Special Issue "Oxidative Stress and Cancer"
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A special issue of Cancers (ISSN 2072-6694).
Deadline for manuscript submissions: closed (6 April 2010)
Special Issue Editor
Guest Editor
Prof. Dr. Alba Minelli
Cellular Biochemistry Unit, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06124, Perugia, Italy
E-Mail: aminelli@unipg.it
Phone: +39 075 7440
Fax: +39 075 7442
Interests: prostate cancer; oxidative stress; prostasomes; adenosine
Special Issue Information
Dear Colleagues,
Over 7,500 articles on oxidative stress related cancers are substantial evidence of the paramount importance of the control of cellular redox homeostasis which is challenged, throughout life, by sustained oxidative stress, chronic inflammation, and excessive antigen-loading. Oxidative stress-induced activation of NADPH oxidase and peroxisome proliferators-activated receptors, oxidants and inflammatory mediators, i.e. IL-6, IL-10, TNF-α, PGs, alterations of redox state of binding proteins, DNA mutations and induction of early response genes and hematopoietic activation seem to be common elements in the induction of hyperplasia, neoplasia, cancer metastasis, and angiogenesis. Therefore, potential health benefits of a number of antioxidants or anti-inflammatory agents, and maintenance of cellular oxido-redox status are crucial for optimal tissue function. This is a complicated topic which can be investigated from a number of perspectives. Our final goal is the compilation of a special issue providing an integrated understanding / identification of developmental phases of oxidative stress-induced cancers that will assist professionals towards effective progress on cancer war.
Thank you for your collaboration.
Prof. Dr. Alba Minelli
Guest Editor
Submission
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access quarterly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 500 CHF (Swiss Francs).
English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.
Published Papers (15 papers)
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Received: 11 November 2009; in revised form: 25 November 2009 / Accepted: 8 December 2009 / Published: 16 December 2009
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Abstract: Cisplatin is an important chemotherapeutic agent in lung cancer treatment. The mechanism of drug resistance to cisplatin is complex and historically has been difficult to overcome. We report here that cisplatin resistant lung cancer cell lines possess high basal levels of reactive oxygen species (ROS) when compared to normal cells and their parental cell counterparts. These resistant cells also have low thioredoxin (TRX) levels which may be one of the contributory factors to high ROS. N′1,N′3-dimethyl-N′1,N'3-bis(phenylcarbonothioyl) propanedihydrazide (elesclomol), an agent known to increase ROS is selectively toxic to cisplatin-resistant cells, while sparing normal cells and the parental counterpart. The cytotoxic effect of elesclomol in resistant cells is accompanied by further decreases in TRX and glutathione (GSH) antioxidant systems, while opposite results were found in parental cells. The ID50 of elesclomol in cisplatin-resistant cells ranged from 5–10 nM, which is well within clinically achievable ranges. N-Acetylcysteine (NAC), which is known to neutralize ROS, can abolish the cytotoxic effect of elesclomol, suggesting that the cytotoxic effect results from increased ROS. Overall, our data suggest that elesclomol selectively kills cisplatin-resistant tumor cells through increased ROS. This agent may hold potential to overcome cisplatin resistance and should be further explored to treat patients who have failed cisplatin therapy.
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Received: 10 December 2009; in revised form: 29 January 2010 / Accepted: 1 February 2010 / Published: 8 February 2010
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Abstract: Lung cancer is one of the few neoplasia in which the principal aetiology is known, with cigarette smoke donating a considerable oxidative burden to the lungs. This may be part of the aetiology of lung cancer, but the neoplastic process is also associated with increased oxidative stress. Nonetheless, it is difficult to study the mechanisms behind the induction of lung cancer in smokers, but newer techniques of breath analysis targeting markers of oxidative stress and anti-oxidant capacity show promise in unravelling some of the pathways. This review highlights recent developments in the assessment of oxidative stress by non-invasive methods of breath analysis which are becoming powerful research techniques with possible clinical applications.
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Received: 21 December 2009; in revised form: 9 February 2010 / Accepted: 10 February 2010 / Published: 12 February 2010
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Abstract: Overexpression of manganese superoxide dismutase (MnSOD) can sensitize a variety of cancer cell lines to many anticancer drugs. Recent work has shown that cancer cells can be sensitized to cell killing by raising peroxide levels through increased manganese superoxide dismutase (MnSOD) when combined with inhibition of peroxide removal. Here we utilize the mechanistic property of one such anticancer drug, BCNU, which inhibits glutathione reductase (GR), compromising the glutathione peroxidase system thereby inhibiting peroxide removal. The purpose of this study was to determine if anticancer modalities known to produce superoxide radicals can increase the antitumor effect of MnSOD overexpression when combined with BCNU. To enhance MnSOD, an adenoviral construct containing the cDNA for MnSOD (AdMnSOD) was introduced into human breast cancer cell line, ZR-75-1. AdMnSOD infection alone did not alter cell killing, however when GR was inhibited with either BCNU or siRNA, cytotoxicity increased. Futhermore, when the AdMnSOD + BCNU treatment was combined with agents that enhance steady-state levels of superoxide (TNF-α, antimycin, adriamycin, photosensitizers, and ionizing radiation), both cell cytotoxicity and intracellular peroxide levels increased. These results suggest that the anticancer effect of AdMnSOD combined with BCNU can be enhanced by agents that increase generation of superoxide.
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Received: 20 February 2010; in revised form: 23 March 2010 / Accepted: 24 March 2010 / Published: 25 March 2010
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Abstract: Thioredoxin is a small redox-regulating protein, which plays crucial roles in maintaining cellular redox homeostasis and cell survival and is highly expressed in many cancers. The tumor environment is usually under either oxidative or hypoxic stress and both stresses are known up-regulators of thioredoxin expression. These environments exist in tumors because their abnormal vascular networks result in an unstable oxygen delivery. Therefore, the oxygenation patterns in human tumors are complex, leading to hypoxia/re-oxygenation cycling. During carcinogenesis, tumor cells often become more resistant to hypoxia or oxidative stress-induced cell death and most studies on tumor oxygenation have focused on these two tumor environments. However, recent investigations suggest that the hypoxic cycling occurring within tumors plays a larger role in the contribution to tumor cell survival than either oxidative stress or hypoxia alone. Thioredoxin is known to have important roles in both these cellular responses and several studies implicate thioredoxin as a contributor to cancer progression. However, only a few studies exist that investigate the regulation of thioredoxin in the hypoxic and cycling hypoxic response in cancers. This review focuses on the role of thioredoxin in the various states of tumor oxygenation.
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Received: 8 February 2010; in revised form: 2 March 2010 / Accepted: 25 March 2010 / Published: 26 March 2010
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Abstract: Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Additional factors, such as the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and endothelial cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids and reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H2O2 are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue can still be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps; from the primary tumor until colonization of a distant organ; metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles.
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Received: 23 February 2010; in revised form: 18 March 2010 / Accepted: 25 March 2010 / Published: 30 March 2010
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Abstract: Reacytive Oxygen Species (ROS) have long been considered to be involved in the initiation, progression and metastasis of cancer. However, accumulating evidence points to the benefical role of ROS. Moreover, ROS production, leading to apoptosis, is the mechanism by which many chemotherapeutic agents can act. Beside direct actions, ROS elicit lipid peroxidation, leading to the production of 4-hydroxynoneal (HNE). Interestingly, HNE also seems to have a dual behaviour with respect to cancer. In this review we present recent literature data which outline the "two-faced" character of oxidative stress and lipid peroxidation in carcinogenesis and in the hallmarks of cancer.
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Received: 9 March 2010; in revised form: 2 April 2010 / Accepted: 6 April 2010 / Published: 8 April 2010
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Abstract: In addition to a wide range of adverse effects on human health, toxic metals such as cadmium, arsenic and nickel can also promote carcinogenesis. The toxicological properties of these metals are partly related to generation of reactive oxygen species (ROS) that can induce DNA damage and trigger redox-dependent transcription factors. The precise mechanisms that induce oxidative stress are not fully understood. Further, it is not yet known whether chronic exposures to low doses of arsenic, cadmium or other metals are sufficient to induce mutations in vivo, leading to DNA repair responses and/or tumorigenesis. Oxidative stress can also be induced by environmental xenobiotics, when certain metabolites are generated that lead to the continuous release of superoxide, as long as the capacity to reduce the resulting dions (quinones) into hydroquinones is maintained. However, the specific significance of superoxide-dependent pathways to carcinogenesis is often difficult to address, because formation of DNA adducts by mutagenic metabolites can occur in parallel. Here, we will review both mechanisms and toxicological consequences of oxidative stress triggered by metals and dietary or environmental pollutants in general. Besides causing DNA damage, ROS may further induce multiple intracellular signaling pathways, notably NF-kB, JNK/SAPK/p38, as well as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that could promote proliferation or confer apoptosis resistance to exposed cells. The significance of these additional modes depends on tissue, cell-type and is often masked by alternate oncogenic mechanisms being activated in parallel.
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Received: 26 February 2010; in revised form: 18 March 2010 / Accepted: 12 April 2010 / Published: 13 April 2010
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Abstract: Reactive oxygen species, produced by oxidative stress, are implicated in the initiation, promotion, and malignant conversion of carcinogenesis through activation/suppression of redox-sensitive transcription factors. NF-E2-related factor 2 (Nrf2) encodes for antioxidant and general cytoprotection genes, while NF-κB regulates the expression of pro-inflammatory genes. A variety of anti-inflammatory or anti-carcinogenic phyto-chemicals suppress NF-κB signalling and activate the Nrf2-ARE pathway. In this review we consider the role of Nrf2 and NF-κB in cancer pathogenesis and progression, focusing on their concerted modulation and potential cross-talk.
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Received: 4 March 2010; in revised form: 31 March 2010 / Accepted: 12 April 2010 / Published: 16 April 2010
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Abstract: Uncoupling proteins (UCPs) are a family of inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, by dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS). Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance.
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Received: 10 March 2010; in revised form: 19 April 2010 / Accepted: 22 April 2010 / Published: 26 April 2010
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Abstract: There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers and periodontal diseases of the supporting structures of the teeth. Enhanced lipid peroxidation, raised levels of TBARS and the oxidative stress marker malondealdehyde have been detected in breast cancer with reduced antioxidant capacity, also characteristic of periodontal diseases. Antioxidants could overcome this deficit and attenuate disease progression by down regulating glutathione detoxification/redox buffering system and inhibiting key transcription factors. Periodontal disease may be a critical marker of a susceptible immune system, or initiate cancer risk with a pro-oxidant inflammatory profile.
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Received: 20 February 2010; in revised form: 20 April 2010 / Accepted: 21 April 2010 / Published: 26 April 2010
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Abstract: Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.
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Received: 4 March 2010; in revised form: 12 April 2010 / Accepted: 6 May 2010 / Published: 17 May 2010
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Abstract: The term ‘‘oxidative stress” refers to a cell’s state characterized by excessive production of reactive oxygen species (ROS) and oxidative stress is one of the most important regulatory mechanisms for stem, cancer, and cancer stem cells. The concept of cancer stem cells arose from observations of similarities between the self-renewal mechanism of stem cells and that of cancer stem cells, but compared to normal stem cells, they are believed to have no control over the cell number. ROS have been implicated in diverse processes in various cancers, and generally the increase of ROS in cancer cells is known to play an important role in the initiation and progression of cancer. Additionally, ROS have been considered as the most significant mutagens in stem cells; when elevated, blocking self-renewal and at the same time, serving as a signal stimulating stem cell differentiation. Several signaling pathways enhanced by oxidative stress are suggested to have important roles in tumorigenesis of cancer or cancer stem cells and the self-renewal ability of stem or cancer stem cells. It is now well established that mitochondria play a prominent role in apoptosis and increasing evidence supports that apoptosis and autophagy are physiological phenomena closely linked with oxidative stress. This review elucidates the effect and the mechanism of the oxidative stress on the regulation of stem, cancer, and cancer stem cells and focuses on the cell signaling cascades stimulated by oxidative stress and their mechanism in cancer stem cell formation, as very little is known about the redox status in cancer stem cells. Moreover, we explain the link between ROS and both of apoptosis and autophagy and the impact on cancer development and treatment. Better understanding of this intricate link may shed light on mechanisms that lead to better modes of cancer treatment.
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Received: 8 April 2010; in revised form: 14 May 2010 / Accepted: 17 May 2010 / Published: 26 May 2010
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Abstract: Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.
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Received: 6 May 2010; in revised form: 8 June 2010 / Accepted: 11 June 2010 / Published: 14 June 2010
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Abstract: A main feature of cancer cells, when compared to normal ones, is a persistent pro-oxidative state that leads to an intrinsic oxidative stress. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells, and ROS are, in turn, responsible for the maintenance of the cancer phenotype. Persistent ROS stress may induce adaptive stress responses, enabling cancer cells to survive with high levels of ROS and maintain cellular viability. However, excessive ROS levels render cancer cells highly susceptible to quercetin, one of the main dietary flavonoids. Quercetin depletes intracellular glutathione and increases intracellular ROS to a level that can cause cell death.
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Received: 7 June 2010; in revised form: 18 June 2010 / Accepted: 21 June 2010 / Published: 21 June 2010
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Abstract: Reactive oxygen species (ROS) signaling has recently sparked a surge of interest as being the molecular underpinning for cancer cell survival, but the precise mechanisms involved have not been completely elucidated. This review covers the possible roles of two ROS-induced transcription factors, Nrf1 and Nrf2, and the antioxidant proteins peroxiredoxin-1 (Prx-1) and Thioredoxin-1 (Txn-1) in modulating AR expression and signaling in aggressive prostate cancer (PCa) cells. In androgen independent (AI) C4-2B cells, in comparison to the parental androgen dependent (AD) LNCaP cells, we present evidence of high Nrf1 and Prx-1 expression and low Nrf2 expression in these aggressive PCa cells. Furthermore, in DHT treated C4-2B cells, increased expression of the p65 (active) isoform of Nrf1 correlated with enhanced AR transactivation. Our findings implicate a crucial balance of Nrf1 and Nrf2 signaling in regulating AR activity in AI-PCa cells. Here we will discuss how understanding the mechanisms by which oxidative stress may affect AR signaling may aid in developing novel therapies for AI-PCa.
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Last update: 25 September 2012
