioxidant defence, redox imbalance becomes inevitable, which leads to toxic effects on the structural and functional integrity of biological tissues. This imbalance can either arise because of the rise in the ROS production or fall in the antioxidant defence or both. Therefore the main mechanism of antioxidant action is either a) suppression of ROS production b) scavenging free radicals c) upregulation of antioxidative defence or a combination of all these (Valadez-Vega et al. 2013). To counteract this inevitable exposure to free radicals from several sources, our physiological system has evolved to develop following mechanisms:
Preventive mechanismsRepair mechanismsPhysical defencesAntioxidant defencesEffect of Oxidative Stress on Life and Disease
Though the average age has increased over the past few decades, simultaneously, the cancer burden has also risen to 19.3 million new cases and 10 million cancer deaths in 2020 (Sung et al. 2021). Persistently elevated ROS causes oxidative stress, which plays a vital role in the development of many age-associated diseases, including cancer. Even in the presence of the cell’s defence system, oxidative damage acquires throughout the life (Arsova-Sarafinovska and Dimovski 2013). Though the production of ROS enhances during aging, proper ROS signaling is an essential requirement for healthy aging as it can regulate the lifespan directly. Endogenous and exogenous antioxidants can prevent and repair damage caused by ROS. Therefore, they can lower the risk of chronic-ROS driven diseases, including cancer or may even improve its prognosis.
Enzymatic antioxidants, like superoxide dismutase (SOD), glutathione peroxidase (GPx), NADPH quinone dehydrogenase (NQO) and catalase (CAT), act by chelating superoxide and other peroxides. In addition, non-enzymatic antioxidants (flavonoids, alkaloids, thiols, vitamins E and C, coenzyme Q, histidine, carotene, retinoic acid and glutathione) serve as an important biological defence against ROS attack (Sies 2017). In fact, the process of carcinogenesis is intricately linked with the inherited or acquired defects in enzymes responsible for the redox-mediated signaling axis (Tan et al. 2018). Therefore, the efficacy of antioxidant molecules that promote chemoprevention or chemotherapy by counteracting oxidative stress is of prior importance. In this chapter, we have highlighted the molecular mechanisms of antioxidants/prooxidants associated with anticancer management.
PHYSIOLOGICAL IMPORTANCE OF ROS
ROS can stimulate pro-inflammatory cytokine secretion from phagocytic cells, fibroblasts, and chondrocytes which can lead to acute disease conditions like, systemic inflammatory response, acute respiratory/renal insufficiencies, ischemia/reperfusion, and acute intestinal/ renal/ arthritic/ cardiac inflammation (Roy et al. 2017). However, it has some essential role too for the healthy maintenance of the body. O2•- due to its highly energized aggressive nature is detrimental and destroys biological macromolecules (protein, nucleotide and lipid). H2O2 has a role in regulating protein functioning as a second messenger or as a signaling molecule when its level is within a physiological range (Helfinger and Schröder 2018). The first role of ROS as a signaling molecule is to sense unfavourable environmental conditions. Therefore, the aim of the cellular antioxidant system is to keep the stress-sensor ROS molecules at a threshold level and any imbalance can trigger the ROS signaling cascade (Mittler 2017). A fine and dynamic balance between the ROS producing enzymes, NADPH oxidases (NOX), NO synthases, cytochrome P-450 (cyt P450) and ROS scavenging enzymes such as SOD, GPx, NQO, and CAT determine the regulation of redox signaling.
Under tight physiological control, a regulated release of ROS is essential for the fundamental life processes. Low basal levels of ROS are required for normal movement of skeletal muscles by stimulating the sarcoplasmic reticulum ATPase activity (Oyagbemi et al. 2009). Another important role of ROS-mediated signaling is the innate immune machinery. Receptor activation of immune-surveillance is promoted by increased ROS production which helps in the release of the pro-inflammatory cytokines interleukin (IL) 1β, tumour necrosis factor α (TNFα) and interferon γ (IFN γ) which all lead to T-cell activation and maturation (Chen et al. 2016). Low ROS levels can cause immunosuppression, whereas high ROS levels mediate autoimmune reactions (Roy et al. 2017). ROS acts as the signaling messenger of the Mitogen-activated protein kinase (MAPK) pathway regulation. Maintenance of normal vascular tone is another typical example of radical-mediated signaling (Oyagbemi et al. 2009). A basal level of ROS maintained by NOX or mitochondria is required for normal cellular proliferation, stem cell renewal and terminal differentiation. Highly-oxidizing environment is a pre-requisite for several types of stem cell growth (Roy et al. 2017).
Pathological Significance of ROS
The beneficial effects of ROS can be confiscated by cancer cells that tilt the ROS status in their favour and sustain an escalated ROS level that favours cancer cell proliferation (Schieber and Chandel 2014). Cancer cells and some stem cells harbour a moderately higher ROS level (below cytotoxic level) that redirects redox-signaling reactions in favour of uncontrolled growth via pro-oncogenic pathways involving hypoxia-inducible factors (HIFs), phosphoinositide3-kinase (PI3K), nuclear factor κ light chain enhancer of activated B cells (NF-κB), MAPK, JUN N-terminal kinase (JNK), cyclin D1, and extracellular signal-regulated kinase (ERK) (Roy et al. 2017). ROS can induce tumorigenicity by, introducing genomic alterations and DNA instability during the initial stages of tumorigenesis, increasing cell proliferation, deregulating cell cycle check-point and apoptosis, and causing abnormal gene expression during cancer progression (Yao et al. 2014).
ROS and Carcinogenesis
One of the prominent features of cancer cells, in comparison to their normal counterparts, is a continuous pro-oxidant status due to metabolic stress and hyperactivation of oxidase enzymes (Martinez-Outschoorn et al. 2010). One of the initial steps in oncogenesis is DNA damage leading to mutation and destabilization which is favoured by increased oxidative load and these altered genes further increase ROS production (Helfinger and Schröder 2018). Moreover, it is reported that the OH•- can bind with whole DNA molecule, and consequently, damage the deoxyribose backbone, including nucleotide bases (Saha et al. 2017). These genomic alterations are primarily represented by 8-hydroxydeoxyguanosine (8-OHdG), an oxidation-product of nucleoside. It is a predominant oxidative lesion and a proportional indicator of ROS-induced carcinogenesis which has been found to be increased in primary tumors compared to neighbouring non-malignant tissue thus promoting neoplastic transformation (Reuter et al. 2010). 8-OHdG causes transcriptional repression by introducing methylation. This global DNA hypomethylation is considered to induce downregulation of tumor suppressor genes and also upregulation of oncogenes (Perillo et al. 2020).
ROS may also deregulate DNA repair, resulting in the production of altered tumor-progenitor cells in a stress-dependent manner (Martinez-Outschoorn et al. 2010). In the promotion stage, the oxidative load may accelerate the abnormal gene expression especially the inactivation of tumor suppressor genes, activation of oncogenes or deregulation of cell-cycle vigilance, modification of second messenger systems, thus culminating in increased cell proliferation or decreased cell-death of the initiated tumor cell population. Finally, oxidative stress may also facilitate the cancer progression by accelerating further DNA abnormalities to the initiated cell population which evades the dependence on cell-cell or cell-matrix interaction (Reuter et al. 2010).
ROS in Cancer Signaling
It is well reported that malignant cells or even some cancer stem cells compared to benign cells show a persistently oxidizing environment with elevated ROS levels (Jelic et al. 2019). To thrive in such sustained redox deregulated environment, cancer cells, optimally utilize the cellular enzymatic and non-enzymatic antioxidant machinery. Oncogenic activation of Kirsten Rat Sarcoma virus (KRas), v-Raf murine sarcoma viral oncogene homolog B (Braf) and v-Raf murine sarcoma viral oncogene homolog B (c-Myc) increase the activity of the main redox regulator of human nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which in turn enhances the expression of the oxidative defence program for maintaining ROS and thereby positively regulates tumor cell proliferation and tumorigenicity (Helfinger and Schröder 2018).
Once the tumorigenesis has well initiated, a chronic but moderate concentration of ROS, acts as a pro-neoplastic factor. It helps in activation of proto-oncogenes such as protein kinase C (PKC), FBJ murine osteosarcoma viral oncogene homolog or cellular oncogene fos (c-Fos), V-jun avian sarcoma virus 17 oncogene homolog (c-jun), c-myc (Surabhi 2019) and inactivation of tumour suppressor genes such as - phosphatase and tensin homolog (PTEN), forkhead box protein O (FOXO)-p53 (Strzelczyk and Wiczkowski 2012) or activation of the cancer cell survival signaling cascade involving MAPK/ERK1/2, p38, JNK, Nrf2 and PI3K / protein kinase B (Akt) (Aggarwal et al. 2019).
Akt revolves at the center of several signaling networks that connect multiple potentially oncogenic molecules. ROS activates Akt by inhibiting PTEN which has been proved to impair antioxidant defences and favour cancer cell survival (Reuter et al. 2010). Akt directly inhibits apoptosis by inactivating pro-apoptotic factors, including the Bcl-2 homology 3 (BH3)-only protein Bcl-XL/Bcl-2-associated death promoter (Bad), Bcl-2 associated X protein (Bax), caspase-9, Bcl-2-like protein 11 or Bcl2-interacting mediator of cell death (Bim) or FOXO (Rahmani et al. 2009). ROS activate transcription factor NF-κB, gelatinolytic enzymes matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). In addition, Akt promotes nuclear translocation of the ubiquitin ligase mouse double minute 2 homolog (MDM2), which counterbalances p53-mediated apoptosis (Reuter et al. 2010).
ROS can directly inactivate p53 by oxidation of cysteine residues in the DNA-binding domain, whereas, constant oxidative stress promotes a selection of cell clones lacking wild-type p53 which favours resistant to apoptosis (Liou and Storz 2010). Negligible to mild oxidative stress causes p53 to activate antioxidant enzymes like SOD, GPx. This rise in the p53 activity is proportional to the ROS level up to a range but subsequently the excess ROS inhibit p53 which in turn prevents apoptosis (Strzelczyk and Wiczkowski 2012). Thus, by avoiding apoptosis and favouring oxidative metabolism, redox stress, and NF-κB upregulation, ROS facilitate neoplastic cell transformation, proliferation, and angiogenesis (Reuter et al. 2010).
ROS in Cancer Metabolism
All cancerous cells show a thorough alteration of their metabolic status by ROS during cancer initiation, promotion, epithelial–mesenchymal transition (EMT), angiogenesis, cell migration, invasion, metastasis, and acquisition of cancer stemness (Lee et al. 2017). These metabolic processes lower cellular dependency on oxygen allowing proliferation in hypoxic interior of solid tumors even in presence of sufficient molecular oxygen (Martinez-Outschoorn et al. 2010). Initiated cells with decreased oxidative phosphorylation favour aerobic glycolysis. Increased oxidative burden and anaerobic glycolysis in the cancer microenvironment can influence tumor cell behaviour. ROS have been indicated in the metabolic rearrangement of both cancer cells and cancer associated fibroblasts (CAFs), allowing an adaptation to oxidative stress that subsequently promotes carcinogenesis and chemoresistance (Costa et al. 2014).
Not only the imbalance in intracellular energy maintenance and stress signaling but also a deregulated production of mitochondrial ROS (mtROS) and other metabolic by-products, disruption in ROS scavenging by the mitochondrial antioxidant machineries [manganese superoxide dismutase (MnSOD), glutaredoxin-2 (Grx2), GPx1, thioredoxin (TRX), and peroxiredoxin] play coordinated roles in carcinogenesis (Idelchik et al. 2017). Increased mtROS generation and mitochondrial DNA (mtDNA) instability due to lack of histone protection is another mechanism that contributes to tumorigenic phenotype in a canonical Wnt/β-catenin independent pathway (Idelchik et al. 2017). Mutations of mtDNA in tumor cells result in a derailment in respiratory complex chains and the aberrant oxidative phosphorylation which contribute to the overproduction of ROS (Chen et al. 2016). The balance of mtROS as a beneficial death-inducer of cancer cells and detrimental activator of cancer cells determines the process of cancer pathophysiology (Sabharwal and Schumacker 2014).
ROS Mediated Inflammation
In the course of inflammation, neutrophils and macrophages usually release large amount of O2•-, H2O2, and •OH. Under chronic inflammatory condition, these ROS are produced from inflammatory and epithelial cells (Kawanishi et al. 2017). Numerous carcinogens exert their deleterious inflammatory action through ROS production. This inflammatory microenvironment promotes carcinogenesis. Inflammatory cells can encourage DNA damage by converting procarcinogens to DNA-damaging species by robust generation of ROS (Ohnishi et al. 2013). Chronic inflammation is a typical example of the impact of cellular microenvironment on neoplastic transformation. ROS can further activate cancer and inflammatory cells to secrete pro-inflammatory cytokines like TNF, NOX2, IL-6, IL-2 and IL-8, which aggravate cancer stem cell (CSC) renewal and ultimately maintains progressive tumor microenvironment (Gu et al. 2018).
ROS Facilitate EMT, Migration and Invasion
NOX1-derived ROS generation promotes cancer cell invasion by enhancing nuclear translocation of NF-κB via pyruvate dehydrogenase kinase 1 (PDK1) which helps proliferative effect of epithelial growth factor receptor (EGFR) and subsequent expression of the MMP-9 (Helfinger and Schröder 2018). During EMT, NOX-mediated ROS formation induces histone H3 acetylation of the slug promoter region and expressional induction (Kamiya et al. 2016). ROS downregulates E-cadherin via hypermethylation of its promoter. This promoter hypermethylation is mediated by a snail-dependent recruitment of DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) which two are further upregulated by the same factor, ROS (Helfinger and Schröder 2018). ROS mediates hypoxia-induced EMT by stabilizing HIF-1α and encouraging cancer cells to produce angiogenic factors (Lv et al. 2017).
ROS promote aberrant MMPs-mediated increase in cell migration and invasion by inducing the Ras-Erk1/2, Rac-1-JNK, activating protein-1 (AP-1) or p38 signaling pathways (Liou and Storz 2010). ROS not only activate the MMPs directly by reacting with the thiol groups of the protease catalytic domain but also suppress their inhibitor, tissue inhibitor of metalloproteinases (TIMPs) (Reuter et al. 2010). Smad2, p38 and phosphorylated ERK1/2, along with α-smooth muscle actin (α-SMA) and fibronectin upregulation, and E-cadherin repression trigger ROS dependent induction of transforming growth factor β (TGF-β) signaling. This in turn facilitates EMT, migration, invasion and metastasis. Integrin activation causes altered mitochondrial metabolism and enhances ROS production by activating many oxidases including lipoxygenase, NOX and cyclooxygenase (COX)-2 (Goitre et al. 2012). A synergistic signaling between integrins and growth factors results into an oxidative burst through ras-related C3 botulinum toxin substrate 1 (Rac1). Rac1-ROS signal transduction is engaged in proto-oncogene tyrosine-protein kinase Src and protein-tyrosine kinase (Pyk2) mediated phosphorylation of β-catenin and p120-catenin, which in turn increases cell adhesion to extra-cellular matrix, cell spreading and proliferation. Anchorage free proliferation or resistance to anoikis takes place most probably via the increased generation of intracellular ROS (Liou and Storz 2010).
ROS in Angiogenesis
ROS-dependent angiogenesis initiates through secretion of angiogenic modulators in the tumor microenvironment. Rac1, an upstream regulator of NOX, elicits ROS, which is involved in dismantling of vascular-endothelial cadherin cell-cell and cell-matrix junction and interaction between endothelial cells. This phenomenon is associated with vascular dysfunctions such as increased permeability, angiogenesis and endothelial migration (Helfinger and Schröder 2018). Endothelial cells derived NOX elevate cellular ROS by upregulation of HIF-1α and receptor phosphorylation of its major downstream VEGF signalling protein (Xia et al. 2007). Along with VEGF, growth factors like fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are secreted into the tumor microenvironment in response to several stimuli including ROS which ultimately helps in angiogenesis (Reuter et al. 2010).
ROS in Cell Cycle Surveillance
Oxidative DNA lesions identified by ataxia telangiectasia-mutated protein (ATM), ATM- and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKs) contribute to several redox signaling pathways and act via modulation of DNA damage repair (DDR) pathways (Davalli et al. 2018). DDR, Cdc25 phosphatases (Cdc25s) and the cyclin dependent kinases (CDKs) are regulated by the intracellular redox environment and ROS induced damaged DNA lesions (Shackelford et al. 2000). ROS induces AP-1 activity in a JNK/MAPK-dependent way leading to increased expression of growth-stimulatory genes including cyclin D1, inhibition of the cell cycle repressor p21 as well as upregulation of MMPs and metastasis (Helfinger and Schröder 2018). ROS can upregulate the mRNA levels of cyclins including cyclin B2, cyclin D3, cyclin E1 and cyclin E2 which regulate the cell cycle to expedite G1 to S phase transition, ultimately leading into aberrant proliferation (Hardwick 2015).
ROS in Cancer Stemness
Contrary to cancer cells, which maintain a high ROS levels throughout stages of malignancy, cancer stem cells have an extraordinary antioxidant capacity (Liou and Storz 2010). CSCs that attribute aggressiveness, resistance and relapse have a strong antioxidant protection against ROS enabling them against conventional chemotherapy and radiotherapy, which functions by elevating ROS level. The stemness marker of CSCs e.g. aldehyde dehydrogenase 1 (ALDH1) and ATP-binding cassette sub-family G member 2 (ABCG2) work by protecting the CSCs from intracellular ROS-induced death (Hatem and Azzi 2016). Redox equilibrium plays an important role in the maintenance of stem cell survival, self-renewal, differentiation (Reuter et al. 2010) through the antioxidative measure and/or anti-inflammatory response and this niche can provide mutation signals. Stem cells that accumulate these mutation signals may become more tumorigenic, resulting in CSCs (Franco et al. 2015).
ROS in Tumor Microenvironment
Cancer cells exploit “oxidative stress” in nearby cancer associated fibroblasts (CAFs) to drive tumor-stroma co-evolution as a “metabolic engine” to fuel their own survival. This process is influenced by stromal production of nutrients to stimulate their mitochondrial biogenesis (Cuyàs et al. 2014). The oxidative burst is used by cancer cells in promoting DNA damage, aneuploidy and genomic instability to progress their own mutagenic evolution towards a more robust phenotype via a bystander effect (Martinez-Outschoorn et al. 2010). Other than the tumor cells, CAFs also release H2O2 extracellularly that induce oxidative stress in normal fibroblasts, initiating the reprogramming to CAFs and promoting cancerization of that field, EMT, invasion and cancer aggressiveness. Immune cells, such as myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells (Treg), neutrophils, eosinophils, and mononuclear phagocytes, can also generate ROS (mostly H2O2) into the tumor microenvironment (Snezhkina et al. 2020).
ROS Prevention as a Part of Chemoprevention
It is an estimate that, more than 30% of human cancers might be prevented through appropriate lifestyle modification. About 10–70% (average 35%) of human cancer is not solely dependent on inherited genetic background but is highly attributable to diet which can be called as human carcinogens (Russo 2007). Phytochemicals are considered as the non-nutritive bio-active components of the diet based on plants and possess multi-modal or pleotropic antimutagenic and anticarcinogenic properties (Russo 2007). Increased consumption of antioxidative fruits and vegetables containing several anticancer compounds have been always more effective than a single agent (Russo 2007). ‘Chemoprevention’ by its definition is the strategy of stopping or retarding the onset of malignant changes with relatively nontoxic natural or (semi)synthetic chemical substances. The National Cancer Institute (NCI) is investigating several hundreds of potential agents out of more than 5000 phytochemicals and is also sponsoring a significant portion of it for Phase I, II and III chemoprevention trials (Surh 2003).
Nature and Types of Chemopreventive Agents
According to the origin and mode of synthesis, chemopreventive antioxidants are of two types- pharmacological and dietary chemopreventives. Pharmacological chemopreventives are chemically synthesized or derived from natural precursors and alone or in combination can work in a synergistic manner like (1) by blocking the cancer initiation via induction of antioxidant enzymes in high risk healthy individuals; (2) by inhibiting the cancer progression via the activation of the apoptotic pathway and cell cycle arrest in individuals already with pre-malignant lesions; (3) by escalating aberrant epigenetic alterations as an anti-cancer mechanism in patients with primary cancer; and (4) by eliminating the self-renewal potential of CSCs in case of relapse after an initial cancer-reduction (Lee et al. 2013b). Anthracyclines, platins, antagonistic antibodies, taxanes, anticancer antibiotics, cyclophosphamides etc. are some well-used pharmacological chemopreventives.
Dietary chemopreventives, which are present in a regular diet but as a non-nutritive part are again of two major types- blocking agents and suppressing agents (Russo 2007). Blocking agents are those, which prevent carcinogens from reaching the target sites or promote rapid detoxification, inhibit carcinogens from undergoing metabolic activation or from subsequent interaction with crucial biomolecules. On the other hand, suppressing agents are those which inhibit the malignant transformation of already initiated cells, either in the promotion or in the progression stage by controlling deregulated cell cycle, tumor-suppressive signal transduction and apoptotic induction (Tanaka and Sugie 2007). Carotenoids, alkaloids, polyphenols, nitrogen-containing and organosulfur compounds are the dietary agents with prominent chemopreventive properties (Russo 2007). The anticancer properties of the major classes of phytochemicals are enlisted in Table 1.
Each chemopreventive compound, within every class, has its own set of adverse reactions. One of the major causes of adverse reactions is the excessive production of ROS and subsequent accumulation of oxidative stress. To curb these unwanted side effects, several dietary supplements have been investigated, amongst which antioxidants have gained increasing acceptability as adjuvant in cancer chemotherapy (Singh et al. 2018). The induction of oxidative stress as the mechanism of action of many anticancer drugs has been well reported (Rigas and Sun 2008). Since, antioxidants may save the malignant cells from ROS-induced toxicity, success of anticancer therapy may be conditioned by maintaining the level of antioxidants in our body, which can be produced de novo (endogenous) or can be ingested through the diet and nutritional supplements (exogenous) (Rodríguez-Serrano et al. 2015). Antioxidants have shown to exert beneficial effect when used along with chemotherapeutic drugs against initiation, promotion and progression of carcinogenesis (Valadez-Vega et al. 2013).
The synergistic and pleiotropic action of low dose endogenous and exogenous antioxidants may neutralize free radicals more effectively during the process of multistep carcinogenesis (Sonam and Guleria 2017, Kaur et al. 2019). The anticancer properties of the antioxidative phytochemicals have therapeutic evidence during early initiation, promotion, local progression even up to distant metastasis. They can work by (Amin et al. 2015).
• Modulating Hormones/Growth Factors Receptors
[Oestrogen, progesterone and their receptors, VEGF, epidermal growth factor (EGF), PDGF, FGF and their respective receptors]
• Phase 1 and 2 Metabolizing Enzyme Mediated Depletion of Potential Carcinogens
[↓SOD, ↓CAT, ↓glutathione, ↓GPx, ↓GSH and ↓cyt P450]
• Inhibiting Oncogenes and Activating Tumour Suppressor Genes
[↓KRas, ↓BRaf, ↓cMyc, ↓EGFR, PI3K/AKT, ↓Cyclins and ↑p53, ↑p27, ↑PTEN, ↑FOXO, ↑poly(ADP) ribose polymerase (PARP), ↑ATM]
• Inducing Terminal Differentiation
[↑IkB kinase α (IKKα), ↑all-trans retinoic acid, ↑retinoid receptors, ↑histone deacetylase inhibitors (HDACI), peroxisome proliferator-activator receptor γ agonists, independent of p53]
• Activating Checkpoints and Apoptosis
[↓Cyclin B, ↓B1, ↓D1, ↓CDK A, ↓E, ↓CDK 1, ↓2, ↓4 and ↑p53, ↑p21, ↑pRb, ↑p57]
• Restoring Immune-Response
[↓cytotoxic T lymphocyte antigen 4, ↓programmed death ligand 1, ↓Treg and ↑Helper T cells, ↑natural killer (NK) cells, ↑macrophage, ↑antibody dependent cellular cytotoxicity]
• Inhibiting EMT and Angiogenesis
[↓snail, ↓twist, cadherins, integrins, ↓MMPs and ↓TGF-β, ↓VEGF, ↓PDGF, ↓FGF, ↓HIF1-α]
• Avoiding the Adverse Effects Associated with the High Drug Doses
[↓immune suppression, ↓mucositis, ↓alopecia, ↓nausea, ↓anorexia]
DEFINITION, TYPES AND FEATURES OF ANTIOXIDANTS
The first definition of antioxidant was proposed by Halliwell et al. in 1989 as “any substance that, present in low concentrations compared to oxidizable substrates (carbohydrates, lipids, proteins or nucleic acids), significantly delays or inhibits the oxidation of the mentioned substrates” or later “any substance that can eliminate ROS directly or indirectly, acting as a regulator of the antioxidant defence, or inhibiting the production of those species” (Rodríguez-Serrano et al. 2015). Antioxidants neutralize free radicals by donating one of their own electrons and ending the electron “stealing” reaction (Singh et al. 2018).
Antioxidants can be differentiated into three types of defence according to their mechanism of action. The first type includes antioxidants that prevent the formation of free radicals such as SOD (IUPAC Enzyme Commission No. 1.15.1.1), CAT (IUPAC Enzyme Commission No. 1.11.1.6), and GPX, (IUPAC Enzyme Commission No.1.11.1.9) (Wiecek et al. 2018).
The second group of antioxidants is responsible for capturing free radicals, and thus they prevent oxidative chain reactions. This group includes metabolic antioxidants, such as lipoic acid, glutathione, L-ariginine, histidine, coenzyme Q, melatonin, uric acid, albumin, bilirubin, metal-chelating proteins, transferrin, etc., and dietary antioxidants, such as vitamin E, vitamin C, flavonoids, carotenoids, trace metals (selenium, manganese, zinc), omega-3 and omega-6 fatty acids (Arsova-Sarafinovska and Dimovski 2013).
The third line of defence includes antioxidant enzymes that are involved in the repair mechanism of the damage caused by free radicals, such as lipases, transferases, proteases, DNA repair enzymes, and methionine-sulfoxide reductases. The antioxidant consumption seems to influence the effectiveness of antitumor therapy depending on the type of cancer, the mechanism of action of the drug used in the treatment, dose and timing of treatment and also on the type of antioxidants and basal antioxidant status (Rodríguez-Serrano et al. 2015). Recent findings reported that antioxidant when given concurrently (a) do not interfere with chemotherapy, (b) enhance the cytotoxic effect of chemotherapy, (c) protects normal tissue and (d) increases patient survival and therapeutic response (Simone et al. 2007).
Two Sides of a Coin: Antioxidants or Pro-oxidants?
“All substances are poisons, the right dose differentiates a poison from a remedy” was an appropriate paraphrase of the great ancient physician, Paracelsus (Russo 2007). Usually preventive dose is a lower dose and a therapeutic dose is a higher dose. Preventive dose has shown protection of benign and malignant cells whereas therapeutic dose has shown inhibition of the growth of cancer cells but not that of normal cells (Singh et al. 2018). High-dose antioxidative supplements may cause hazardous health effects as it may negatively interact with some anti-cancer medications. It has also been seen that continuous use of ROS-scavenging enzymes may work as the barrier against effective apoptosis by excessively reducing ROS beyond a necessary threshold (Asadi-Samani et al. 2019). Dose and exposure duration of an administered compound play the crucial fate-determining role in cancer. The concept of hormesis, a biphasic dose-response relationship in which a chemical exerts opposite effects dependent on the dose, has become effective in the field of cancer management.
An antioxidant is present at low concentrations in the cell and significantly reduces oxidation of the oxidizable substrates, decreases levels of cells’ oxidants like ROS, causes increase in apoptosis and therefore can be considered as an approach to treat fatal cancers. Phytochemical derived antioxidants often exhibit their chemopreventive effects in a prooxidant manner (Block et al. 2008). This dual nature of phytochemicals depends on their concentration, pH and solubility but ultimately lead to promotion of antiproliferative process and apoptosis (Babich et al. 2011). Antioxidant treatment may be more fruitful during the initiation phase, when a mild increase in ROS concentrations over the physiological threshold can cause genotoxic damage (Russo 2007). Much of the late-stage cancer’s inertness may be due to its possession of excess antioxidants where prooxidative measures may give fruitful outcome (Watson 2013).
Important Phytochemicals with Anti-Oxidant and Pro-Oxidant Effect in Cancer Prevention
Free radicals increase oxidative stress that induce chronic inflammation, reduce apoptosis, promote abnormal cell proliferation, angiogenesis and metastasis via DNA damage and activation of oncogenes and transcriptional factors. Dietary phytochemicals on the other hand show anti-cancer properties through both pro-oxidant and anti-oxidant properties (Kaur et al. 2018). Innumerable studies have been done on antioxidative effect of phytochemicals. An in-depth discussion of the dose and mechanisms of antioxidants responsible for redox regulation of cancer and their mode of anticancer efficacies might provide a detailed approach for potential anticancer mechanisms (Fig. 1). Some of the selected dietary phytochemicals that elicited anti-cancer properties by virtue of anti-oxidant properties have been depicted in Table 2 and those by pro-oxidant properties in Table 3.
Fig. (1)) Modulation of carcinogenic process by phytochemicals: Some globally used phytochemicals like, curcumin, resveratrol, EGCG, genistein, diallyldisulphide, quercetin, lycopene, sulforaphane obtained from plant sources of our daily diets like- turmeric, grapes, green tea, soy bean, garlic, broccoli, tomato etc. have shown wide anticancer properties by modulating the cancer signaling, metabolism, EMT, angiogenesis, microenvironment and stemness with their unique redox regulating property. Phytochemicals may be both beneficial and harmful depending on concentration and duration of exposure.Curcumin
The polyphenol curcumin, derived from the plant Curcuma longa, of family Zingiberaceae is the principal constituent of Indian spice turmeric (Pubchem CID 969516). It exhibited both anti-oxidant and pro-oxidant properties along with chemopreventive, anti-inflammatory and anti-cancer effects. In benzo(a)pyrene (BaP) induced lung carcinoma of swiss albino mice curcumin exhibited antioxidant property, reduced lipid peroxidation and upregulated anti-oxidative enzymes such as SOD, GPx, CAT and glutathione S transferase (GST) (Sehgal et al. 2012). Another study reported that in human pancreatic cancer (BxPC-3 and Panc-1) cells curcumin reduced oxidative stress by quenching ROS and H2O2 and retarded EMT and cell migration (Li et al. 2018). On the other hand, curcumin by virtue of pro-oxidant nature increased ROS level, induced apoptosis and sub G0/G1 phase growth arrest in human papillary thyroid carcinoma (PTC)-[BCPAP and TPC-I] cells. The study has shown induced expression of cleaved caspase-3, -8 and -9 along with reduced expression of cell cycle molecules (Khan et al. 2020). Curcumin has been reported to induce apoptosis in A375 melanoma cells along with upregulated ROS production (Liao et al. 2017).
Epigallocatechin Gallate (EGCG)
EGCG is a phenolic tea phytochemical extracted from green and black tea plants (Pubchem CID 65064). EGCG was found to have anti-oxidant effect along with chemopreventive and anti-cancer effects but several studies have shown pro-oxidant effect of EGCG. In human cervical cancer (HeLa) cells and tumor biopsy samples, EGCG was found to induce expression of anti-oxidant enzymes which promoted anti-cancer effect (Hussain 2017). In lung adenocarcinoma (NCI-H23 and A549) cells, EGCG exhibited antioxidant effect in NCI-H23 and pro-oxidant effect in A549 through differential modulation of Nrf2 at a high and low doses respectively (Datta and Sinha 2019). In another study EGCG was found to induce pro-oxidant effect in human colon cancer (HT-20) cells through increased ROS generation, apoptosis and reduced expression of pro-survival genes (Hwang et al. 2007). In human endometrial Ishikawa cancer cells and normal HEK-293 cells, EGCG showed anti-cancer effect by elevated ROS generation, reduced anti-oxidant enzymes and increased Bax/caspase-3 mediated apoptosis (Manohar et al. 2013). EGCG induced ROS production and upregulated apoptosis signal-regulating kinase 1 (ASK1)-p38/JNK signaling pathway along with apoptosis in human chondrosarcoma (JJ012) cells (Yang et al. 2011).
Resveratrol
Resveratrol is a phytoalexin belonging to polyphenolic group which is extracted from grapes, nuts, fruits, and red wine (Pubchem CID 445154). Resveratrol exhibited anti-inflammatory, anti-cancer activity along with anti-oxidative and pro-oxidative properties. Anti-oxidative properties of resveratrol exhibited in human pancreatic cancer (BxPC-3 and Panc-1) cells where it curtailed ROS production along with reduction in cancer cell invasion due to hypoxia (Li et al. 2016). On the other hand, resveratrol inflicted ROS production in human colon carcinoma (HCT116) cells along with G1 phase and senescence like cell growth arrest (Heiss et al. 2007). Pro-oxidant behaviour of resveratrol was also observed in human gastric adenocarcinoma (SGC7901) cells along with induction of apoptosis and reduction of cell proliferation (Wang et al. 2012).
Quercetin
Quercetin is a flavonoid belonging to polyphenolic group, derived from apples, onions, and green tea (Pubchem CID 5280343). It exhibited chemopreventive, anti-inflammatory and anti-allergic effects along with anti-oxidative and pro-oxidative properties. In human fibrosarcoma (HT1080) cells, quercetin inhibited phenazinemethosulfate (PMS) induced ROS production and also abated cell motility through reduced expression of MMP-2 and -9 (Lee et al. 2013a). On the other hand, in several other studies quercetin was found to have pro-oxidative properties. In HA22T/VGH and HepG2 hepatoma cells, quercetin aggravated ROS production and malondialdehyde along with inhibition in cell growth (Chang et al. 2006). In rat hepatoma (H4IIE) cells, quercetin downregulated gene expression of anti-oxidative enzymes dose dependently (Röhrdanz et al. 2003). Quercetin induced autophagy through increased expression of nuclear protein1 (NUPR1) which is needed for the expression of stress-response genes along with ROS production in osteosarcoma (MG-63) cells (Wu et al. 2020).
Fisetin
Fisetin, a flavonoid belonging to polyphenolic group, derived from edible vegetables, fruits, and wine, exhibited anti-inflammatory, anti-cancer, anti-oxidant and pro-oxidant properties (Pubchem CID 5281614). In Aflatoxin-B1 (AFB1)-induced hepatocarcinogenesis of rats, fisetin elicited anti-cancer effect through reduced ROS production and increased expression of anti-oxidative enzymes (Maurya and Trigun 2016). Fisetin also showed anti-oxidant properties through increased antioxidant enzyme mediated free radical in BaP-induced lung carcinogenesis in male Swiss albino mice (Ravichandran et al. 2011
