Do all roads lead to the Rome? The glycation ...

Seminars in Cancer Biology 49 (2018) 9–19

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Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer

Review

Do all roads lead to the Rome? The glycation perspective! a,b,⁎

a,c,⁎⁎

d

e

T b

Saheem Ahmad , Firoz Akhter , Uzma Shahab , Zeeshan Rafi , Mohd. Sajid Khan , Rabia Nabib, Mohd Salman Khanb, Khurshid Ahmadf, Jalaluddin Mohammad Ashrafg, Moinuddinh a

IIRC-1 Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India Department of Biosciences, Integral University, Lucknow, India c Department of Pharmacology and Toxicology, Higuchi Biosciences Center, University of Kansas, KS, USA d Department of Biochemistry, King George Medical University, Lucknow, India e Department of Bioengineering, Integral University, Lucknow, India f Department of Medical Biotechnology, Yeungnam University, Gyeongsan, Republic of South Korea g Department of Biochemistry, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia h Department of Biochemistry, J.N. Medical College, A.M.U., Aligarh, India b

A R T I C LE I N FO

A B S T R A C T

Keywords: Oxidative stress Glycative stress Carbonyl stress AGE-RAGE interaction Cancer

Oxidative, carbonyl, and glycative stress have gained substantial attention recently for their alleged influence on cancer progression. Oxidative stress can trigger variable transcription factors, such as nuclear factor erythroid-2related factor (Nrf2), nuclear factor kappa B (NF-κB), protein-53 (p-53), activating protein-1 (AP-1), hypoxiainducible factor-1α (HIF-1α), β-catenin/Wnt and peroxisome proliferator-activated receptor-γ (PPAR-γ). Activated transcription factors can lead to approximately 500 different alterations in gene expression, and can alter expression patterns of inflammatory cytokines, growth factors, regulatory cell cycle molecules, and antiinflammatory molecules. These alterations of gene expression can induce a normal cell to become a tumor cell. Glycative stress resulting from advanced glycation end products (AGEs) and reactive dicarbonyls can significantly affect cancer progression. AGEs are fashioned from the multifaceted chemical reaction of reducing sugars with a compound containing an amino group. AGEs bind to and trigger the receptor for AGEs (RAGE) through AGE-RAGE interaction, which is a major modulator of inflammation allied tumors. Dicarbonyls like, GO (glyoxal), MG (methylglyoxal) and 3-DG (3-deoxyglucosone) fashioned throughout lipid peroxidation, glycolysis, and protein degradation are viewed as key precursors of AGEs. These dicarbonyls lead to the carbonyl stress in living organisms, possibly resulting in carbonyl impairment of proteins, carbohydrates, DNA, and lipoproteins. The damage caused by carbonyls results in numerous lesions, some of which are involved in cancer pathogenesis. In this review, the effects of oxidative, carbonyl and glycative stress on cancer initiation and progression are thoroughly discussed, including probable signaling pathways and the effects on tumorigenesis.

1. Introduction Rome was not built in a day so do the oxidants, carbonyls, and advanced glycation end-products (AGEs). AGE formation is a non-enzymatic reaction, carried out by the covalent attachment of sugars to the biological macromolecules, like DNA, proteins, and lipids [1,2]. It takes months to years for its deposition in various tissues of human body. This review primarily focuses on the inter-link between oxidation, glycation, and carbonizations and their probable role in disease pathogenesis. Glycation is a universal reaction, occurs in most of the cells between carbonyl group (eC]O) of the reducing sugars with the

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amino group (eNH2) of proteins, initially leading to the formation of an unstable product known as Schiff’s base. Schiff’s bases are ephemeral and prone to the backward reaction resulting again in the formation of original reactants, i.e., protein(s) and reducing sugar(s). They have a tendency to undergo re-arrangement of atoms resulting in the formation of Amadori products [3,4]. The Amadori products are more stable than Schiff’s base and more favorable toward the forward reaction in the product formation. The Amadori products further undergo re-arrangement, dehydration, and cyclization to form AGEs. AGEs can also be formed during the oxidation of nucleotides and lipids. The exogenously and endogenously formed AGEs and reactive dicarbonyls are

Corresponding author at: Department of Biosciences, Integral University, Lucknow, India. Corresponding author at: Department of Pharmacology and Toxicology, Higuchi Biosciences Center, University of Kansas, KS, USA. E-mail addresses: [email protected], [email protected] (S. Ahmad), fi[email protected] (F. Akhter).

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https://doi.org/10.1016/j.semcancer.2017.10.012 Received 3 May 2017; Received in revised form 29 October 2017; Accepted 30 October 2017 Available online 04 November 2017 1044-579X/ © 2017 Elsevier Ltd. All rights reserved.


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which is responsible for the accumulation of intracellular oxidants. The glycation reactions are also referred to as ‘glycoxidation’ due to the generation of free radicals, wherein glycation and oxidation, both take place simultaneously [3,5,25]. On the other hand free radicals and ROS are continuously generated during regular cell metabolism in the body, which is essential for biological homeostasis and normal functioning of various cells and tissues. For example, free radicals, such as %OH, are required for a mitogenic response (cell division) in most of the cells, smooth muscle relaxation, cell signaling, and many others. However, over a period of months to years, there is a gradual accumulation of these oxidants or free radicals due to the imbalance between oxidants and anti-oxidants or the amount of oxidants/ROS exceeds than antioxidants. In such situations, dietary antioxidants are needed to mitigate the effect of oxidants and ROS, otherwise, an oxidative burst may occur, which is a serious threat to the organelles and the biomolecules present in a cell [22,26,27]. Specifically, the genetic material (DNA) when oxidized may cause mutation and result in cancer or other metabolic derangements. There are many studies that have reported the role of toxicants and free radicals in the formation of cancer, arthritis, and diabetes mellitus [28]. Moreover, the free radicals which are generated either by glycoxidation or cellular metabolism (mitochondrial electron transport chain reactions) may cause membrane lipid peroxidation. The lipid peroxidation of membranes of cells or the mitochondria may result in the formation of carbonyl species, such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), etc. These carbonyls have also been reported to play certain roles in various types of cancers [27,29]. The situation could be further aggravated by the transformation of Amadori products into AGEs, generating highly reactive dicarbonyl species (RCS) such as Methylglyoxal (MG), Glyoxal (GO), and 3-deoxyglucosone (3-DG), which are produced during AGEs formation. The accumulation of these dicarbonyl species leads to a condition known as glycative stress [29,30]. Furthermore, MG is also produced by triosphosphate in most of the living organisms during anaerobic glycolysis and GO is formed by lipid peroxidation and degradation of monosaccharides and saccharide derivatives. The concentration of MG in the blood ranges from 10 to 20 μM. The level of the same is even less than that present in the blood [30]. Depending upon the concentration of these dicarbonyls, they might have various roles in the initiation and progression of cancer.

major AGE precursors, responsible for the development and progression of various diseases and associated complications including diabetes, nephropathy, retinopathy, neuropathy, obesity, cardiovascular diseases, and aging [5,6]. The formation of dicarbonyls and AGEs, which are categorized as pro-oxidant and pro-inflammatory mediators and affect numerous biological responses, culminates into the activation of various signaling pathways mediated by a sequence of cell surface receptors. The utmost studied AGE receptor is the multiligand receptor of immunoglobin super-family known as the receptor of AGE (RAGE). AGE-RAGE signaling plays a causal role in various chronic diseases. In addition, few in-vitro and in-vivo studies have been focused on the tumor-promoting roles of the AGE-RAGE interaction, considered to be a critical link between chronic inflammation and cancer [4,7]. Several reports have addressed the particular role of RAGE in regulating pro-tumorigenic signaling in immune, somatic, cancer cells, and in the microenvironment of a tumor [8]. RAGE initiation by the highly versatile amphoterin or proteinS100 can prolong tumor-elevating inflammation, adding to cancer development [9]. In this regard, the mitogen-activated protein kinase (MAPK)/NF-κB cascade signaling pathway is of particular interest [9]. The activation of a signal transducer and activator of transcription factor 3 (STAT3), triggered by various mechanisms including RAGE-dependent pathways, prompts extended initiation of NF-κB [10]. NF-κB and STAT3 signaling pathways cause tumor-promoting reactions by the generation of interleukin-6 (IL6), prostaglandin E2 (a vital metabolic product of cyclooxygenase-2), matrix metalloproteinases (which have a strong effect on tumor metastasis), and RAGE expression/stimulation in the microenvironment of a tumor [7,10–13]. AGE-RAGE interaction and metabolic disorder related cancer development have indicated that AGEs and dicarbonyls may further worsen malignant lesions [11]. These signaling pathways also promote β-catenin transcriptional activity and facilitate tumor growth [14]. In the tumor microenvironment, high energy consumption leads to the accumulation of AGEs, dicarbonyls, and ROS formation [15]. These molecules actively participate in tumor progression due to their properties in genomic variability [16], inducing tumor causing inflammation, metastasis, invasion, proliferation, apoptosis evasion, and angiogenesis [7]. The oxidative and glycative stress signaling pathways induce various gene expressions [12]. The up- and downregulation of microRNAs (miRNAs) have also been implicated in inflammation and tumorigenesis (Table 1) [17–24]. During the glycation reaction, several free radicals specifically, superoxides (O2%−) and hydroxyl (%OH), are formed. O2%− radicals are formed during the initial glycation reaction, i.e., conversion of a Schiff’s base into an Amadori product. However, %OH radicals are formed at the late stage of the glycation reaction, when the AGEs are generated from Amadori products (Scheme 1). The rate of the formation of these free radicals is independent of the cellular machinery (like, mitochondria),

2. Oxidative stress and redox signaling ROS are the normal products of the molecular oxygen produced via endogenous metabolic reactions through aerobic cells such as hydrogen peroxide (H2O2), hydroxyl radical (%OH), superoxide anion (O2%−), and organic peroxides. ROS play a key role in the induction of signaling pathways [26,27]. Additionally, ROS are the products of regular

Table 1 Important genes and other genetic elements responsible through oxidative, carbonyl, and glycative stress in cancer. Induced stress (ROS/ AGE)

Stress affected gene/Genetic element in Cancer

Expression mechanism

References

Oxidative stress

Oxidative stress

Mutations in the Periaxin (Prx) and Ref-1

Glycative stress

Receptor for advanced glycosylation end products (RAGE) Expression of KDR, Src, OLC-y, DSCR1/MCIP, NR4A, and Egr3 Expression of Mdm2, Gadd45b, XIAP, A20, CYLD, MnSOd, Fhc, HIF-1 Up- and downregulation of micro RNA (MiR-29, MiR-9, MiR-125b, MiR-146a)

It forms heterodimers with small Maf proteins in the nucleus and binds with AREcontaining gene promoters to induce their expression and tumorigenesis Trx over-expression is one of the enhancers of tumorigenesis, Trx negatively regulates apoptosis in the cytoplasm via redox regulation of ASK-1 and inhibition of Iκβ degradation Cancer cells are often under high oxidative or hypoxic stress thus express high levels of antioxidant proteins, including, Prx, and Ref-1. Over-expression of RAGE induced inflammation and cancer

[17]

Oxidative stress

Nuclear factor erythroid 2-related factor 2 (Nrf2) Thioredoxin (Trx)

Glycative stress Oxidative stress Oxidative stress

Vascular endothelial growth factor (VEGF) induced expression, inflammation, and tumorigenesis NF-κB induced inflammation and Tumorigenesis NF-κB upregulated MiR-9, MiR-125b, MiR-146a and downregulated MiR-29 and induced inflammation and tumorigenesis

10

[18]

[19] [20] [21] [22,23] [24]


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Scheme 1. Schematic representation for the generation of superoxide and hydroxyl radical generation during the initial and intermediate stages of the glycation reaction. Pathophysiological condition is also mentioned as a consequence of the glycation reaction.

3. Chemical pathways for AGE

cellular metabolism in animal cells generated in response to the changes in intracellular metabolites and extracellular conditions. A large fraction of ROS is produced in cells by the respiratory chain of mitochondria. Under hypoxic environments, the mitochondrial respiratory chain also produces reactive nitrogen species (RNS), which can further produce reactive 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) by tempting undue lipid peroxidation [27,29]. All biomolecules are affected by an oxidative stress and any alteration in these molecules can induce the process of mutagenesis [28]. ROS generation can also be induced by drug metabolism, the overexpression of ROS producing enzymes, ionizing radiations, and the deficiency of antioxidant enzymes. The maintenance of ROS homeostasis is crucial for maintaining normal cell functions [26]. Any disruption in the equilibrium between oxidation and anti-oxidation would lead to oxidative stress along with a wide spectrum of disorders including age-related diseases, chronic inflammation, and cancer. Therefore, the divergent metabolic activities, disturbed cellular signaling, mitochondrial dysfunction, oncogenetic activity, and immune and cancer cells can result in abnormally high ROS levels. An elevated ROS production or impaired ROS detoxification can damage intracellular macromolecules (DNA, proteins, and lipoproteins) [22]. The regulation of ROS by generation and detoxification is the core event responsible for the maintenance of suitable redox signaling and redox homeostasis in cells. The disruption of redox critically affects cellular physiology and leads to deviant signaling. The deregulation in redox homeostasis is a sign of cancer cells which can be a cause of malignant resistance and failure to treatment [31]. The lower levels of ROS are presumed to normalize metabolic pathways and redox signaling, while high levels of ROS may induce tumor growth by tempting genomic instability and DNA modification and genomic variability (Fig. 1) [22,31,32]. The ROS generation can be both endo- and exogenous which might lead to the oxidative stress and eventually may cause damage to the chromosomal DNA and thus tumor. This can subsequently trigger an inflammatory retort, steadying the hypoxiainducible factor-1 (HIF1) and metabolism reprogramming [32]. Such activity affects tumor growth by divesting the cell from redox state and engaging in explicit metabolic pathways within a tumor cell.

AGEs are a series of compounds formed from composite chemical reactions, which contribute to the changes in biomolecular conformation, loss of function, and irreversible crosslinking [33,34]. The aldose sugar glycates the free eNH2 group of nucleic acids, proteins, and lipoproteins to produce a reversible Schiff’s base and ketoamines (Amadori products). These unstable compounds are decidedly prone to degradation and oxidation, and later form reactive dicarbonyl intermediates, such as methylglyoxal (MG), glyoxal (GO), and 3-deoxyglucosone (3-DG) (Fig. 2) [34,35]. The exogenous AGEs which are the part of the process/grilled/baked foods are also the incidence of tumorigenesis. At the end of the reaction, the Amadori products and reactive dicarbonyls react non-enzymatically with arginine or lysine residues to yield stable and lethal AGEs. The AGEs are of two main types: (i) crosslinking and fluorescent AGEs, such as MG-lysine dimer, GOlysine dimer, and pentosidine; (ii) non-crosslinking and non-fluorescent AGEs, i.e., Nε-(carboxyethyl)lysine (CEL), Nε-(carboxymethyl)lysine (CML), Nε-(5-hydro-5-methyl-4-imidazolon-2-yl) ornithine, pyrraline and argpyrimidine[Nδ-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine]. Chiavarina et al. analyzed the expression of argpyrimidine adducts in breast cancer cell lines [35] and later a consistent increase in argpyrimidine accumulation in breast cancer cell lines was observed in contrast to non-tumor counterparts. The induced AGEs are involved in the intricate pathology of uremia, diabetes, Alzheimer’s disease and likely in cancer progression.

3.1. AGE-RAGE signaling and stress response The glycative stress induces inflammation and oxidative stress through binding of AGEs to RAGE. The AGE-RAGE interaction triggers signaling pathways, which involve a diverse repertoire of pro-inflammatory ligands such as S100/calgranulins, amyloid-β peptide and amphoterin. The CML adduct has been documented as a signal transducing ligand for RAGE. AGE-RAGE interaction triggers the induction of ROS and generation of dicarbonyls compounds, increases the expression of adhesion molecules, and activates NADPH oxidase (Fig. 3). The activation of NADPH oxidase incites NF-κB and thus upregulates inflammation and additional signaling pathways [7,36,37]. Inflammatory mediators are upregulated over AGE-RAGE signaling [7]. 11


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Fig. 1. Various exogenous and endogenous sources that induce oxidative stress, role of mitochondria in free radical generation, and enzyme catalytic activity with signaling pathways illustrating the source of ROS and their role in the development of cancer.

ligands leads to tissue damage and chronic inflammation with the migration, endurance, proliferation, and incursion of tumor cells [7].

The NF-κB pathway includes IL-6, C-reactive protein (CRP), TNF-α, STAT3, and HIF1 [36]. AGE-RAGE interaction is vital for maintaining the expression of various cytokines and the inflammatory microenvironment in tumor cells [38] (Table 2) [39–43]. The upregulation of acute transcription factors increases the release of cytokines prior to the recruitment of myeloid immune and lymphoid cells at the microenvironment of the tumor-inducing ROS generation and inflammatory reaction [44]. RAGE inducers contain NF-κB sites regulating RAGE expression through activation of NF-κB [7,39]. RAGE expression arises in an inducible approach and is upregulated at areas where its ligands accrue. The fixed RAGE expression by endothelium, smooth muscle cells (SMC) and mononuclear cells (MC) due to the excitement of their

3.2. Effect of RAGE/sRAGE levels on susceptibility to cancer RAGE mediates the intracellular signaling of AGEs while the other ligands for AGEs possess scavenging and detoxification properties, such as type I, II, 80 K-H phosphoproteins, galectin-3 and oligosaccharyl transferase-48 (OST-48). The multiligand receptor of RAGE apart of AGEs quandaries to high mobility group Box 1 (HMGB1), amyloid-β, S100 family proteins, and phosphatidylserine [7,36]. AGE-RAGE interaction triggers nicotinamide adenine dinucleotide phosphate

Fig. 2. The chemical reaction which induces AGEs generation. The AGEs generation and accumulation are also enhanced by high fat/high sugar intake, and also by consuming processed and fried/grilled foods. The sources of common AGEs rich food and cancer causes are same as represented in figure. 12


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Fig. 3. The impact of different pathways in various AGEs generation; cytokine generation via AGE-RAGE interaction; the production of ROS and induction of inflammation through glycative, carbonyl, and oxidative stress and their putative role in the induction and progression of cancer. Table 2 AGEs-RAGE axis induced cytokines and their possible aftereffects in cancer models. Induced cytokines

Mechanism

Effects

References

Interleukin-1 and −6 (IL-1 & IL-6)

Activate immune cells of lymphoid and myeloid origin and trigger signaling pathways Upregulate co-stimulatory molecules such as CD80 and CD86, and expand effector T cells Signals through the IL-1R/IL-1RAcP complex or associates with lipopolysaccharide HMGB1 helps in maturation of immature DCs (iDCs) with upregulation of co-stimulatory molecules and MHC class II

Production of a large number of pro-inflammatory mediators Generation of ROS, oxidation of HMGB1 and delivery of tolerogenic signals to dampen immune activation Activated TLR4 and induced inflammation by HMG B1

[39–42]

Stimulation of allogeneic T cells and enhancement of pro-inflammatory activity and apoptosis.

[43]

Interferon (IFN-α) and Tumor necrosis factor α (TNF-α) Interleukin 1 beta (IL-1β) Interleukin-12 (IL-12) and Interferon- γ (IFN-γ)

[43] [43]

of AGEs, sRAGE, and RAGE in cancer progression [14].

(NADPH) oxidase and ROS generation and induces intracellular signaling that leads to inflammatory propagation and immune response [39]. Soluble RAGE (sRAGE) is a secretory spliced isoform of RAGE, which is generated by the privations of the transmembrane domain and circulates in plasma. sRAGE competes with cell-surface RAGE for ligand binding and thus acts as a snare [38]. Therefore, it has been projected as an endogenous defense factor against pathogenesis facilitated by ligands-RAGE axis, including cancer development [36]. The initiation of RAGE-dependent signaling pathways leads to inflammation, apoptosis, autophagy, and cell proliferation [36,45]. NF-κB induced signaling pathways have been studied in a great detail. The RAGE expression is consistently augmented by sRAGE expression during NF-κB activation. A positive feedback loop may also be induced at the same time to antagonize the RAGE-dependent signaling pathways by counteracting the RAGE ligands [14,36]. The exogenously or endogenously derived AGEs, through NF-κB activation, can increase the gene expression of RAGE, thereby prominent to RAGE expression. Moreover, nuclear factor erythroid-2-related factor (Nrf2) can also be triggered by oxidative stress arbitrated by RAGE, leading to the induced expression of metalloproteases like a disintegrin and metallopeptidase domain containing protein10 (ADAM10). ADAM10 eases ectodomain cracking of RAGE by inducing RAGE levels. In addition, these biological molecular interactions may contribute to the miscellaneous expression

3.3. Biochemical and physiological consequences of glycative, oxidative, and carbonyl stress Glycative stress significantly increases the levels of AGEs. The highly reactive dicarbonyls primarily reacting to arginine residues at the efficient sites of proteins produce dihydroxyimidazolidine and hydroimidazole, which are the most quantitative and functionally vital AGEs in normal conditions [14]. Furthermore, the modification of lysine residues may also result in the formation of two common adducts CML and CEL [14,46]. The glycated biomolecules have a lesser half-life and frequently lose their activity due to misfolding and attraction to the proteasome for proteolysis. On the other hand, the glycated biomolecules can adopt a modified structure and become smaller and denser resulting into MG-altered LDL [38]. AGEs adducts can affect both intracellular and extracellular proteins like serum proteins (ApoB100), long-lived proteins (collagen), globulin proteins (hemoglobin), etc., which signify direct targets of glycative stress resulting in advanced protein crosslinking and subsequent modifications [45–47]. Oxidative and dicarbonyl stress are also an important cause of cell damage in cancer, affecting cell viability in a variety of ways. The most effective stress is a swift and considerable decrease in cell volume, which in turn normalizes a broad range of cell tasks, including the 13


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Fig. 4. Schematic representation of the effects of glycative, oxidative, and dicarbonyls induced stress on cell cycle, biomolecules, and cell apoptosis.

Furthermore, the induced cytokine secretion (IL-1β, IL-6, TNF-α) elevates the generation of cell adhesion molecules (VCAM-1, ICAM-1, endothelin-1), vascular endothelial growth factor (VEGF) and reduces the expression of endothelial nitric oxide synthase (eNOS). Cell adhesion molecules arbitrate recruitment of myeloid and lymphoid immune cells into the tumor microenvironment, which induces inflammation and promote angiogenesis [36,53]. Dicarbonyls/AGEs further elevate this inflammation through ROS production, leading to an inflammatory state that promotes cell proliferation, genetic instability, survival, and metastatic potential contributing to tumor progression [54]. AGE-RAGE signaling regulates the activity of an important metabolic transcription factor, viz., carbohydrate response element binding protein (ChREBP) in the liver and colorectal cancer cells, by directly promoting their proliferation [55,45]. This explains an augmented cancer progression in diabetes. STAT3 and NF-κB transcriptional factors leading to sustained tumor-promoting responses through RAGE activation, prostaglandin E2 production, and β-catenin, facilitate the tumor growth in the same way as enhanced matrix metalloproteinases and IL-6 production favor tumor metastasis [7,48]. In addition, the AGE-RAGE signaling pathway induces tumor formation in colorectal, pancreatic, liver, oral, renal, breast, leukemia, and skin cancer by regulating the invasion, growth, and angiogenesis of cancer cells [54]. Moreover, AGEs may also induce the secretion and translocation of HMGB1 (High mobility group Box 1), an additional RAGE ligand, leading to the AGE-RAGE interaction and signaling. AGEs and HMGB1 in the activation of RAGE signaling can bolster the tumor microenvironment and co-expression induced in aggressive phenotypes of colorectal adenomas [54]. Several studies indicate that AGE-RAGE interactions and induced inflammatory response are implicated in colorectal tumorigenesis while the blockade of RAGEHMGB1 interaction reduces tumor growth and metastasis [54,56].

development of apoptosis cancer cells. The circulating AGEs are more prone to generate dicarbonyl compounds and intracellular ROS. The dysfunctions related with the extracellular and intracellular AGEs enhance the crosslinking of proteins and permanently alter cellular structure and function, and also simultaneously increase the levels of oxidative stress through reactive dicarbonyls and ROS generation [48]. An altered mitochondrial protein function, through obstruction of the electron transport chain (ETC), elevates inflammatory protein expression via mitochondrial pathway initiated apoptosis or cancer (Figs. 1 and 4) [49]. The free radicals generated as result of the Maillard reaction may also cause damage to the DNA or protein and may initiate or cancer. It is the quantity of the ROS generated matters the most, because same ROS may cause apoptosis (a normal phenomenon), and may be a reason for the tumor (abnormal condition) (Fig. 4). 3.4. Glycative stress and cancer metabolism Glycative stress causes various biologic consequences including chronic inflammation. Induced oxidative stress is also an underlying factor in cancer onset and tumor growth. AGEs have been used as an independent determinant of the inflammatory marker CRP, which is associated with systemic diseases and cancer [14]. Numerous studies have indicated an optimistic correlation between glycative stress induced by smoking and the risk of colorectal, liver, and pancreatic cancer [50]. Said et al. determined the impact of glycated and carbamylated collagen type I drifting performance of the highly invasive human fibrosarcoma cells (HT1080) [51]. They also monitored the focal adhesion kinase (FAK) expression and revealed that glycated collagen type I is involved in cancer induction due to delayed cell adhesion time and may affect tumor cell metastasis. Collagen crosslinking and extracellular matrix stiffening are the common findings in tumor progression and invasion [51]. The alterations of AGE-modified basement membranes have been associated with metastatic breast cancer and prostate cancer [52]. RAGEs activated by AGE and dicarbonyl induced inflammation and glycative stress are the main links between metabolic diseases and cancer development. The AGE-RAGE signaling axis under pathogenic mechanisms leads to the increased ROS induction and generation of inflammatory transcriptional factors (NF-kB, HIF1a STAT3) [36].

4. Oxidative stress and cancer metabolism Metabolism is vital for life and variation in the metabolism is central in several human diseases, including cancer. The metabolism of cancer is the current area of focus in the field, relying on advancing chemical biology and molecular techniques. A crucial hallmark of cancer is unrestrained cell proliferation. The metabolism of cancer denotes the variations in cellular metabolism pathways that regulate proliferation 14


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previous investigations depicted that the high levels of oxidative stress are associated with malignant progression, signifying tumor-specific modification in cancer cells and an increased susceptibility to the elevation of ROS leading to DNA damage. It is also believed that oxidative stress can be more tumorigenic by promoting genomic instability [60,59] and both intrinsic and extrinsic factors can be involved in producing persistent levels of ROS in tumors [57]. To inhibit oxidative stress induction and stimulate redox signaling, tumor cells deliberately alter numerous antioxidant enzymes and make the wide use of their metabolic pathways to deliver a sufficient supply of antioxidant molecules (superoxide dismutase (SOD), catalase, thioredoxin, GSH, and NADPH) [63]. Wang et al. observed in colorectal cancer (CRC) patients through the whole human genome microarray (WHDM) that LDL significantly elevates oxidative stress and enhances CRC accumulation and inflammation in intestines by inducing ROS formation and the activation of some signaling pathways including MAPK pathway [64].

and metabolism in cancer cells, where the metabolic changes deliver the anabolic and energetic demands of induced cell proliferation. A collective feature of cancer cell metabolism is the aptitude to attain obligatory nutrients from often nutrient-poor environments and consume these nutrients to both build new biomass and maintain viability [57]. The metabolic amendments in cancer cells are abundant, including reduced oxidative phosphorylation, aerobic glycolysis, and the induced generation of biosynthetic intermediates needed for proliferation and cell growth. The initiation and progression of cancer is related to oxidative stress, a condition in which the equilibrium between production and removal of ROS is altered [58]. Numerous studies suggest that ROS production controls various secondary-messenger signaling cascades. Kumar et al. characterized the state of oxidative stress in various cancer cells (DU145, PC3, and LNCaP) and prostate cells (RWPE1, WPMY1, and primary cultures of normal epithelial cells) revealing numerous grades of belligerence [59]. The elevated levels of ROS formation were also observed in cancer cells in comparison to normal cells and an extramitochondrial source of the ROS formation was found. NAD(P)H oxidase (Nox) systems have been proved perilous for the malignant phenotype of prostate cancer cells and are associated with the accumulation of ROS [60]. Oxidative stress has several pro-tumorigenic properties, such as induced DNA mutation or DNA impairment, cell proliferation, and genome instability [57]. Zhang et al. found that cigarette smoke extract (CSE) stimulates resistance in epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) by accelerating EGFR signaling and ROS formation in somatic mutated non-small lung cancer cell lines (NSCLC) [61]. Conversely, oxidative stress has also been implicated in anti-tumorigenic actions, linked to two major mechanisms, apoptosis and senescence, which counteract the tumor development. The reconfiguration of cancer metabolism over oxidative stress is related to metabolic network and flux topology of pathways. It has been established that oxidative stress results in mitophagy, oxidative phosphorylation limitation, cysteine oxidation, and the inactivation of the M2 isoform of pyruvate kinase that are reconverted to the pentose phosphate pathway (PPP), which is involved in cancer metabolism [62]. Cancer-associated mutations and microenvironments can increase oxidative stress, which may prompt the activation of tumorigenic signaling and metabolic reprogramming (Fig. 5). An induced oxidative stress has often been perceived to be a hallmark of cancer cell lines and many tumors [60]. Few

5. Effects of dicarbonyls in cancer biology and development Dicarbonyls are produced by carbohydrates during thermal processing in the Maillard reactions, lipid peroxidation, glycolysis, or protein degradation. These molecules are precursors of AGEs and are hundreds to thousands of times more reactive than glucose in glycation processes [65]. They act as intermediates in a composite reaction flow where they respond mainly to the N-terminal arginine and lysine side chains of proteins leading to AGEs. Dicarbonyl compounds are formed from hexoses, such as GO, MG, and 3-DG [65,66]. Due to their high reactivity, dicarbonyls lead to the carbonylation and impairment of biomolecules (protein, DNA, and lipoproteins) resulting in oxidative stress, inflammation, and carcinogenesis [66]. Dicarbonyl stress may also enhance tumor progression by inducing aerobic glycolysis where glyoxalase 1 (GLO 1) expression is a sign of cancer malignancy [66,67]. MG is the most reactive and genotoxic compound, present in various food materials and produced in metabolic pathways, such as glycolysis, protein degradation, and lipid peroxidation [68]. Strong oxidative stress and carbonyl stress result in the dysfunction of a variety of biomolecules, necrosis, and/or apoptosis [69]. Egyud and Szent Gyorgyi observed that MG inhibits glycolysis and mitochondrial respiration in human leukemic leucocytes [70]. Therefore, MG mediated damage of glyceraldehyde-3-phosphate dehydrogenase catalyzes various vigorous reactions in carbonylation and tumor glycolysis of mitochondrial Fig. 5. Signaling pathways that regulate cancer metabolism: mTORC1 actuates an anabolic development program bringing in nucleotide, protein, and lipid synthesis. The loss of tumor suppressors like p53 or actuation of oncogenes like MYC further promotes anabolism through transcriptional regulation of metabolic genes which regulate signaling through methylation, acetylation, and ROS.

15

16

Increased ROS levels due to redox cycling; increased susceptibility to oxidation due to GSH decrease

[88] [90]

[88] [89] [88]

Decrease in ATP synthesis by targeting glycolytic pathways Decrease in ATP synthesis by targeting glycolytic pathways GSH oxidation and inactivation of Trx1, Trx2, Prx3 and Gpx2; decrease in ATP synthesis due to factor B inhibition ROS increase due to GSH depletion Tyrosine kinase inhibitor

[85] [62] [87] Increase in intracellular ROS accumulation, decrease in GSH content ROS increase through NADPH and GSH decrease Decrease in ATP synthesis by targeting glycolytic pathways

Glioblastoma cells (GL15) Chronic myelogenous leukemia cell line (K562 cells) A549 lung cancer cells 3-Bromopyruvate (3BP) Imatinib

Menadione

HepG2Cells Breast cancer cells Hepatocellular carcinoma cells 3-bromopyruvate (3-BrPA) 2-deoxyglucose 2-(DG) Arsenic trioxide

Pro-apoptotic LKB-1/AMPK pathway activation Inhibition of glucose 6-phosphogluconate dehydrogenase (G-6PD) Suppresses PPP by inhibiting transketolase (TLKT1); inhibits pyruvate dehydrogenase Inhibition of hexokinase (HK) Inhibition of HK Inhibition of glycerol-dehyde-3-phosphate dehydrogenase (GAPDH) Inhibition of HK and acting as an alkylating agent Inhibition of Bcr-Abl tyrosine kinase; causing a decrease in HK and G6PD activity Activation of redox cycling reactions; GSH depletion Human Acute Myeloid Leukemia Cells Jurkat leukemia cell line LLC xenografted mice

Mode of action

Etomoxir 6-amino-nicotinamide (6AN) Oxythiamine

Many carbonyl species are derived from glycoxidation by enzymatic reactions and involved in alcohol and aldehyde dehydrogenases, carbonyl reductase, aldo-keto-reductases, glutathione-S-transferases, and cytochrome P450 [83,84]. During these reactions, the carbonyl products transformed to less toxic compounds are debarred from the cell or organism. Considering this evolving lethal role of combative carbonyls and their unconventional products in cancer, numerous therapeutic schemes have been established. Several researchers have found success in developing new strategies and describing redox regulation and ROS levels in a perspective of cancer metabolism, by targeting metabolic obstruction and anticancer treatment (Table 3) [62,85,86]. The different stages of carbonyl stress, glycolytic stress, and oxidative stress could be possible therapeutic targets. The carbonyl species induced stress can be advantageous owing to an augmented capability to eliminate reactive carbonyl species [84]. It can also induce cell competence with other reactive species like ROS under some conditions. The

Experimental model

5.1. Significance and boundaries in cancer research

Inhibitor

Table 3 Various inhibitors of cancer, their mode of action, effects on redox balance, and the employed experimental model.

Effects

References

proteins [71]. Chan et al. reported that the increased levels of MG are more cytotoxic and induce apoptotic biochemical changes such as the mitochondrial release of caspase-3, activation of cytochrome c, and cleavage of poly [ADP-ribose] polymerase (PARP) in human hepatoma G2 cells (HepG2) [72]. They also observed MG induced ROS generation by using cell-permeable dye 2′,7′-dichlorofluorescein diacetate (DCFDA) in HepG2 cells [72]. Moreover, Chakrabarti et al. demonstrated that chitosan nanoparticle conjugated MG triggers peritoneal macrophage treatment of tumor-bearing mice (S-180), indicating a raised expression of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) and surface receptors [Toll like receptor-4 (TLR4) and Toll-like receptor-9 (TLR-9)] to combat cancer [73]. The anticancer effects of highdose MG (200 M) have also been observed in the apoptosis of HepG2 human hepatoma and deliberated in colon, liver, lung, cervix, and breast cancer models [74,75]. Furthermore, cancer research on the liver specified that fairly low concentrations of MG (1 M) might damage the invasion, adhesion, and voyage of liver cancer cells via the directive of p53 [76]. However, the inhibitory upshot of low dose MG on cancer development needs to be established in other cancer types by in vivo or in vitro modeling. The non-enzymatic glycoxidation of proteins under glycative and oxidative stress has been allied with carcinogenesis over the RAGE axis. Glycoxidative proteins are highly immunogenic and stimulate humoral and cellular immune responses. Mir et al. [77] reported the structural alterations, adducts formation, and accretion in histone H2A upon in vitro alteration by MG. The immunogenicity of altered histone H2A and its immune complex formation with cancer auto-antibodies was also assessed and showed induced binding associated with the native histone and the sharing of epitopes on histones and MG-H2As in cancer patients. Furthermore, α-oxoaldehyde (GO) is also a highly reactive dicarbonyl, produced endogenously at a high rate during hyperglycemia. GO is a food-processing toxin and shows to have mutagenic effects and genotoxicity in the liver of C3H/HeN male mice [67,78]. GO also stimulates chemically altered gastric carcinoma and has potential effects upon the conquest of metastatic cancer by inhibiting the proteolytic action of extracellular matrix metalloproteinase-2 and playing a crucial role in metastasis [79]. 3-DG, a combative α-oxoaldehyde, is a physiological metabolite generated in the polyol pathway and the Maillard reaction [80]. The higher concentrations of 3-DG (100 M) showed an increase in oxidative stress and caused U937 cell line apoptosis [81]. By downregulating the p38-MAPK dependent pathway, 3-DG altered collagen repressed fibroblast proliferation and migration [81]. Furthermore, the cancerous lesions of chemically induced hepato-carcinomas caused increased levels of aldose reductase that may help in 3-DG detoxification. Consequently, 3-DG might be lethal to liver cancer cells and could also assist as a presumed anticancer mediator [82].

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carbonyl species-induced stress can also overwhelm the defense system, possibly helping in maintaining the steady state level of reactive carbonyl species for an extended time. The condition may be called “chronic carbonyl stress”, which can result in the progression of various pathological states, either alone or in combination with additional mechanisms prior to cancer [100]. The interaction between carbonyl, glycolytic, and oxidative stress under precise circumstances may be used as a defensive strategy. For example, an unregulated movement of glutathione-S-transferase, ROS, and carbonyl species can be used to augment the state of RCS resistance mechanisms by the stimulation of trivial oxidative stress, which is suggested to play a significant role in cancer metabolism [92]. Since RCS have also been shown as being related to cancer, the above features can be used to recognize promising therapeutic goals. Many RCS have already been identified but from a medical point of view, glycative stress and oxidative stress mechanisms and their components, glutathione and glutathione-dependent enzymes, are the best-studied targets along with the other components of the antioxidant system [92]. The exploration of altered metabolism could be very useful in cancer but it is still not very well explored because of its limitations. Oxidative and carbonyl stress, as well as stress from glycosylation, are linked together, where carbonyl compounds and ROS accelerate glycosylation processes. However, the influence of carbonyl stress, oxidative stress and glycative stress are mostly mediated by nonspecific receptors that exhibit supplementary biological properties. Therefore, it is difficult to perceive the influence of these processes in cancer therapy. At a molecular level, they interrupt the structure and functions of nucleic acids, proteins, and lipids. As a consequence of these undesirable effects at the organismal and cellular levels, forfeiture of function and even viability can arise. All of these stress mechanisms and their offshoots could be targeted to find an effective cancer treatment but it requires a deep insight of these mechanisms.

implicated in various types of human tumors [94]. Recently our research team has reviewed the role of AGE and RAGE in various cancers including the pancreatic and hepatocellular carcinoma [95–99]. The need of the hour is stop the progress of the glycation reaction and the metabolic diseases associated with it including the cancer [100–104]. The induced level of stress from AGEs, ROS, and dicarbonyl overproductions results in prolonged inflammation, which offers an appropriate microenvironment for tumor growth. Additionally, it endorses cancer inception in regular tissues such as liver, pancreas, prostate, and colon through stress dependent DNA damage and a surplus of inflammatory response and various cytokines generations [105]. In conclusion, the present review states in brief the various findings on oxidative, carbonyl, and glycative stress and the effects of these menaces on cancer progression. The role and effects of AGEs, ROS, and dicarbonyls in human tumors is still mostly uncharted. We have the foremost research going on the glycative, oxidative and dicarbonyl stress correlations and their effects on human cancer tissues, as well as delineating their manifestation in diverse forms of tumors. It is required that we pay more attention to this as a defensive strategy for chronic diseases, such as neuronal diseases. The associated research on metabolic disorders is presently deficient and we still need to identify more targets and explore respective mechanisms to develop new effective strategies. Though, the identification of a natural bioactive compound that can detoxify the reactive carbonyl species might offer some novel therapeutic agents to combat these diseases. Further research will shed light on the physiological significance of these lethal stresses in the biology of cancer cells and, consequently, will assist in the expansion of the cancer treatments by blocking these deadly consequences.

6. How to overcome the issue

Acknowledgements

The use of plant-derived natural bioactive compounds or extracts that can effectively sequester ROS may offer an innovative strategy that can block the progression of tumorigenesis. In addition, new techniques such as nanocarriers and nanoparticles, which can induce the bio-efficacy and bioavailability of natural bioactive compounds in vivo, may open up a field for stopping oxidative/carbonyl and glycative stressinduced tumor progression. Furthermore, the inhibitory effects of bioactive compounds such as epigallocatechin gallate as well as notoginsenoside have been deliberated in human colorectal cancer and human hepatocellular carcinoma cells [93]. Furthermore, numerous studies using animal models have also shown promising results. Several in vivo studies utilizing D-galactose injected in C57BL 56F-irradiated mice, and 2,2′-Azobis (2-amidinopropane) dihydrochloride [AAPH] injected in Monglian Gerbils and high cholesterol-fed C58BL mice have shown promising outcomes on these stresses and inflammation [94]. These studies showed that such diseases could be amended by blocking the damages caused by oxidative, glycative, and carbonyl stresses. Mercaptoethane sulfonate was used for tumbling oxidative stress increased by doxorubin treatment in cancer patients. Therefore, nanotechnologies are being used to overwhelm the curb of bioavailability and bio-efficacy of natural or bioactive compounds in humans.

The authors are highly thankful to the DBT, DST, and Govt. of India for providing an International grant under Indo-Russia joint project (No. DBT/IC-2/Indo-Russia-2014-16). The Authors are also thankful to the SERB (No. SB/LS-142/2015) and UP-CST (No. CST/SERPD/D-1117) for providing ‘Young Scientist’ project award. In addition to it, intramural fund in the form of BRTF of Integral University deserves special thanks as well. The manuscript number assigned from Dean R& D office of the University is IU/R&D/2017-MCN000201.

Conflict of interest The authors declare that there is no conflict of interest to disclose.

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