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New insights on oxidative stress in cancer

Journal:

Aug-2008-0034

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Manuscript ID:

KeyOpinions

Manuscript Type:

Review

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New insights on oxidative stress in cancer

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Roberta Visconti1,2 & Domenico Grieco1,3* Addresses 1

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CEINGE Biotecnologie Avanzate via Comunale Margherita 482 80145 Naples, Italy 2 IEOS, CNR via S. Pansini, 5 80131 Naples, Italy 3 Faculty of Biotechnological Sciences, DBPCM University of Naples “Federico II” via S. Pansini, 5 80131 Naples, Italy

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*To whom correspondence should be addressed.

Cancer initiation and progression has been linked to oxidative stress, a conditions in which the balance between production and disposal of reactive oxygen or nitrogen species is altered. Oxidative stress has been shown to have several protumorigenic effects like increasing DNA mutation rate, inducing DNA damage, genome instability and cell proliferation. However, oxidative stress also exerts antitumorigenic actions as it is has been linked to senescence and apoptosis, two major mechanisms that counteract tumor development. Here we highlight recent findings that relate oxidative stress to cancer-associated conditions such as chronic inflammation, steroid hormone signaling and altered chromosome segregation and emphasize how these studies may identify new targets for the development of drugs and strategies for cancer prevention and cure.

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Keywords Redox, oxidative stress, DNA damage, DNA oxidation, chronic inflammation, cell cycle, chromosome segregation.

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Abbreviations

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ROS reactive oxygen species, RNS reactive nitrogen species, RONS reactive oxygen and nitrogen species, DEN diethylnitrosamine, DSS dextran sulfate sodium, AOM azoxymethane, IL

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interleukine, INF interferon, TNF tumor necrosis factor, VEGF vascular endothelial growth factor, Aag alkyladenine DNA glycosylase, Hsp heat shock protein, IL-1R interleukine 1 receptor, GSH

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reduced glutathione, 8-oxo-G 7,8-dihydro-8-oxoguanine, Ogg1 8-oxoguanine DNA glycosylase, Dsb DNA double strand breaks, SAC spindle assembly checkpoint.

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Introduction

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Changes in the balance between oxidation/reduction reactions, the redox balance, is crucial for several cellular functions and regulated production and disposal of Reactive Oxygen Species (ROS), as well as Reactive Nitrogen Species (RNS), is central for the redox balance. ROS and RNS

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(collectively RONS) are highly reactive metabolites capable of damaging several cellular structures (cytoskeleton, membranes, genome) by subtracting electrons from their molecular components [1•]. ROS were originally considered a toxic by-product of important cellular functions (i.e. cellular respiration), or actively produced only by specialized cellular types (i.e. netrophils, macrophages) for their destructive potential [2]. More recently a very large number of observations have indicated that ROS can be actively produced in a large variety of cell types and appear crucial in regulating several normal cellular functions [1•, 2]. Indeed, regulated changes in ROS concentration has been

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found critical for functions like respiration, control of enzymatic activities, transcriptional regulation, modulation of signal transduction pathways, cell cycle progression, apoptosis and inflammatory response [3, 4, 5, 6, 7, 8, 9]. Given the potential deleterious effects of ROS, however,

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normal cells have enzymatic and non-enzymatic ways of ROS disposal that help maintaining the redox balance and prevent the potential damaging effects of ROS on cellular structures [1]. Perturbations of redox balance may lead to a condition that can be called oxidative stress. Oxidative

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stress has been linked to pathological conditions such as cellular senescence and cancer initiation and progression [10, 11, 12•, 13]. Oxidative stress can increase DNA mutation rate, induce DNA

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damage, genomic instability and cell proliferation, in addition, oncogenes have been described to increase ROS concentration. Thus, oxidative stress can be considered protumorigenic by several

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mechanisms [14]. Oxidative stress has, however, also an antitumorigenic action as it can induce senescence and apoptosis, two mechanisms that counteract tumor development. Indeed, the higher oxidative rate observed in cancer cells is exploited to kill cancer cells by antiblastic drug-induced

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oxidative stress [15]. In this review we will highlight recent findings that relate oxidative stress to cancer-promoting conditions such as chronic inflammation, steroid hormone signaling and altered

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chromosome segregation and emphasize how these findings may provide new targets for the development of drugs and therapeutic strategies for cancer prevention and cure.

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Inflammation

The existence of an association between chronic inflammation and cancer has been first proposed as

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early as in 1863 by Virchow when he noted that inflammatory cells often infiltrate malignant

tumors and, on the other hand, that tumors frequently arise in chronically inflammed regions [16].

Several clinical and epidemiological evidences have later supported this association. Many human


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3 chronic inflammatory diseases, such as inflammatory bowel disease or prostatitis, do predispose to cancer development [17, 18]. Correspondingly, there is a strong association between inflammation

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induced by chronic infections and cancer, with the evidence that the longer the infection-generated inflammation persists, the higher is the risk for cancer development. For example, the association

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between Helicobacter pylori-caused peptic ulcer disease and the development of gastric adenocarcinoma and MALT lymphoma is widely ascertained [19]. Of note also the risk of developing hepatocellular carcinoma, the third leading cause of cancer deaths, is greatly enhanced in patients with chronic viral hepatitis (Hepatitis B and C viruses), that causes persistent liver injury and inflammation [20]. Overall, it has been estimated that chronic infection and associated inflammation contribute to about one in four of all cancer cases worldwide [21]. Thus, a great effort has been recently made for elucidating the molecular mechanisms linking chronic inflammation and cancer in order to develop new strategies for cancer prevention and cure. Solid evidences have

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indicated ROS and RNS as key chemical effectors linking inflammation to genetic alterations and cancer. The regulated ROS and RNS levels [10] are altered under chronic inflammation conditions.

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Activated phagocytic cells release RONS during the inflammatory response to injuries or infections and non-phagocytic cells are stimulated to increase their RONS concentration under the stimulus of pro-inflammatory cytokines such as TNF-α, IL-1β and INF-γ [11]. When inflammation chronically

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persists, the redox balance is upset; RONS production is no longer balanced by anti-oxidant enzymatic and non-enzymatic scavengers resulting in oxidative stress [22]. A mild oxidative stress

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is often associated with induction of cell proliferation; a stronger or more persistent oxidative stress conditions can damage DNA and modify other biomolecules such as RNA, lipids and proteins.

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Generally, as modifiers of proteins crucial to several cell functions, unbalanced RONS production can deregulate vital cellular processes such as cell-cycle checkpoints, DNA repair and apoptosis [11, 23]. Moreover, deregulated RONS production can constitutively activate signaling pathways

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they physiologically control, resulting in constitutive transcriptional induction of proto-oncogenes, such as c-fos and c-jun [10], and of pro-angiogenic proteins, such as VEGF [24], strongly suggesting a role for RONS in both cancer initiation and progression.

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Recently, two papers have further contributed to our understanding of the impact of the

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inflammation-associated reactive species on tumor development. Meira and colleagues [25••] have demonstrated that RONS-induced DNA damage contributes to colon carcinogenesis in mice. For their studies the authors have utilized mice lacking Alkyladenine DNA glycosylase (Aag), an

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enzyme required to excise oxidatively damaged DNA bases. The authors have induced colon

tumorigenesis in wild type and Aag-/- mice by administering five cycles of the promoter dextran sulfate sodium (DSS), preceded or not by a single injection of the initiator azoxymethane (AOM).



4 In the AOM+DSS-treated Aag-/- mice there was a significant increase in tumor multiplicity respect to wild type mice. Moreover, the tumors in AOM+DSS-treated Aag-/- mice were more severely

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dysplastic and were affecting a wider area. The authors also noted in AOM+DSS-treated Aag-/mice an increase in spleen weight, attributable to extramedullary hematopoiesis, for replenishing

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blood lost through ulceration and for supplying neutrophils to the inflamed area, and a decrease in colon length due to the fistulas and ulcers healing. Of note, the same defects were also observed in Aag-/- mice treated with DSS alone for five cycles, suggesting that Aag-/- mice were more susceptible than wild types to DSS-induced colitis. To better evaluate the effects of the sole DSS, the authors administrated it alone for 7 cycles, the Aag-/- mice displaying an increase in spleen weight and a decrease in colon length. Moreover, epithelial defects and crypt atrophy were significantly higher in Aag-/- mice versus the controls. Conclusively, the DSS-treated Aag-/- mice developed more tumors than wild types. Thus, even in the absence of the initiating treatment with

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AOM, Aag influences the disease progression to cancer in a mouse model of colon chronic inflammation induced by DSS. Remarkably, the authors show that Aag has the same function in at

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least another tissue. Upon infection with H. Pylori Aag-/- mice were more susceptible than wild types to develop gastric mucosal metaplasia and other lesions that are precursors to gastric cancer although no visible tumors developed during the 32-week experiment. Importantly, the authors also

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formally prove that Aag deficiency does not influence tumor development in the absence of chronic inflammation. By crossing Aag-/- mice with the APCMin mice, a model of inflammation-independent

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colon cancer, they show that Aag absence had no effects on number, distribution, and size of the intestinal tumors that spontaneously develop in the APCMin mice, these data strongly suggesting that

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Aag deficiency indeed enhances only the chronic inflammation-induced cancerogenesis. Cleverly, the authors also clarified the molecular mechanism by which chronic colitis induces tumor development in the Aag-/- mice. They showed that in both wild type and knock out mice

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AOM+DSS-induced inflammation caused production of RONS. Remarkably, upon DSS treatment, the levels of the DNA typical lesions induced by RONS were significantly higher in Aag-/- colon cells than in wild type colon cells. Intriguingly, in 5 out of 6 tumors developed in DSS-treated Aag/-

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mice the authors find mutations in Ctnnb1, the β-catenin encoding gene frequently mutated in

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mouse colon cancers, these data suggesting that unrepaired RONS-induced DNA lesions can cause oncogene activation.

The molecular mechanisms of reactive species-enhanced cancerogenesis have been further

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expanded on by Sakurai and colleagues [26••]. These authors showed that, upon exposure to the

procarcinogen diethylnitrosamine (DEN), liver damage, neutrophil infiltration and hepatocyte apoptosis were enhanced in mice lacking the p38α kinase in hepatocytes (p38αDhep mice). In these


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5 mice the enhanced DEN-induced liver damage resulted not only in an increased compensatory proliferation of the hepatocytes, as physiologically expected, but also in the development of more

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and larger hepatocellular carcinomas. Remarkably, the authors demonstrated that the p38αDhep mice

accumulated more ROS than controls 12 hrs after DEN administration. Accordingly, DEN-induced

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hepatocyte damage and compensatory proliferation is prevented by administration of the antioxidant butylated hydroxyanisole. In search for the signaling pathways mediating p38α effects on ROS production, the authors show, by microarray analysis, that in wild type mice DEN treatment induced a marked increase of the mRNAs encoding for the heat shock protein Hsp25. This response was defective in p38αDhep mice and the authors demonstrate that it is indeed the defective Hsp25 induction to be responsible for ROS accumulation in p38αDhep mice. In fact, the tail vein injection of an adenovirus expressing Hsp25 restored liver Hsp25 expression, reducing ROS

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accumulation, liver damage and compensatory proliferation in DEN-treated p38αDhep mice. The authors propose that Hsp25 inhibits ROS accumulation by increasing the concentration of reduced glutathione (GSH), as suggested by the evidence that p38αDhep mice had lower levels of GSH in the

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liver and that its levels returned to normal upon adenovirus-mediated Hsp25 re-expression. The authors also show that in p38αDhep mice DEN- and ROS-induced hepatocyte necrosis triggers IL-1α

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release. By using IL-1R-/- mice or by administering the IL-1R antagonist anakinra, the authors demonstrate that it is indeed IL-1α the molecule stimulating liver inflammation and, by inducing IL-6 secretion, compensatory proliferation. Finally, the authors conclusively demonstrate that ROS-

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induced IL-1α is the critical mediator of the hepatocellular carcinoma development by showing that

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the interference with IL-1α signaling inhibits hepatocellular carcinomas number and size in DENtreated animals. The great importance of the approach of Sakurai and colleagues resides in the identification of intermediate effector molecules that link oxidative stress to cancer. Recognition of

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these intermediate molecular links is crucial for the development of targeted drugs for cancer prevention and therapy with increased selectivity and efficacy. In this specific case, we expect great impulse in the search for potent inhibitors of IL-1α action for their potential cancer prevention effects in chronically inflamed livers and possibly other organs.

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Steroid hormone signaling.

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Steroid hormone signaling and cancer development in hormone-sensitive cells has been linked over

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the years both by epidemiological and mechanistic observations [27]. However, although steroid

hormones signaling is known to transcriptionally activate many genes involved in cell proliferation and survival, only recently it is becoming clear that their action on the DNA is more subtle and complex than anticipated and appears tightly linked to ROS metabolism. Estrogens, for instance, Thomson Reuters, 77 Hatton Garden, London, EC1N 8JS


6 even independently of the presence of the receptor, are able to induce directly ROS formation and, albeit at high dose (100 nM), can form within the cells highly reactive quinone derivatives [28].

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These actions may be genuine DNA damaging activities that can generate mutations or permanent changes in the DNA. The most frequent estrogen- and ROS-induced DNA modification is the

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oxidation of guanine and the formation of 8-oxo-G [29]. Oxidized guanines are recognized by very efficient enzymes, oxoguanine glycosylases (NTH1, endonuclease III homolog; Ogg1, 8oxoguanine DNA glycosylase), which remove the oxidized base and leave an apurinic site, which is further processed by the base excision repair system [29]. Inefficiency of the repair system or excessive estrogen stimulation may lead to genome destabilizing effects like mutations, such as Gto-T transversions, or even DNA double strand breaks (dsb), by prolonged pausing of the DNA replication machinery. Recently, studies on estrogen signaling have put new emphasis on the potential DNA damaging action of estrogen-dependent transcription.

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Ju and coworkers have reported that estrogen-dependent transcription initiation is coupled with topoisomeraseIIβ-dependent DNA dsb formation at estrogen-sensitive promoters. DNA dsb

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formation is dependent on estrogen receptors and appears to be required to change nucleosome topography and chromatin structure to initiate transcription [30••]. The DNA dsb is rapidly repaired thanks to the contextual recruitment, at the DNA dsb sites, of the DNA repair enzyme polyADP-

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ribose polymerase-1. The authors also provided evidence that other transcription factors may use a similar strategy of DNA dsb formation and repair for transcriptional regulation of their target genes.

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While pointing to the crucial role of coupling transcription to repair, this manuscript focused the attention on the potential direct genotoxic effect of estrogen-dependent transcription: estrogen-

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dependent transcription is inevitably coupled with DNA damage. A more recent manuscript further extended these observations and pointed to the crucial role for formation of ROS-dependent DNA single strand nicks, at sensible promoters, in estrogen-dependent gene transcription [31••]. The

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authors demonstrated that chromatin remodeling, required for active estrogen-dependent transcription, relies on localised histone H3 demethylation at lysine 9. H3-lysine 9 demethylation, operated by LSD1, is a redox reaction that produces the ROS hydrogen peroxide. The authors

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provide evidence that local hydrogen peroxide production induces formation of 8-oxo-G formation

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and recruits Ogg1. They further propose that the action of Ogg1, producing an apurinic site, relaxes tightly packed DNA allowing bending of chromatin and formation of loops that bring in close proximity the bound receptor and RNA polymerase. Thus, in their model, production of 8-oxo-G

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and its removal is a necessary step for productive estrogen- and estrogen receptor-dependent

transcription. Taken together, these experiments highlight a novel aspect of transcription induced by estrogens. Estrogen-responsive regions, spread out in the genome, recruit transcription and repair


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7 proteins to initiate productive transcription by oxidizing DNA. In doing so, DNA has to be dangerously modified and, albeit faithfully reversed, these modifications in the long run may

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represent preferred sites of mutation and damage. Is this the mechanism explaining the long sought relation between estrogens and cancer? It may well be, but definite answer to this question awaits

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isolation of genomic regions containing estrogen-responsive sites and the evaluation of mutation rates at these sites relative to other areas.

Chromosome segregation

Alterations of the normal chromosome number by gain or loss of entire chromsomes (numerical aneuploidy) is the most common feature in cancer and among the first cancer cell abnormalities to be recognized [32, 33]. Whether aneuploidy has a role in the early steps of tumorigenesis or just contributes to the genetic instability required for tumor progression is still debated [34, 35].

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However, rather compelling evidence suggests that aneuploidy may initiate tumorigenesis: a rare, tumor-prone, human disease, variegate mosaic aneuploidy, is caused by mutation in a gene required

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for accurate chromosome segregation [36•], and mice genetically modified in another gene involved in the fidelity of chromosome segregation are susceptible to develop lung cancer [37]. Chromosome gain or loss may ensue from a variety of aberrant mitotic conditions (aberrant mitotic figures have

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been described in tumor cells; i.e. mono or multipolar mitosis) [32, 33] if the spindle assembly checkpoint (SAC) [38], a crucial safeguard mechanism that ensure that anaphase only begins after

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spindle assembly completion, fails. Recent observations indicate that ROS may affect mitosis progression and SAC proficiency. Several observations indicate that ROS concentration increases

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in mitosis. Goswani and coworkers reported, by direct measurements with an oxidation sensitive dye, that ROS concentration is lowest in G1, increases during S-phase and reaches peak in mitosis [39]. In addition, Chang et al. reported that decreased peroxiredoxin I activity, by cyclin-dependent

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kinase (cdk) 1-dependent phosphorylation, results in accumulation of hydrogen peroxide during mitosis [40]. We also have performed measurements of ROS concentration during cell cycle by oxidation-sensitive fluroescent probe (dichlorofluorescein) and found, similarly to the results

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published by Goswani and coworkers, that ROS increase in mitosis until metaphase and decrease at

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mitosis exit and early G1. In addition, we have also gathered some preliminary observations that indicate that active ROS production in mitosis is required for spindle assembly. Challenging HeLa cells in prophase with antioxidant/reducing agents induced a significant delay in spindle assembly

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and consequently in mitosis exit (our unpublished results). Moreover, antioxidant treatment of metaphase cells induced disassembly of already formed spindle (our unpublished results). The

spindle alterations we observed when HeLa cells are treated with antioxidants appear similar to the



8 spindle alteration described by Pandey and coworkers in Drosophyla melanogaster cells under anoxic conditions [41•]. It is, therefore, possible to formulate the hypothesis that reduced ROS

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concentrations may affect spindle dynamic under anoxic conditions. We have also recently

published the observation that a relatively mild oxidative stress in SAC-arrested cells is capable of

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inducing the override of the safeguard SAC mechanism [42], possibly by an oxidation-dependent down-regulation of the activity of the cdk1 activating phosphatase Cdc25C. Indeed, it has been demonstrated that Cdc25C can be regulated by reversible oxidation of crucial cysteine residues [6], while cdk1 activity is required for SAC-dependent cell cycle arrest [43]. Thus, regulation of ROS concentration appears crucial for mitotic events. While reduced ROS concentrations (our unpublished results) and anoxia [41•] delay spindle assembly and exit from mitosis in as SACdependent way, oxidative stress induces SAC failure and may lead to altered chromosome segregation. We believe that these observations may be relevant to our understanding of how

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aneuploidy can be generated during tumor development when oxygen supply becomes limiting and neoangiogenesis is required for progression. It is possible to envisage that cycles of anoxia-hypoxia

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and re-oxygenation may lead to an uncontrolled oxidative metabolism and ROS concentrations that may ultimately affect mitotic progression leading to the generation of aneuploidy [44].

Conclusions

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Although several mechanisms can be hypothesized to link oxidative stress and cancer development

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in a cause/effect relationship, we are still far away from having pinpointed the precise nature of this connection. Nevertheless, the approaches and the results of the recent reports highlighted in this

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review may help to pilot the development of new drugs and therapeutic strategies for cancer cure and prevention. For instance, controlling the IL-1α signaling may turn useful in prevention and cure of inflammation-associated neoplasia, while controlling the enzymes that couple transcription-

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dependent and ROS-mediated changes in chromatin structure may turn useful in prevention and cure of hormone-associated tumors. In addition, further elucidation of the potential relationship among ROS, anoxia and chromosome segregation may provide the conceptual basis to extend the

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use of the combination of antiangiogenic therapy with drugs that kill cells by perturbing mitotic

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spindle physiology.

Acknowledgment

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The authors wish to thank Rosa Marina Melillo for helpful suggestions and the Associazione Italiana per la Ricerca sul Cancro (AIRC) for support.


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