Cited by 452Redox biology and oxidative stressCancer and biochemical researchAntioxidant Activity and Oxidative Stress

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The multifaceted role of reactive oxygen species in tumorigenesis

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Kirtonia, Anuradha, Sethi, Gautam, Garg, Manoj·2020·Cellular and Molecular Life Sciences

DOI 10.1007/s00018-020-03536-5PMC PMC11105050

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Abstract

Redox homeostasis is an essential requirement of the biological systems for performing various normal cellular functions including cellular growth, differentiation, senescence, survival and aging in humans. The changes in the basal levels of reactive oxygen species (ROS) are detrimental to cells and often lead to several disease conditions including cardiovascular, neurological, diabetes and cancer. During the last two decades, substantial research has been done which clearly suggests that ROS are essential for the initiation, progression, angiogenesis as well as metastasis of cancer in several ways. During the last two decades, the potential of dysregulated ROS to enhance tumor formation through the activation of various oncogenic signaling pathways, DNA mutations, immune escape, tumor microenvironment, metastasis, angiogenesis and extension of telomere has been discovered. At present, surgery followed by chemotherapy and/or radiotherapy is the major therapeutic modality for treating patients with either early or advanced stages of cancer. However, the majority of patients relapse or did not respond to initial treatment. One of the reasons for recurrence/relapse is the altered levels of ROS in tumor cells as well as in cancer-initiating stem cells. One of the critical issues is targeting the intracellular/extracellular ROS for significant antitumor response and relapse-free survival. Indeed, a large number of FDA-approved anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production. Thus, the modulation of oxidative stress response might represent a potential approach to eradicate cancer in combination with FDA-approved chemotherapies, radiotherapies as well as immunotherapies.

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“Besides, ROS can drive angiogenesis by regulating Ang1 and p44/42 MAPK signaling pathways as well as p300, vascular endothelial growth factor-a , hypoxia inducible factor 1 (HIF1), p53, and MMPs (Kirtonia et al., 2020).”
Water-Soluble Alkali Lignin as a Natural Radical Scavenger and Anticancer Alternative
Ivanova, D., Nikolova, G., Karamalakova, Y. D., Semkova, S., Marutsova, V., & Yaneva, Z. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612705 · Cited by 11
“There is indisputable evidence about the role of oxidative stress during cancer initiation as well as during malignant progression process [70,71], and various strategies for the elimination of excess ROS levels have been elaborated.”
Background
Jian Yun Qing Hua Decoction inhibits malignant behaviors of gastric carcinoma cells via COL12A1 mediated ferroptosis signal pathway
Liu, B., Li, Y., Xu, Y., Xue, W., & Jin, Z. (2023) · Chinese Medicine · doi:10.1186/s13020-023-00799-5 · Cited by 11
“In general, abnormal lipid metabolism and ROS generation make critical effects on modulating ferroptosis [16, 17].”
Background
Berberine inhibits the progression of renal cell carcinoma cells by regulating reactive oxygen species generation and inducing DNA damage
Zhao, Y., Lin, X., Zeng, W., Qin, X., Miao, B., Gao, S., Liu, J., & Li, Z. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08381-w · Cited by 11
Carcinogenicity of metal compounds
Liu, S., & Costa, M. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823292-7.00014-0 · Cited by 10
Expression Pattern and Molecular Mechanism of Oxidative Stress-Related Genes in Myocardial Ischemia–Reperfusion Injury
Wu, J., Luo, J., Cai, H., Li, C., Lei, Z., Lu, Y., Ni, L., Cao, J., Cheng, B., & Hu, X. (2023) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd10020079 · Cited by 12
“damage to proteins, lipids, and DNA, generates a large number of oxidative intermediates, increases neutrophil infiltration and protease secretion, activates the regulatory cell death process, and ultimately leads to tissue damage [9].”
Background
The Role of Oxidative Stress in Hypomagnetic Field Effects
Tian, L., Luo, Y., Ren, J., & Zhao, C. (2024) · Antioxidants · doi:10.3390/antiox13081017 · Cited by 10
“TNF receptor-associated factor (TRAF)2 and TRAF6 are then recruited to the ASK1 signalosome, resulting in the activation of the JNK and p38 MAPK pathways [89,90].”
Background
Chemical modulation of the tumor microenvironment enabled by nanomaterials for enhanced cancer treatment
Yan, Y., Zhang, L., & Feng, L. (2025) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2025.102452 · Cited by 10
Mechanistic Aspects of Inflammation and Oxidative Stress and Their Association With Thyroid Cancer Risk
Zhang, B., Guo, M., Lü, Y., Zeng, Y., & Jiang, J. (2025) · Cancer Medicine · doi:10.1002/cam4.71030 · Cited by 11
“In tissues, elevated intracellular levels of ROS, which may arise from tumorigenic events such as metabolic alterations or oncogene activation, can facilitate tumor initiation or progression [86].”
Autophagy in doxorubicin resistance: basic concepts, therapeutic perspectives and clinical translation
Zhang, Y., Ji, Y., Tu, Y., & Li, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1642050 · Cited by 10
“Other factors for overcoming DOX depends on targeting special organelles in the cells such as mitochondria due to its function in apoptosis regulation and also, impact of ROS on this organelle (95, 96).”
NRF2 and Primary Cilia: An Emerging Partnership
Martín-Hurtado, A., Lastres‐Becker, I., Cuadrado, A., & García-Gonzalo, F. R. (2020) · Antioxidants · doi:10.3390/antiox9060475 · Cited by 11
Reactive Oxygen Species Signaling Differentially Controls Wound Healing and RegenerationPreprint
Huizen, A. V. V., Hack, S. J., Greene, J. M., Kinsey, L. J., & Beane, W. S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.05.487111 · Cited by 13
scFASTCORMICS: A Contextualization Algorithm to Reconstruct Metabolic Multi-Cell Population Models from Single-Cell RNAseq Data
Pacheco, M. P., Ji, J., Prohaska, T., Garcia, M. M., & Sauter, T. (2022) · Metabolites · doi:10.3390/metabo12121211 · Cited by 9
“While lower concentrations of ROS favour tumorigenesis, higher rates induce apoptosis [42,43].”
Background
Mitochondrial enzyme FAHD1 reduces ROS in osteosarcoma
Heberle, A., Cappuccio, E., Andric, A., Kuen, T., Simonini, A., & Weiss, A. K. H. (2024) · Scientific Reports · doi:10.1038/s41598-024-60012-x · Cited by 10
Suppression of multiple myeloma by mitochondrial targeting
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Dehydrocrenatidine inhibits head and neck cancer cells invasion and migration by modulating JNK1 /2 and ERK1 /2 pathway and decreases MMP ‐2 expression
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“metastasis, it can lead to the overexpression of MMP1/2/9 to enhance metastasis.(19) However, according to the results, dehydrocrenatidine was no affect the production of ROS (data not show).”
Background
APOL3-LDHA axis related immunity activation and cancer ferroptosis induction
Feng, Y., & Dai, Y. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.83342 · Cited by 9
“Additionally, high level of ROS in ferroptotic cells may lead to immunosuppressive TME and dampen the cytotoxic capacity of CD8 T cells [7].”
Background
Antioxidant and Antitumorigenic Activities of the Standardized Water Extract From Fruit of Terminalia chebula Retz. var. chebula
Takuathung, M. N., Wongnoppavich, A., Jaijoy, K., Soonthornchareonnon, N., & Sireeratawong, S. (2023) · Natural Product Communications · doi:10.1177/1934578x231176925 · Cited by 8
“At low concentrations, ROS are essential to cellular communication, but excessive ROS production can damage cellular components such as DNA, lipids, and proteins, leading to oxidative stress, inflammation, and ultimately, tumorigenesis.(5,6) Skin cancer or tumorigenesis has been associated with an imbalance between RO…”
Background
Small molecules targeting mitochondria as an innovative approach to cancer therapy
Kamble, O., Chatterjee, R., Abishek, K. G., Chandra, J., Alsayari, A., Wahab, S., Sahebkar, A., Kesharwani, P., & Dandela, R. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111396 · Cited by 8
Compound K-enriched Korean red ginseng prevents lung cancer progression by targeting cancer cells and fibroblasts
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Qidan Tiaozhi capsule attenuates metabolic syndrome via activating AMPK/PINK1-Parkin-mediated mitophagy
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Discovery of novel organoarsenicals as robust thioredoxin reductase inhibitors for oxidative stress mediated cancer therapy
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AMPK activation; a potential strategy to mitigate TKI-induced cardiovascular toxicity
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“…and activator of transcription 3 (StAt3), along with the inactivation of phosphatases such as protein tyrosine phosphatase B1 (PtPB1), protein phosphatase A2 (PPA2), and phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and tensin homolog (PteN) (Kirtonia et al. 2020, Feng et al. 2024).”
Multifactorial Distress, the Warburg Effect, and Respiratory and pH Imbalance in Cancer Development
Drochioiu, G. (2023) · Stresses · doi:10.3390/stresses3020036 · Cited by 10
Qingjie decoction attenuated E.coli-induced diarrhea by regulating energy metabolism and alleviating inflammation based on network analysis and metabolomics
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MiRNAs function in the development of resistance against doxorubicin in cancer cells: targeting ABC transporters
Lu, X., & Jin, H. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1486783 · Cited by 7
Glutaraldehyde-crosslinked Naringenin-loaded Albumin Nanoparticles (GNANPs) induce antimicrobial properties and apoptosis in gastric cancer cells.
Munusamy, M. A., Bharathi, M., Alarfaj, A., Hussein-Al-Ali, S., Nagaiya, R., & Subbarayan, S. (2025) · Toxicology in Vitro · doi:10.1016/j.tiv.2025.106037 · Cited by 6
Phospholipid Metabolism Reprogramming of Cancer Stem Cells and Its Impacts on Stemness
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“Studies have found that the anti-tumor effect can be enhanced by inducing ferroptosis of tumor cells, and this anti-cancer strategy has broad prospects [169,170].”
Breaking the hypoxia barrier: Advances and challenges of hyperbaric oxygen therapy in cancer treatment
Meng, Y., Zhou, L., Xia, Y., Jia, C., & Huang, L. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118703 · Cited by 12
Chemopreventive potential of hydroethanolic Murraya koenigii leaves extract against DMBA induced breast carcinogenesis: In-silico and in-vivo study
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Selenium-doped carbon dots inhibit ferroptosis by multi-hierarchy iron chelation and mitochondrial homeostasis regulation to control inflammation
Zhang, K., Mao, X., Zhao, H., Bianco, A., Ge, S., & Ma, B. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.156544 · Cited by 7
Leelamine Exerts Antineoplastic Effects in Association with Modulating Mitogen‑Activated Protein Kinase Signaling Cascade
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Mechanism of Action and Implication of Naphthoquinone as Potent Anti-trypanosomal Drugs
Rani, R., Sethi, K., Gupta, S., Varma, R. S., & Kumar, R. (2022) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026622666220912101332 · Cited by 8
Does each Component of Reactive Oxygen Species have a Dual Role in the Tumor Microenvironment?
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Ferroptosis-related alternative splicing signatures as potential biomarkers for predicting prognosis and therapy response in gastric cancer
Long, G., Li, Z., Gao, Y., Zhang, X., Cheng, X., Daniel, I. E., Zhang, L., Wang, D., & Li, Z. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e34381 · Cited by 7
“ROS and angiogenesis are also connected, suggesting a potential relationship between angiogenesis and ferroptosis [40].”
Nanoparticle-driven reactive oxygen species therapy: A new frontier in osteosarcoma treatment
He, L., Habibović, P., & van Rijt, S. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114289 · Cited by 6
Mitochondrial DNA mutations and intercellular mitochondrial transfer in cancer: mechanisms, biological effects, and clinical potential
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7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds
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Background
Platinum Deposition in the Central Nervous System: A Novel Insight into Oxaliplatin-induced Peripheral Neuropathy in Young and Old Mice
dos Reis, A. S., Paltian, J. J., Domingues, W. B., Novo, D. L. R., Bolea‐Fernandez, E., Acker, T. V., Campos, V. F., Luchese, C., Vanhaecke, F., Mesko, M. F., et al. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04430-y · Cited by 7
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Exploration and validation of a novel reactive oxygen species–related signature for predicting the prognosis and chemotherapy response of patients with bladder cancer
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“ROS has been indicated to be crucial secondary messengers governing various cellular biological processes, including proliferation, angiogenesis, differentiation, metastasis, autophagy, drug resistance, immune response, and cancer stem cells (12).”
Dietary rational targeting of redox-regulated genes
Bagyi, J., Sripada, V., Aidone, A. M., Lin, H., Ruder, E. H., & Crawford, D. R. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.021 · Cited by 6
Bauhinia variegata Bark Extract: Assessment of its Anti-proliferative and Apoptotic Activities on A549 and H460 Lung Cancer Cell Lines
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Oxidative stress, glutathione, and CYP2E1 in 1,4-dioxane liver cytotoxicity and genotoxicity: insights from animal models
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Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis
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Positive Inotropic Agents in Cancer Therapy: Exploring Potential Anti-Tumor Effects
Ribeiro, E., & Vale, N. (2024) · Targets · doi:10.3390/targets2020009 · Cited by 7
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Plant Antioxidants from Agricultural Waste: Synergistic Potential with Other Biological Properties and Possible Applications
Carpena, M., Garcia‐Oliveira, P., Pereira, A. G., Soria-López, A., Chamorro, F., Collazo, N., Jarboui, A., Simal‐Gándara, J., & Prieto, M. A. (2021) · Reference series in phytochemistry · doi:10.1007/978-3-030-45299-5_35-1 · Cited by 7
Mitochondrial dysfunction and its impact on pyroptosis and ferroptosis cross talk in glioma cells
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Roles of hypoxia in tumor progression and novel strategies for cancer treatment
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Authors: Kirtonia, A., Sethi, G., & Garg, M.
Affiliations: Amity University (IN)
National University of Singapore (SG)
Corresponding author: Sethi, Gautam
Garg, Manoj
ORCID: Kirtonia, Anuradha
Sethi, Gautam
Garg, Manoj
Venue: Cellular and Molecular Life Sciences
Publisher: Springer Science and Business Media LLC
Published: 2020-05-01
Volume: 77
Issue: 22
Pages: 4459-4483
ISSN: 1420-682X (ISSN-L)
1420-9071
DOI: 10.1007/s00018-020-03536-5
PMC: PMC11105050
OpenAlex: W3022746266
Cited by: 452
References: 257
Citations by year: 2026: 33 · 2025: 45 · 2024: 90 · 2023: 72 · 2022: 106 · 2021: 80 · 2020: 26
FWCI: 6.79
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Cellular and Molecular Life Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Department of Biotechnology , Ministry of Science and Technology
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords: reactive oxygen species, carcinogenesis, redox homeostasis, oxidative stress, metastasis, angiogenesis, oncogenic signaling, DNA mutations, tumor microenvironment, cancer stem cells, drug resistance, anticancer agents, immunotherapy, radiotherapy, chemotherapy
MeSH terms: Animals, Humans, Neoplasm Recurrence, Local, Neoplasms, Oxidation-Reduction, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Carcinogenesis

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The multifaceted role of reactive oxygen species in tumorigenesis

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