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Paradox Role of Oxidative Stress in Cancer: State of the Art

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 34947

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Prof. Dr. Cinzia Domenicotti

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Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Interests: neuroblastoma; MYC amplification; cancer stemness; drug resistance; protein kinase C; oxidative stress; lipoperoxidation; apoptosis
Special Issues, Collections and Topics in MDPI journals

Dr. Barbara Marengo

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Guest Editor

Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Interests: chemoresistance; cancer cell metabolism; stress adaptative cell response; cell death; redox homeostasis; redox signalling; antioxidants; glutathione
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Reactive oxygen species (ROS) are produced by healthy cells and are maintained at physiological levels by antioxidant systems such as superoxide dismutases, peroxiredoxins, and glutathione. However, when ROS increase, a condition of oxidative stress occurs with damage to cellular macromolecules, leading to many human diseases, including cancer.

The relationship between oxidative stress and cancer is difficult to understand for many reasons. Firstly, oxidative stress plays an important role during all phases of carcinogenesis, and cancer cells display high ROS levels compared to healthy cells as the consequence of an increased metabolic activity, alterations in electron transport chain of mitochondria, and hypoxic conditions.

Moreover, moderate levels of ROS may have a role as second messengers by activating receptor kinases, MAP kinases, and redox sensitive transcription factors such as NF-kB, AP-1, Nfr2, and HIF-1 and controlling the expression of tumor suppressor genes such as p53. The activation of these signaling molecules can lead to chronic inflammation and an enhanced antioxidant response, promoting cancer cell survival.

Several studies have shown that most chemotherapeutic and radiotherapeutic agents kill cancer cells through ROS production, and long-term anticancer treatment can induce an adaptive antioxidant cell response contributing to the development of chemio/radioresistance. Interestingly, ROS have also been implicated in chemopreventive and chemosensitive action of nutraceuticals derived from natural products. On the basis of these contradictory findings, this Special Issue aims to collect original articles and reviews dealing with the double-edged role of ROS, which can determine beneficial or detrimental outcomes in cancer development. This paradox represents a great challenge for researchers and needs to be investigated in order to light up the molecular mechanisms underlying the dual role of ROS in cancer prevention and therapy.

Prof. Cinzia Domenicotti
Dr. Barbara Marengo
Guest Editors

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Keywords

ROS in cancer initiation, promotion, and progression
ROS and cancer stem cells
Ferroptosis
Glutathione and glutathione peroxidase 4
Redox signaling in cancer
Nrf2 and related pathways
Metabolic reprogramming in cancer
Chemoresistance and radioresistance
Chemoprevention
Natural antioxidants

Published Papers (11 papers)

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Editorial

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4 pages, 197 KiB

Open AccessEditorial

Paradox Role of Oxidative Stress in Cancer: State of the Art

by Cinzia Domenicotti and Barbara Marengo

Antioxidants 2022, 11(5), 1027; https://doi.org/10.3390/antiox11051027 - 23 May 2022

Cited by 4 | Viewed by 1374

Abstract

The modulation of oxidative stress is essential for the maintenance of redox homeostasis in healthy and cancer cells [...] Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

Research

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22 pages, 5355 KiB

Open AccessArticle

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

by Lorenzo Monteleone, Andrea Speciale, Giulia Elda Valenti, Nicola Traverso, Silvia Ravera, Ombretta Garbarino, Riccardo Leardi, Emanuele Farinini, Antonella Roveri, Fulvio Ursini, Claudia Cantoni, Maria Adelaide Pronzato, Umberto Maria Marinari, Barbara Marengo and Cinzia Domenicotti

Antioxidants 2021, 10(5), 691; https://doi.org/10.3390/antiox10050691 - 28 Apr 2021

Cited by 23 | Viewed by 3382

Abstract

Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance. In this study, Etoposide-sensitive and -resistant neuroblastoma CSCs were chronically treated with Etoposide, given alone or in combination with Sulfasalazine (SSZ) or with an inhibitor of PKCα (C2-4), which target xCT directly or indirectly, respectively. Both combined approaches are able to sensitize CSCs to Etoposide by decreasing intracellular GSH levels, inducing a metabolic switch from OXPHOS to aerobic glycolysis, down-regulating glutathione-peroxidase-4 activity and stimulating lipid peroxidation, thus leading to ferroptosis. Our results suggest, for the first time, that PKCα inhibition inducing ferroptosis might be a useful strategy with which to fight CSC chemoresistance. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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21 pages, 3331 KiB

Open AccessArticle

Plasma Treated Water Solutions in Cancer Treatments: The Contrasting Role of RNS

by Eloisa Sardella, Valeria Veronico, Roberto Gristina, Loris Grossi, Savino Cosmai, Marinella Striccoli, Maura Buttiglione, Francesco Fracassi and Pietro Favia

Antioxidants 2021, 10(4), 605; https://doi.org/10.3390/antiox10040605 - 14 Apr 2021

Cited by 26 | Viewed by 2655

Abstract

Plasma Treated Water Solutions (PTWS) recently emerged as a novel tool for the generation of Reactive Oxygen and Nitrogen Species (ROS and RNS) in liquids. The presence of ROS with a strong oxidative power, like hydrogen peroxide (H₂O₂), has been proposed as the main effector for the cancer-killing properties of PTWS. A protective role has been postulated for RNS, with nitric oxide (NO) being involved in the activation of antioxidant responses and cell survival. However, recent evidences proved that NO-derivatives in proper mixtures with ROS in PTWS could enhance rather than reduce the selectivity of PTWS-induced cancer cell death through the inhibition of specific antioxidant cancer defenses. In this paper we discuss the formation of RNS in different liquids with a Dielectric Barrier Discharge (DBD), to show that NO is absent in PTWS of complex composition like plasma treated (PT)-cell culture media used for in vitro experiments, as well as its supposed protective role. Nitrite anions (NO₂^-) instead, present in our PTWS, were found to improve the selective death of Saos2 cancer cells compared to EA.hy926 cells by decreasing the cytotoxic threshold of H₂O₂ to non-toxic values for the endothelial cell line. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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14 pages, 2452 KiB

Open AccessArticle

Water Soluble Iron-Based Coordination Trimers as Synergistic Adjuvants for Pancreatic Cancer

by Marco Cordani, Esther Resines-Urien, Arturo Gamonal, Paula Milán-Rois, Lionel Salmon, Azzedine Bousseksou, Jose Sanchez Costa and Álvaro Somoza

Antioxidants 2021, 10(1), 66; https://doi.org/10.3390/antiox10010066 - 07 Jan 2021

Cited by 9 | Viewed by 3064

Abstract

Pancreatic cancer is a usually fatal disease that needs innovative therapeutic approaches since the current treatments are poorly effective. In this study, based on cell lines, triazole-based coordination trimers made with soluble Fe(II) in an aqueous media were explored for the first time as adjuvant agents for the treatment of this condition. These coordination complexes were effective at relatively high concentrations and led to an increase in reactive oxygen species (ROS) in two pancreatic cancer cell lines, PANC-1 and BXPC-3, and this effect was accompanied by a significant reduction in cell viability in the presence of gemcitabine (GEM). Importantly, the tested compounds enhanced the effect of GEM, an approved drug for pancreatic cancer, through apoptosis induction and downregulation of the mTOR pathway. Although further evaluation in animal-based models of pancreatic cancer is needed, these results open novel avenues for exploring these iron-based materials in biomedicine in general and in pancreatic cancer treatment. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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15 pages, 4171 KiB

Open AccessArticle

Low Dose Combined Treatment with Ultraviolet-C and Withaferin a Enhances Selective Killing of Oral Cancer Cells

by Sheng-Yao Peng, Yen-Yun Wang, Ting-Hsun Lan, Li-Ching Lin, Shyng-Shiou F. Yuan, Jen-Yang Tang and Hsueh-Wei Chang

Antioxidants 2020, 9(11), 1120; https://doi.org/10.3390/antiox9111120 - 13 Nov 2020

Cited by 20 | Viewed by 2157

Abstract

Withaferin A (WFA), a Withania somnifera-derived triterpenoid, is an anticancer natural product. The anticancer effect of nonionizing radiation such as ultraviolet-C (UVC) as well as the combined treatment of UVC and WFA is rarely investigated. Low dose UVC and/or WFA treatments (12 J/m² and/or 1 μM) were chosen to evaluate antioral cancer cell line effects by examining cytotoxicity, cell cycle disruption, apoptosis induction, and DNA damage. For two cancer cell lines (Ca9-22 and HSC-3), single treatment (UVC or WFA) showed about 80% viability, while a combined treatment of UVC/WFA showed about 40% viability. In contrast, there was noncytotoxicity to normal oral cell lines (HGF-1). Compared to single treatment and control, low dose UVC/WFA shows high inductions of apoptosis in terms of flow cytometric detections for subG1, annexin V, pancaspase changes as well as Western blotting for detecting cleaved poly (ADP-ribose) polymerase (c-PARP) and caspase 3 (c-Cas 3) and luciferase assay for detecting Cas 3/7 activity. Low dose UVC/WFA also showed high inductions of oxidative stress and DNA damage in terms of flow cytometric detections of reactive oxygen species (ROS), mitochondrial superoxide (MitoSOX) generation, and membrane potential (MitoMP) destruction, γH2AX and 8-oxo-2’deoxyguanosine (8-oxodG) types of DNA damages. For comparison, low dose UVC/WFA show rare inductions of annexin V, Cas 3/7 activity, ROS, MitoSOX, and MitoMP changes to normal oral HGF-1 cells. Therefore, low dose UVC/WFA provides a novel selectively killing mechanism to oral cancer cells, suggesting that WFA is a UVC sensitizer to inhibit the proliferation of oral cancer cells. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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18 pages, 5000 KiB

Open AccessArticle

Using C-doped TiO₂ Nanoparticles as a Novel Sonosensitizer for Cancer Treatment

by Chun-Chen Yang, Chong-Xuan Wang, Che-Yung Kuan, Chih-Ying Chi, Ching-Yun Chen, Yu-Ying Lin, Gin-Shin Chen, Chun-Han Hou and Feng-Huei Lin

Antioxidants 2020, 9(9), 880; https://doi.org/10.3390/antiox9090880 - 17 Sep 2020

Cited by 42 | Viewed by 3970

Abstract

Sonodynamic therapy is an effective treatment for eliminating tumor cells by irradiating sonosentitizer in a patient’s body with higher penetration ultrasound and inducing the free radicals. Titanium dioxide has attracted the most attention due to its properties among many nanosensitizers. Hence, in this study, carbon doped titanium dioxide, one of inorganic materials, is applied to avoid the foregoing, and furthermore, carbon doped titanium dioxide is used to generate ROS under ultrasound irradiation to eliminate tumor cells. Spherical carbon doped titanium dioxide nanoparticles are synthesized by the sol-gel process. The forming of C-Ti-O bond may also induce defects in lattice which would be beneficial for the phenomenon of sonoluminescence to improve the effectiveness of sonodynamic therapy. By dint of DCFDA, WST-1, LDH and the Live/Dead test, carbon doped titanium dioxide nanoparticles are shown to be a biocompatible material which may induce ROS radicals to suppress the proliferation of 4T1 breast cancer cells under ultrasound treatment. From in vivo study, carbon doped titanium dioxide nanoparticles activated by ultrasound may inhibit the growth of the 4T1 tumor, and it showed a significant difference between sonodynamic therapy (SDT) and the other groups on the seventh day of the treatment. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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Review

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30 pages, 1115 KiB

Open AccessReview

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

by Mariapaola Nitti, Caterina Ivaldo, Nicola Traverso and Anna Lisa Furfaro

Antioxidants 2021, 10(5), 789; https://doi.org/10.3390/antiox10050789 - 17 May 2021

Cited by 25 | Viewed by 3356

Abstract

Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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25 pages, 1904 KiB

Open AccessReview

Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics

by Marta Menegazzi, Pellegrino Masiello and Michela Novelli

Antioxidants 2021, 10(1), 18; https://doi.org/10.3390/antiox10010018 - 28 Dec 2020

Cited by 30 | Viewed by 4577

Abstract

In this paper we review the mechanisms of the antitumor effects of Hypericum perforatum L. (St. John’s wort, SJW) and its main active component hyperforin (HPF). SJW extract is commonly employed as antidepressant due to its ability to inhibit monoamine neurotransmitters re-uptake. Moreover, further biological properties make this vegetal extract very suitable for both prevention and treatment of several diseases, including cancer. Regular use of SJW reduces colorectal cancer risk in humans and prevents genotoxic effects of carcinogens in animal models. In established cancer, SJW and HPF can still exert therapeutic effects by their ability to downregulate inflammatory mediators and inhibit pro-survival kinases, angiogenic factors and extracellular matrix proteases, thereby counteracting tumor growth and spread. Remarkably, the mechanisms of action of SJW and HPF include their ability to decrease ROS production and restore pH imbalance in tumor cells. The SJW component HPF, due to its high lipophilicity and mild acidity, accumulates in membranes and acts as a protonophore that hinders inner mitochondrial membrane hyperpolarization, inhibiting mitochondrial ROS generation and consequently tumor cell proliferation. At the plasma membrane level, HPF prevents cytosol alkalization and extracellular acidification by allowing protons to re-enter the cells. These effects can revert or at least attenuate cancer cell phenotype, contributing to hamper proliferation, neo-angiogenesis and metastatic dissemination. Furthermore, several studies report that in tumor cells SJW and HPF, mainly at high concentrations, induce the mitochondrial apoptosis pathway, likely by collapsing the mitochondrial membrane potential. Based on these mechanisms, we highlight the SJW/HPF remarkable potentiality in cancer prevention and treatment. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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19 pages, 1361 KiB

Open AccessReview

Oxidative Stress-Inducing Anticancer Therapies: Taking a Closer Look at Their Immunomodulating Effects

by Jinthe Van Loenhout, Marc Peeters, Annemie Bogaerts, Evelien Smits and Christophe Deben

Antioxidants 2020, 9(12), 1188; https://doi.org/10.3390/antiox9121188 - 27 Nov 2020

Cited by 38 | Viewed by 3074

Abstract

Cancer cells are characterized by higher levels of reactive oxygen species (ROS) compared to normal cells as a result of an imbalance between oxidants and antioxidants. However, cancer cells maintain their redox balance due to their high antioxidant capacity. Recently, a high level of oxidative stress is considered a novel target for anticancer therapy. This can be induced by increasing exogenous ROS and/or inhibiting the endogenous protective antioxidant system. Additionally, the immune system has been shown to be a significant ally in the fight against cancer. Since ROS levels are important to modulate the antitumor immune response, it is essential to consider the effects of oxidative stress-inducing treatments on this response. In this review, we provide an overview of the mechanistic cellular responses of cancer cells towards exogenous and endogenous ROS-inducing treatments, as well as the indirect and direct antitumoral immune effects, which can be both immunostimulatory and/or immunosuppressive. For future perspectives, there is a clear need for comprehensive investigations of different oxidative stress-inducing treatment strategies and their specific immunomodulating effects, since the effects cannot be generalized over different treatment modalities. It is essential to elucidate all these underlying immune effects to make oxidative stress-inducing treatments effective anticancer therapy. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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22 pages, 1196 KiB

Open AccessReview

Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies

by Andrea Gaetano Allegra, Federica Mannino, Vanessa Innao, Caterina Musolino and Alessandro Allegra

Antioxidants 2020, 9(11), 1116; https://doi.org/10.3390/antiox9111116 - 12 Nov 2020

Cited by 9 | Viewed by 2515

Abstract

Radiation therapy plays a critical role in the management of a wide range of hematologic malignancies. It is well known that the post-irradiation damages both in the bone marrow and in other organs are the main causes of post-irradiation morbidity and mortality. Tumor control without producing extensive damage to the surrounding normal cells, through the use of radioprotectors, is of special clinical relevance in radiotherapy. An increasing amount of data is helping to clarify the role of oxidative stress in toxicity and therapy response. Radioprotective agents are substances that moderate the oxidative effects of radiation on healthy normal tissues while preserving the sensitivity to radiation damage in tumor cells. As well as the substances capable of carrying out a protective action against the oxidative damage caused by radiotherapy, other substances have been identified as possible enhancers of the radiotherapy and cytotoxic activity via an oxidative effect. The purpose of this review was to examine the data in the literature on the possible use of old and new substances to increase the efficacy of radiation treatment in hematological diseases and to reduce the harmful effects of the treatment. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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Other

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11 pages, 1036 KiB

Open AccessPerspective

Opportunities for Ferroptosis in Cancer Therapy

by Kenji M. Fujihara, Bonnie Z. Zhang and Nicholas J. Clemons

Antioxidants 2021, 10(6), 986; https://doi.org/10.3390/antiox10060986 - 21 Jun 2021

Cited by 15 | Viewed by 3762

Abstract

A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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