Liu et al. have identified a noteworthy association between the CAT rs polymorphism and platinum-based chemotherapy-related progression-free survival in patients with lung cancer, indicating its potential as a prognostic biomarker for such patients.

A pioneering review by Li et al. has uncovered the importance of ROS in regulating multiple signaling pathways. Cancer cells can resist therapy by increasing their antioxidant defense system to cope with high levels of ROS. The authors summarized the molecular mechanisms behind this resistance, including drug efflux, DNA repair, stemness maintenance and tumor microenvironment alteration.

Zhuo et al. They demonstrated that the oncogene eIF3a plays a crucial role in cancer development and responses to various therapies, especially those known to promote oxidative stress. Using a proteomics approach, they systematically elucidated its relationship with oxidative stress and found that it is involved in lipid peroxidation, which affects the response of cancer cells to cytotoxic antitumor drugs.

These findings suggest that eIF3a may serve as a bridge between oxidative stress and cancer, providing insights into cancer development and therapy from cellular processes, molecular signaling pathways, metabolism, and immune responses.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Cheung, E. The role of ROS in tumour development and progression. Cancer 22 5 , — PubMed Abstract CrossRef Full Text Google Scholar.

Coradduzza, D. Ferroptosis and senescence: A systematic review. Luo, M. Antioxidant therapy in cancer: Rationale and progress. Antioxidants 11 6 , WHO-IARC World health organization — international agency research on cancer.

Google Scholar. Citation: Liao Q, Wang Z and Cadena SMSC Editorial: Targeting oxidative stress in cancer: what is new in the prevention, diagnostic, treatment and prognostic strategies?. doi: Received: 27 May ; Accepted: 12 June ; Published: 19 June Copyright © Liao, Wang and Cadena.

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ROS can directly activate PI3K, leading to the activation of AKT. The activated AKT can inhibit pro-apoptotic factors like Bad and caspase-9, promoting cell survival [ 35 ]. Keap1-Nrf2 pathway is the main stress response pathway that is reported to be activated in cells in response to oxidative stress.

It is comprised of four different and interlinked components that include chemical inducers ROS , Kelch-like ECH-associated protein 1 KEAP1 , nuclear factor erythroid related factor 2 NRF2 , and target genes.

Under normal cellular conditions, KEAP1 is reported to control the activity of NRF2 through NRF2 ubiquitination as well as proteasome-dependent degradation [ 36 ]. Whereas, under oxidative stress condition, NRF2 skips the ubiquitination process and translocate to the nucleus where it is reported to get attached to sMAF proteins and antioxidant response elements ARE to stimulate transcription program for the regulation of oxidative stress in cell Fig.

KEAP1-NRF2 pathway. Under oxidative stress condition, NRF2 detached from KEAP1 translocated to nucleus and trigger antioxidant response in cells by activating cytoprotective genes.

Oxidative stress can induce the activation of JAKs, which in turn phosphorylate and activate STATs; activated STATs translocate to the nucleus and regulate the expression of genes involved in inflammation, cell proliferation, and apoptosis [ 37 , 38 ].

ROS can induce DNA damage, leading to the activation of the p53 pathway; activated p53 can either promote cell cycle arrest for DNA repair or induce apoptosis if the damage is irreparable [ 40 ]. Each of these pathways intricately interacts with oxidative stress, either amplifying its effects or mitigating its damage, and plays a significant role in the onset and progression of cancer [ 41 ].

Cells employ a sophisticated array of mechanisms to counterbalance reactive oxygen species ROS , oscillating between antioxidative strategies and the activation of tumor suppressor genes. These tumor suppressor genes serve not merely as passive barriers to tumorigenesis, but actively engage in the regulation of cellular processes; they control DNA repair mechanisms, enforce cell cycle checkpoints, and initiate apoptosis, thereby acting as cytoprotective agents.

In the face of oxidative stress, tumor suppressor proteins act as pivotal regulators that dynamically modulate the cellular redox status [ 43 ].

These proteins can induce the transcription of antioxidant genes like glutathione peroxidases GPx , superoxide dismutases SOD , and catalases; simultaneously, they can suppress prooxidative genes that might otherwise exacerbate cellular stress and this dual regulatory ability enables tumor suppressor genes to create a finely tuned response that adapts to varying levels of oxidative stress [ 43 , 44 ].

Regulation of ROS by tumor suppressor genes. In response to ROS, tumor suppressor genes activate the expression of antioxidant genes or prooxidative genes in cells for cell survival or apoptosis respectively, to prevent tumor growth. p53 is the chief regulator of programmed cell death and prevents tumorigenesis by facilitating the regulation of oxidative stress in cells.

At high oxidative stress levels, p53 promotes cell death by suppressing the expression of antioxidant genes and inducing the expression of prooxidative genes, including PIG3, PIG6, FDRX, Bax, Puma to further stimulate ROS production in cell that leads towards senescence [ 40 , 45 , 46 , 47 ].

Inactivation of p53 is reported to be responsible for glioblastoma, retinoblastoma, neuroblastoma, medulloblastoma, lymphoma, bladder, pancreatic, breast, prostate, lungs, uterine, head and neck cancer [ 48 , 49 , 50 ]. Breast cancer susceptibility gene 1 BRCA1 plays a significant role in the genomic stability of cells in response to oxidative DNA damage [ 51 ].

Under oxidative stress, the genomic integrity of the cell is compromised. BRCA1 is reported to regulate cellular oxidative stress by activating the expression of genes that encode paraoxonase 2 PON2 , Klotho KL , ubiquitin carboxyl-terminal esterase L1 UCHL1 , glutathione S-transferase GST , glutathione peroxidase GPX3 , alcohol dehydrogenase 5 ADH5 , and malic enzyme ME2 [ 52 , 53 , 54 ].

Similar to BRCA1, BRCA2 is also reported to be involved in the regulation of cellular oxidative stress and protects DNA double-strand breaks [ 55 ]. Mutations in BRCA1 and BRCA2 genes are reported to be associated with breast, ovarian, esophageal, uterine, pancreatic, colorectal, cervical, stomach, prostate, and liver cancer [ 56 ].

The nuclear factor erythroid related factor 2 NRF2 gene plays a critical role in tumor suppression by stimulating antioxidant response in cells against oxidative damage due to ROS [ 57 ].

It encodes NRF2 protein that is reported to initiate cytoprotective mechanism by binding with sMAF proteins and antioxidant response element ARE altogether in the nucleus.

Thereby, activating the expression of cytoprotective genes encoding glutathione reductases, thioredoxin reductases, glutathione peroxidases, aldehyde dehydrogenases, transaldolases, transketolases, carbonyl reductases, ferritin light and heavy chains, thioredoxin, peroxiredoxin, sulfiredoxin, glutaredoxin, and malic enzymes to regulate oxidative stress [ 7 , 58 ].

Pathogenic mutations in the NRF2 gene and their overexpression are reported to trigger colorectal, breast, liver, gall bladder, prostate, gastric, ovarian, and lung cancer [ 59 , 60 ]. Retinoblastoma transcriptional corepressor 1 RB1 is a tumor suppressor gene that encodes RB1 protein. RB1 protein prevents tumorigenesis when dephosphorylated by protein phosphatase 2A PP2A.

Dephosphorylation allows RB1 protein to trigger cell quiescence by inhibiting the expression of E2f1, E2f2, and E2f3 transcription factors [ 62 ].

RB1 gene inactivation is reported to be involved in the induction and progression of retinoblastoma, glioblastoma, breast, prostate, lungs, and bladder cancer [ 61 , 63 ].

The P21 gene, encoding the p21 protein is reported to help in tumor suppression by repairing DNA damage created due to oxidative stress.

At low cellular ROS levels, p21 is reported to induce NRF2 dependent cytoprotective response to prevent cells from damage. At moderate ROS and oxidative stress levels, p21 triggers cell cycle arrest in between G1 and S phases to allow DNA to repair.

However, at high cellular ROS level, p21 triggers the induction of pro-apoptotic response in cells by inhibiting NRF2-induced pro-survival response and causing cellular apoptosis [ 64 ].

It is noted that mutations in the p21 gene and its overexpression are responsible for causing gastric cancer, and esophageal squamous cell carcinoma [ 65 , 66 ]. The adenomatous polyposis coli APC tumor suppressor gene is also reported to maintain the genomic stability of a cell by either DNA repair mechanism or mechanisms regulating cell death [ 67 , 68 ].

Thereby, facilitating apoptotic cell death and preventing cancer development and progression [ 67 ]. It is reported that mutations, including hypermethylation and deletions in the APC gene are responsible for triggering prostrate [ 69 ], gastric [ 70 ], pancreatic [ 71 ], and colorectal cancer [ 72 , 73 , 74 ].

Table 1 summarizes the roles and interactions of tumor suppressor genes with oxidative stress in various cancers.

Various approaches are reported to be utilized to evaluate the status of oxidative stress in clinical samples. Currently, the evaluation of oxidative stress in samples has been done in many ways, including direct measurement of ROS, assessment of oxidative damage, assessment of antioxidant status and other various methods.

In the direct measurement of ROS, fluorogenic probes i. Lipid Peroxidation Assays like Malondialdehyde MDA and 4-Hydroxynonenal 4-HNE are used to assess oxidative damage to cellular lipids, which is implicated in cancer progression [ 77 ].

Genomic and transcriptomic approaches also offer valuable insights. RNA-Sequencing RNA-Seq identifies differentially expressed genes that are part of the oxidative stress response in cancer cells [ 78 ]. Proteomic approaches like Redox Proteomics specifically identify proteins that undergo oxidative modifications, providing insights into cancer pathology [ 80 ].

Phosphoproteomics techniques identify oxidative stress-induced phosphorylation changes, crucial in oncogenic signaling pathways [ 81 ]. Untargeted Metabolomics gives a comprehensive overview of metabolic changes due to oxidative stress and can provide potential biomarkers for cancer [ 83 ].

Imaging techniques like reactive oxygen species ROS -sensitive Magnetic Resonance Imaging MRI and Optical Imaging with ROS-sensitive probes are employed for in vivo visualization and real-time monitoring of ROS levels within tumors [ 84 ].

Cellular and tissue techniques like Immunohistochemistry IHC for oxidative stress markers and Cytofluorometric Analysis using fluorescent probes are used for quantifying intracellular levels of ROS or antioxidants [ 75 ].

In Silico and Computational Methods such as Pathway Analysis and Molecular Dynamics Simulations offer insights into ROS-induced signaling cascades and structural changes in biomolecules due to oxidative stress, respectively [ 85 ]. Liquid Biopsy approaches like circulating microRNAs miRNAs and cell-free DNA cfDNA can serve as non-invasive biomarkers for oxidative stress in cancer patients [ 86 ].

Table 2. summarizes the comprehensive methods currently employed for oxidative stress profiling in oncology, ranging from direct measurements of ROS to advanced genomic, transcriptomic, and metabolomic approaches. Various treatment approaches have been incorporated to beat the cancer progression either in the form of chemotherapy, radiotherapy, hormonal therapy and combined therapies, to target various interlinked cancer signaling pathways.

But still, there is a need for detailed molecular and machine learning approaches to introduce improved treatment strategies. Recently, two ROS modulated therapeutic approaches are reported to be employed to target cellular oxidative stress for the prevention of various cancers.

In ROS scavenging therapeutic approach, NADPH oxidase blocking agents, including diphenylene iodonium and apocynin, and various dietary antioxidants like polyphenols are reported to be incorporated to minimize the production and accumulation of cellular ROS. In ROS boosting therapeutic approach, increased concentration of nitroxide derivatives i.

ROS-modulated therapeutic strategies can be broadly classified into ROS-scavenging and ROS-boosting approaches, each with an array of agents acting through various mechanisms Table 3. ROS-Scavenging therapeutic -approaches [ 90 , 91 ]. NADPH oxidase inhibitors e. Antioxidant vitamins e. Selenium compounds e.

Natural compounds e. Enzyme mimetics e. Polyamines e. Miscellaneous e. ROS-Boosting therapeutic approaches [ 92 , 93 ]. Nitroxide derivatives e. Pro-oxidant drugs e. Photodynamic therapy agents e. Natural pro-oxidants e.

Metal chelators e. Thiol antioxidants e. Redox-cycling drugs e. Increased expression or administration of antioxidant enzymes e. Ionophores e. Nanotechnology based treatment strategy is the use of nanoparticles as a carrier for efficient therapeutic drug delivery on the destined spot; it is reported that nanocarrier based therapeutic dose delivery systems increase the therapeutic index of the drug with even small amount load, minimize system toxicity, and allow the drug to remain in the body for extended period to perform its therapeutic action towards cancer cells.

Invitro experiments have shown that organic dye-doped silica NPs effectively target HepG2 liver cancer cells [ 94 , 95 , 96 ]. Besides, thermoresponsive chitosan-g-poly N-vinylcaprolactam NPs, and silver NPs are also reported to be utilized as anticancer drug carriers for efficient and effective delivery [ 97 , 98 ].

Nanotechnology offers a sophisticated strategy for the targeted modulation of oxidative stress in cancer cells; utilizing various forms of nanocarriers, it is possible to either attenuate or exacerbate the cellular redox state, thereby influencing cancer cell fate [ 95 ].

Cerium oxide nanoparticles: these nanoparticles act as regenerative antioxidants, mimicking the activity of both superoxide dismutase and catalase; once localized within the tumor microenvironment, they catalytically convert superoxide anions and hydrogen peroxide into harmless species, thus lowering intracellular ROS levels [ 99 ].

Manganese dioxide nanoparticles: these nanoparticles are activated in the acidic tumor microenvironment, where they catalyze the decomposition of hydrogen peroxide into oxygen and water, effectively reducing oxidative stress [ ].

Gold Nanoparticles: upon irradiation with near-infrared light, gold nanoparticles generate heat that can induce the formation of ROS; the generated ROS can disrupt mitochondrial membranes, causing cytochrome c release and initiating apoptosis [ ].

Copper Sulfide Nanoparticles: these nanoparticles, upon exposure to specific wavelengths of light, undergo electron-hole pair separation, leading to ROS generation, specifically singlet oxygen, which induces oxidative DNA damage and subsequent apoptosis [ ].

Polymeric nanocarriers with redox-responsive bonds: these nanocarriers encapsulate both ROS-generating and -scavenging agents. The disulfide bonds in the polymer matrix are cleaved in the high glutathione environment of cancer cells, releasing the encapsulated agents to modulate ROS levels dynamically [ , ].

Co-Delivery Systems: Nanocarriers such as liposomes can be engineered to encapsulate both chemotherapy agents like doxorubicin and antioxidant agents like curcumin. Doxorubicin induces ROS generation, while curcumin mitigates this effect in normal cells but enhances apoptosis in cancer cells through multiple pathways, including NF-κB inhibition [ ].

Targeted drug delivery systems: nanotechnology allows for the creation of nanoparticles like liposomes and polymeric micelles that can be functionalized with ligands such as antibodies or peptides [ 95 ].

These ligands have a high affinity for specific receptors overexpressed on cancer cells. Upon binding, these functionalized nanoparticles are internalized via receptor-mediated endocytosis, thereby ensuring the localized release of encapsulated ROS-modulating agents.

This results in the targeted alteration of cellular redox balance, either by scavenging ROS with antioxidants or by generating ROS to induce cancer cell apoptosis [ 95 ].

Epigenetic modulators: epigenetic drugs like 5-Azacitidine and Vorinostat act by inhibiting enzymes responsible for DNA methylation and histone deacetylation, respectively [ , ]. These actions lead to the re-expression of genes that encode for antioxidants like glutathione and superoxide dismutases SOD , thus altering the cellular redox state and making cancer cells more susceptible to oxidative stress-induced apoptosis [ ].

Enzyme inhibition strategies: specific inhibitors such as Allopurinol target xanthine oxidase, an enzyme involved in the conversion of hypoxanthine to xanthine and subsequently to uric acid, a process that generates ROS [ ]. By inhibiting this enzyme, the cellular levels of ROS are reduced, which can inhibit the oxidative stress-induced signaling pathways that promote cancer cell proliferation [ ].

Immunotherapies: checkpoint inhibitors like anti-PD-1 antibodies function by blocking the interaction between PD-1 receptors on T cells and PD-L1 on cancer cells [ ].

This blockage enhances the cytotoxic activity of T cells and produces cytokines that can induce oxidative stress in cancer cells, leading to apoptosis; this adds a new dimension to how immunotherapies can modulate the redox state within the tumor microenvironment [ ]. Combination therapies: antioxidants such as N-Acetylcysteine NAC can mitigate the side effects of chemotherapy by donating electrons to free radicals generated by the drugs, neutralizing them [ , ].

When used in conjunction with chemotherapy, this can both protect normal cells from oxidative damage and enhance the efficacy of the chemotherapy by allowing for higher tolerable doses [ , ]. Cancer continues to pose a substantial public health challenge, with diverse factors contributing to its onset and progression.

One such pivotal factor is oxidative stress, mediated by the cellular production of reactive oxygen species ROS. The role of ROS extends beyond being mere cellular cofactors and influences the onset of a wide array of cancers such as lymphoma, retinoblastoma, and various solid tumors including breast and lung cancer.

They are implicated in key cellular processes such as epithelial-to-mesenchymal transition EMT and angiogenesis, which are precursors to metastasis. ROS modulation affects critical signaling pathways like Keap1-Nrf2, which traditionally regulates oxidative stress, and impacts tumor suppressor genes including p53, BRCA1, BRCA2, and RB1.

These pathways and genes are either hyperactivated or inactivated under oxidative stress, leading to tumor growth and suppression, respectively. Current diagnostic approaches for oxidative stress, such as fluorogenic probes and d-ROMs tests, offer some insights but are not exhaustive.

Likewise, existing treatment modalities like chemotherapy and radiotherapy have their limitations. Emerging strategies, such as ROS-modulated therapies and nanotechnology-based drug delivery systems, show promise in enhancing the effectiveness of anticancer drugs.

Moreover, in accordance with the valuable suggestions received during the review process, we have expanded our discussion to include a wider range of ROS-modulatory agents, as reflected in a comprehensive table outlining these approaches. In summary, understanding the multifaceted role of oxidative stress in cancer biology is crucial for the development of more effective diagnostic tools and therapeutic interventions.

Future research should focus on deciphering the complex interactions between oxidative stress and cellular pathways, with the aim of translating these findings into clinically applicable strategies for cancer management. Feel free to incorporate this into your manuscript.

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Cancer cells are vulnerable to reactive oxygen species ROS due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of cancer. We report a novel seleno-prodrug of gemcitabine Gem , Se—Gem , and evaluated its activation and biological effects in cancer cells.

Se—Gem was prepared by introducing a 1,2-diselenolane a five-membered cyclic diselenide moiety into the parent drug Gem via a carbamate linker. Se—Gem is preferably activated by glutathione GSH and displays a remarkably higher potency than Gem up to a 6-fold increase to a panel of cancer cell lines.

The activation of Se—Gem by GSH releases Gem and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG oxidized GSH and ROS via redox cycling reactions.

Thus Se—Gem may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of Se—Gem as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency via a combination of chemotherapy and oxidative stress.

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