Reactive Oxygen Species In Cancer Research Articles

Targeting ROS in cancer: rationale and strategies.

Reactive oxygen species (ROS) in biological systems are transient but essential molecules that are generated and eliminated by a complex set of delicately balanced molecular machineries. Disruption of redox homeostasis has been associated with various human diseases, especially cancer, in which increased ROS levels are thought to have a major role in tumour development and progression. As such, modulation of cellular redox status by targeting ROS and their regulatory machineries is considered a promising therapeutic strategy for cancer treatment. Recently, there has been major progress in this field, including the discovery of novel redox signalling pathways that affect the metabolism of tumour cells as well as immune cells in the tumour microenvironment, and the intriguing ROS regulation of biomolecular phase separation. Progress has also been made in exploring redox regulation in cancer stem cells, the role of ROS in determining cell fate and new anticancer agents that target ROS. This Review discusses these research developments and their implications for cancer therapy and drug discovery, as well as emerging concepts, paradoxes and future perspectives.

Targeting ROS in cancer: rationale and strategies.

Reactive oxygen species (ROS) in biological systems are transient but essential molecules that are generated and eliminated by a complex set of delicately balanced molecular machineries. Disruption of redox homeostasis has been associated with various human diseases, especially cancer, in which increased ROS levels are thought to have a major role in tumour development and progression. As such, modulation of cellular redox status by targeting ROS and their regulatory machineries is considered a promising therapeutic strategy for cancer treatment. Recently, there has been major progress in this field, including the discovery of novel redox signalling pathways that affect the metabolism of tumour cells as well as immune cells in the tumour microenvironment, and the intriguing ROS regulation of biomolecular phase separation. Progress has also been made in exploring redox regulation in cancer stem cells, the role of ROS in determining cell fate and new anticancer agents that target ROS. This Review discusses these research developments and their implications for cancer therapy and drug discovery, as well as emerging concepts, paradoxes and future perspectives.

The pleiotropic functions of reactive oxygen species in cancer.

Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells.

Oxidative Stress and Cancer: Harnessing the Therapeutic Potential of Curcumin and Analogues Against Cancer.

Reactive oxygen species (ROS) are a class of bioactive molecules that are the by-products of many cellular functions. These molecules are present in normal cells at homeostatic levels but have been studied extensively in cancer due to their dysregulation resulting in pro- and anti-tumorigenic environments. Completely understanding the paradoxical nature of ROS in cancer is imperative to fully realize its modulation as cancer therapy. Studies into ROS have shown far-reaching effects in cancer, including how ROS levels regulate signaling, response to treatment, drug resistance, etc. Many drugs were studied with the hopes of regulating the ROS levels in cancer; however, patient response varied. Plant-derived medications offered new avenues of drug treatment over the last few decades, and the phytochemical Curcumin gained ground as an interesting cancer therapeutic. Curcumin is an active phenolic compound used in traditional medicine around the world. Although it suffers from a poor pharmacokinetic profile, Curcumin exerts anti-tumorigenic, as well as ROS-modulating activities. Analogs and derivatives of Curcumin are under development to improve upon its anti-cancer properties and enhance its bioavailability, currently a major limitation of its usage. This review highlights ROS function in cancer treatment focused on ROS, including Curcumin and its analogs.

Regulation of Redox Homeostasis Through DNA/RNA Methylation and Post-Translational Modifications in Cancer Progression.

Significance: Aberrant redox homeostasis, characterized by the enhancement of intracellular reactive oxygen species (ROS) and antioxidant defenses, is among the well-known cancer hallmarks. Understanding the regulatory mechanisms of redox homeostasis in cancer cells has become the focus of many studies. Epigenetic and post-translational modifications (PTMs), as pivotal regulators of multiple biological processes, play critical roles in tumorigenesis and development. Recent Advances: DNA and RNA methylation are important forms of epigenetic modifications. Recent evidence suggests that DNA/RNA methylation and PTMs can modulate redox homeostasis in multiple manners including affecting key molecules in ROS production, elimination, and redox-related signaling, thereby participating in tumor progression. Critical Issues: The regulatory effects of DNA/RNA methylation and PTMs on ROS are of crucial importance for tumor progression. In this review, we introduce the dual role of ROS in cancer, and then focus on the mechanistic role of DNA/RNA methylation and PTMs, especially ubiquitination and acetylation, in regulating redox homeostasis to involve in cancer progression. Future Directions: A complete understanding of how epigenetics and PTMs function in the regulation of redox homeostasis in cancer progression might expand a new direction for the progression mechanisms and therapeutic targets of cancer. Antioxid. Redox Signal. 39, 531-550.

Targeting the Interplay of Autophagy and ROS for Cancer Therapy: An Updated Overview on Phytochemicals.

Autophagy is an evolutionarily conserved self-degradation system that recycles cellular components and damaged organelles, which is critical for the maintenance of cellular homeostasis. Intracellular reactive oxygen species (ROS) are short-lived molecules containing unpaired electrons that are formed by the partial reduction of molecular oxygen. It is widely known that autophagy and ROS can regulate each other to influence the progression of cancer. Recently, due to the wide potent anti-cancer effects with minimal side effects, phytochemicals, especially those that can modulate ROS and autophagy, have attracted great interest of researchers. In this review, we afford an overview of the complex regulatory relationship between autophagy and ROS in cancer, with an emphasis on phytochemicals that regulate ROS and autophagy for cancer therapy. We also discuss the effects of ROS/autophagy inhibitors on the anti-cancer effects of phytochemicals, and the challenges associated with harnessing the regulation potential on ROS and autophagy of phytochemicals for cancer therapy.

Role of metal complexes in oxidative stress and ROS generation leading to Cancer

Reactive oxygen species (ROS) are recognized as essential participants in normal cellular processes, while their intricate involvement in the emergence of various diseases, notably cancer, has garnered significant attention. Elevated levels of ROS isassociated with pro-tumorigenic signalling, heightened cell survival, increased proliferation, and DNA damage, thereby making substantial contributions to the genetic instability. Intriguingly, at elevated levels, ROS paradoxically initiate anti-tumorigenic signalling pathways, thereby instigating cell death through oxidative stress. In this comprehensive review, a focus is given on ROS generation, which encompasses both endogenous and exogenous sources that collectively referred to as oxidative stress. To provide a comprehensive understanding, an exploration of the structural, chemical, and biochemical aspects of free radicals is undertaken.Diverse sources contributing to ROS generation, including metal-mediated free radical formation is also discussed. This review additionally conducts an in-depth examination of oxidative stress within the context of cancer. Moreover, noteworthy contributions of key antioxidant enzymes, namely, superoxide dismutase, catalaseand glutathione peroxidase over the multifaceted landscape of carcinogenesis have been discussed, drawing insights from a multitude of studies. Understanding the intricate interplay between pro- and anti-tumorigenic ROS signalling pathways offers a multitude of potential avenues for cancer therapy. The disrupted redox balance observed in cancer cells presents promising opportunities for ROS manipulation, thereby emerging as a viable and innovative treatment strategy. This present review may serve as an invaluable resource, offering profound insights into the multifaceted roles of ROS in cancer while simultaneously highlighting their therapeutic potential, thereby paving the way for novel and effective cancer interventions.

Role of Phosphoinositide 3-Kinase in Regulation of NOX-Derived Reactive Oxygen Species in Cancer.

Activation of NADPH oxidases (NOX) and the ensuing formation of reactive oxygen species (ROS) is a vital aspect of antimicrobial defense but may also promote tumorigenesis. Enhanced NOX activity has been associated with aberrant activation of oncogenic cascades such as the phosphoinositide 3-kinase (PI3K) signaling pathway, which is upregulated in several malignancies. In this review, we examine the role of PI3K on the regulation of NOX-induced ROS formation in cancer.

Phytochemicals from Indian Ethnomedicines: Promising Prospects for the Management of Oxidative Stress and Cancer.

Oxygen is indispensable for most organisms on the earth because of its role in respiration. However, it is also associated with several unwanted effects which may sometimes prove fatal in the long run. Such effects are more evident in cells exposed to strong oxidants containing reactive oxygen species (ROS). The adverse outcomes of oxidative metabolism are referred to as oxidative stress, which is a staple theme in contemporary medical research. Oxidative stress leads to plasma membrane disruption through lipid peroxidation and has several other deleterious effects. A large body of literature suggests the involvement of ROS in cancer, ageing, and several other health hazards of the modern world. Plant-based cures for these conditions are desperately sought after as supposedly safer alternatives to mainstream medicines. Phytochemicals, which constitute a diverse group of plant-based substances with varying roles in oxidative reactions of the body, are implicated in the treatment of cancer, aging, and all other ROS-induced anomalies. This review presents a summary of important phytochemicals extracted from medicinal plants which are a part of Indian ethnomedicine and Ayurveda and describes their possible therapeutic significance.

Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities.

Simple SummaryColorectal cancer is a disease associated with a high mortality rate. During the tumorigenic process, several factors and signaling molecules produced by tumor cells and the cells that surround them (forming the tumor microenvironment) regulate and modify cancer proliferation and metastasis. These regulatory agents include reactive oxygen species (ROS), which are involved in different metabolic networks and in the maintenance of cell homeostasis. Their excess, however, can cause oxidative stress and be detrimental to the cell. In fact, oxidative stress has been linked to several processes related to colorectal cancer initiation and progression. The different activities where ROS are involved suggest that ROS level modulators could be used to benefit cancer patients.Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.

Reactive oxygen species in cancer: Current findings and future directions.

Reactive oxygen species (ROS), a class of highly bioactive molecules, have been widely studied in various types of cancers. ROS are considered to be normal byproducts of numerous cellular processes. Typically, cancer cells exhibit higher basal levels of ROS compared with normal cells as a result of an imbalance between oxidants and antioxidants. ROS have a dual role in cell metabolism: At low to moderate levels, ROS act as signal transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death. Extensive studies have revealed that anticancer therapies that manipulate ROS levels, including immunotherapies, show promising in vitro as well as in vivo results. In this review, we summarize molecular mechanisms and oncogenic functions that modulate ROS levels and are useful for the development of cancer therapeutic strategies. This review also provides insights into the future development of effective agents that regulate the redox system for cancer treatment.

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies.

The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy.

Reactive oxygen species (ROS) play a dual role in the initiation, development, suppression, and treatment of cancer. Excess ROS can induce nuclear DNA, leading to cancer initiation. Not only that, but ROS also inhibit T cells and natural killer cells and promote the recruitment and M2 polarization of macrophages; consequently, cancer cells escape immune surveillance and immune defense. Furthermore, ROS promote tumor invasion and metastasis by triggering epithelial-mesenchymal transition in tumor cells. Interestingly, massive accumulation of ROS inhibits tumor growth in two ways: (1) by blocking cancer cell proliferation by suppressing the proliferation signaling pathway, cell cycle, and the biosynthesis of nucleotides and ATP and (2) by inducing cancer cell death via activating endoplasmic reticulum stress-, mitochondrial-, and P53- apoptotic pathways and the ferroptosis pathway. Unfortunately, cancer cells can adapt to ROS via a self-adaption system. This review highlighted the bidirectional regulation of ROS in cancer. The study further discussed the application of massively accumulated ROS in cancer treatment. Of note, the dual role of ROS in cancer and the self-adaptive ability of cancer cells should be taken into consideration for cancer prevention.

NOX2-Derived Reactive Oxygen Species in Cancer.

The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.

Reactive oxygen species in cancer: a paradox between pro- and anti-tumour activities.

Cancer constitutes a group of heterogeneous diseases that share common features. They involve the existence of altered cellular pathways which result in uncontrolled cell proliferation. Deregulation of production and/or elimination of reactive oxygen species (ROS) appear to be a relevant issue in most of them. ROS have a dual role in cell metabolism: they are compromised in normal cellular homeostasis, but their overproduction has been reported to promote oxidative stress (OS), a process that may induce the damage of cell structures. ROS accumulation is implicated in the activation of signaling pathways that promote cell proliferation and metabolic adaptations to tumour growth. One characteristic of cancer cells is the sensitivity to OS, which often results from the combination of high anabolic needs and hypoxic growth conditions. However, there is still no clear evidence about the levels of oxidant species that promote cellular transformation or, otherwise, if OS induction could be adequate as an antitumour therapeutic tool. There is a need for novel therapeutic strategies based on the new knowledge of cancer biology. Targeting oncogenic molecular mechanisms with non-classical agents and/or natural compounds would be beneficial as chemoprevention or new adjuvant therapies. In addition, epigenetics and environment, and particularly dietary factors may influence the development and prevention of cancer. This article will present a revision of the current research about molecular aspects proposed to be involved in the anticancer features of oxidant and antioxidant-based therapies targeting cancer cells, and their participation in the balance of oxidative species and cancer cell death.

The Complex Interplay between Antioxidants and ROS in Cancer.

Reactive oxygen species (ROS) play important roles in tissue homeostasis, cellular signaling, differentiation, and survival. In this review, we discuss the types ofROS, their impact on cellular processes, and their pro- and antitumorigenic effects. Further, we discuss recent advances in our understanding of both endogenous and exogenous antioxidants in tumorigenic processes. Finally, wediscuss how aberrant activation of antioxidant programs by the transcription factor NFE2-related factor 2 (NRF2) influences tumorigenesis and metastasis, and where the current gaps in our knowledge remain.

The Yin-Yang Regulation of Reactive Oxygen Species and MicroRNAs in Cancer.

Reactive oxygen species (ROS) are highly reactive oxygen-containing chemical species formed as a by-product of normal aerobic respiration and also from a number of other cellular enzymatic reactions. ROS function as key mediators of cellular signaling pathways involved in proliferation, survival, apoptosis, and immune response. However, elevated and sustained ROS production promotes tumor initiation by inducing DNA damage or mutation and activates oncogenic signaling pathways to promote cancer progression. Recent studies have shown that ROS can facilitate carcinogenesis by controlling microRNA (miRNA) expression through regulating miRNA biogenesis, transcription, and epigenetic modifications. Likewise, miRNAs have been shown to control cellular ROS homeostasis by regulating the expression of proteins involved in ROS production and elimination. In this review, we summarized the significance of ROS in cancer initiation, progression, and the regulatory crosstalk between ROS and miRNAs in cancer.

Targeting Reactive Oxygen Species in Cancer via Chinese Herbal Medicine.

Recently, reactive oxygen species (ROS), a class of highly bioactive molecules, have been extensively studied in cancers. Cancer cells typically exhibit higher levels of basal ROS than normal cells, primarily due to their increased metabolism, oncogene activation, and mitochondrial dysfunction. This moderate increase in ROS levels facilitates cancer initiation, development, and progression; however, excessive ROS concentrations can lead to various types of cell death. Therefore, therapeutic strategies that either increase intracellular ROS to toxic levels or, conversely, decrease the levels of ROS may be effective in treating cancers via ROS regulation. Chinese herbal medicine (CHM) is a major type of natural medicine and has greatly contributed to human health. CHMs have been increasingly used for adjuvant clinical treatment of tumors. Although their mechanism of action is unclear, CHMs can execute a variety of anticancer effects by regulating intracellular ROS. In this review, we summarize the dual roles of ROS in cancers, present a comprehensive analysis of and update the role of CHM—especially its active compounds and ingredients—in the prevention and treatment of cancers via ROS regulation and emphasize precautions and strategies for the use of CHM in future research and clinical trials.

Metabolic Regulation of Redox Balance in Cancer.

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis.

Nanomedicines for Reactive Oxygen Species Mediated Approach: An Emerging Paradigm for Cancer Treatment.

Growth in the knowledge of cancer biology has led to the emergence and evolution of cancer nanomedicines by providing the rationale for leveraging nanotechnology to develop better treatment options. The discovery of nanometer-sized intercellular openings in the defective angiogenic tumor vasculature contributed to the development of an idea for the well-known cancer passive targeting regime, enhanced permeability and retention (EPR) effect, of the nanomedicines. Recently, reactive oxygen species (ROS) have been highlighted as one of the key players that underlie the acquisition of the various hallmarks of cancer. As ROS are associated with all stages of cancer, their applications in cancer treatment based on the following concentration-dependent implications have attracted much attention: (1) low to moderate levels of ROS as key signaling molecules, (2) elevated levels of ROS in cancer cells as one of the unique characteristics of cancer, and (3) excessive levels of ROS as cytotoxic agents. Considering ROS from a different point of view, various cancer nanomedicines have been designed to achieve spatiotemporal control of therapeutic action, the main research focus in this area. This Account includes our efforts and preclinical achievements in development of nanomedicines for a range of ROS-mediated cancer therapies. It begins with general background regarding cancer nanomedicines, the significance of ROS in cancer, and a brief overview of ROS-mediated approaches for cancer therapy. Then, this Account highlights the two key roles of ROS that define therapeutic purposes of cancer nanomedicines: (1) ROS as drug delivery enhancers and (2) ROS as cell death inducers. The former inspired us to develop nitric oxide-generating nanoparticles for improved EPR effect, endogenous ROS-responsive polymeric micelles for enhanced intracellular drug delivery, and exogenous ROS-activated micelles for subcellular localization via photochemical internalization. While refining conventional chemotherapy, recent researches also have focused on the latter, the cytotoxic ROS, to advance alternative treatment modalities such as oxidation therapy, photodynamic therapy (PDT), and sonodynamic therapy (SDT). In particular, we have been motivated to develop polymeric nanoreactors containing enzymes to produce H2O2 for oxidation therapy, photosensitizer-loaded gold-nanoclustered polymeric nanoassemblies for photothermally activated PDT overcoming the oxygen dependency of PDT, and hydrophilized TiO2 nanoparticles and Au-TiO2 nanocomposites as novel sonosensitizers for improved SDT efficiency. The integration of nanomedicine and ROS-mediated therapy has emerged as the new paradigm in the treatment of cancer, based on promising proof-of-concept demonstrations in preclinical studies. Further efforts to ensure clinical translation along with more sophisticated cancer nanomedicines to address relevant challenges are expected to be made in the coming years.