The Double-Edged Sword of Oxidative Stress in Skin Damage and Melanoma: From Physiopathology to Therapeutical Approaches

Emanuelli, Monica; Sartini, Davide; Molinelli, Elisa; Campagna, Roberto; Pozzi, Valentina; Salvolini, Eleonora; Simonetti, Oriana; Campanati, Anna; Offidani, Annamaria

doi:10.3390/antiox11040612

Cited by 132Redox biology and oxidative stressMelanoma and MAPK Pathwaysmelanin and skin pigmentation

The Double-Edged Sword of Oxidative Stress in Skin Damage and Melanoma: From Physiopathology to Therapeutical Approaches

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Emanuelli, Monica, Sartini, Davide, Molinelli, Elisa, Campagna, Roberto, Pozzi, Valentina, Salvolini, Eleonora, Simonetti, Oriana, Campanati, Anna +1 more·2022·Antioxidants

DOI 10.3390/antiox11040612PMC PMC9027913

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Abstract

The skin is constantly exposed to exogenous and endogenous sources of reactive oxygen species (ROS). An adequate balance between ROS levels and antioxidant defenses is necessary for the optimal cell and tissue functions, especially for the skin, since it must face additional ROS sources that do not affect other tissues, including UV radiation. Melanocytes are more exposed to oxidative stress than other cells, also due to the melanin production process, which itself contributes to generating ROS. There is an increasing amount of evidence that oxidative stress may play a role in many skin diseases, including melanoma, being the primary cause or being a cofactor that aggravates the primary condition. Indeed, oxidative stress is emerging as another major force involved in all the phases of melanoma development, not only in the arising of the malignancy but also in the progression toward the metastatic phenotype. Furthermore, oxidative stress seems to play a role also in chemoresistance and thus has become a target for therapy. In this review, we discuss the existing knowledge on oxidative stress in the skin, examining sources and defenses, giving particular consideration to melanocytes. Therefore, we focus on the significance of oxidative stress in melanoma, thus analyzing the possibility to exploit the induction of oxidative stress as a therapeutic strategy to improve the effectiveness of therapeutic management of melanoma.

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Cancers of the skin and lung are particularly exposed to additional sources of environmental ROS which contribute to cancer initiation and aggravation.
“This is particularly true for cancers of the skin and lung, as both organs are directly exposed to additional sources of environmental ROS which contribute to cancer initiation and aggravation [158,159].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [158]

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Urinary biomarker of oxidative stress in patients with psoriasis vulgaris and atopic dermatitis
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Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression.
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Interleukin-17 gene polymorphism is associated with Vogt–Koyanagi–Harada syndrome but not with Behçet's disease in a Chinese Han population
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Generation of superoxide during the enzymatic action of tyrosinase
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Targeting Nitric Oxide Signaling with nNOS Inhibitors As a Novel Strategy for the Therapy and Prevention of Human Melanoma
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Pre‐eclampsia onset and SPARC: A possible involvement in placenta development
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DNA repair enzymes in sunscreens and their impact on photoageing—A systematic review
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A potential role for resveratrol as a radiation sensitizer for melanoma treatment
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Curcumin inhibited growth of human melanoma A375 cells via inciting oxidative stress
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Paraoxonase-2 Silencing Enhances Sensitivity of A375 Melanoma Cells to Treatment with Cisplatin
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Dysplastic Melanocytic Nevi Contain High Levels of Pheomelanin: Quantitative Comparison of Pheomelanin/Eumelanin Levels Between Normal Skin, Common Nevi, and Dysplastic Nevi
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Selenium for the Prevention of Cutaneous Melanoma
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UVA Irradiation Enhances Brusatol‐Mediated Inhibition of Melanoma Growth by Downregulation of the Nrf2‐Mediated Antioxidant Response
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ROS as Regulators of Cellular Processes in Melanoma
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Tumor Cytotoxicity by Endothelial Cells
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Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated
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Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers
Campagna, R., Pozzi, V., Sartini, D., Salvolini, E., Brisigotti, V., Molinelli, E., Campanati, A., Offidani, A., & Emanuelli, M. (2021) · Cancers · doi:10.3390/cancers13194943 · Cited by 46 · see citing works
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Nilotinib Treatment of Patients Affected by Chronic Graft-versus-Host Disease Reduces Collagen Production and Skin Fibrosis by Downmodulating the TGF-β and p-SMAD Pathway
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Role of glutathione S-transferases in melanoma susceptibility: association with GSTP1 rs1695 polymorphism: GSTP1 rs1695 polymorphism associated with melanoma
Ibarrola-Villava, M., Martin-Gonzalez, M., Lazaro, P., Pizarro, A., Lluch, A., & Ribas, G. (2012) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2012.10831.x · Cited by 44 · see citing works
Nicotinamide N‐methyltransferase gene silencing enhances chemosensitivity of melanoma cell lines
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TRP-2 specifically decreases WM35 cell sensitivity to oxidative stress
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Nicotinamide N-methyltransferase: potential involvement in cutaneous malignant melanoma
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Paraoxonase‐2: A potential biomarker for skin cancer aggressiveness
Bacchetti, T., Salvolini, E., Pompei, V., Campagna, R., Molinelli, E., Brisigotti, V., Togni, L., Lucarini, G., Sartini, D., Campanati, A., et al. (2020) · European Journal of Clinical Investigation · doi:10.1111/eci.13452 · Cited by 43 · see citing works
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Correlation Between Antioxidants and Phototypes in Melanocytes Cultures. A Possible Link of Physiologic and Pathologic Relevance
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Activity of antioxidant enzymes and concentration of lipid peroxidation products in selected tissues of mice of different ages, both healthy and melanoma-bearing
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Signaling by Reactive Oxygen and Nitrogen Species in Skin Diseases
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[Ultraviolet A-induced DNA damage: role in skin cancer].
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Oxidative Stress and Autophagy as Key Targets in Melanoma Cell Fate
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Over-expression of Mn-superoxide dismutase as a marker of oxidative stress in lesional skin of chronic idiopathic urticaria
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Bladder Cancer Chemosensitivity Is Affected by Paraoxonase-2 Expression
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Bioactivation of luteolin by tyrosinase selectively inhibits glutathione S-transferase
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Recent Advances in Phenolic Metabolites and Skin Cancer
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Differential immunohistochemical expression of paraoxonase-2 in actinic keratosis and squamous cell carcinoma
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Increased sensitivity to peroxidizing agents is correlated with an imbalance of antioxidants in normal melanocytes from melanoma patients
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Photooxidation of Tetrahydrobiopterin under UV Irradiation: Possible Pathways and Mechanisms
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Cancer stem cell enrichment is associated with enhancement of nicotinamide N‐methyltransferase expression
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Self-citation
Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions
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Treatment of psoriasis with topical NG-monomethyl- l-arginine, an inhibitor of nitric oxide synthesis
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The skin redoxome
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Untitled work
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Polymorphisms of GSTM1 and GSTT1, Sun Exposure and the Risk of Melanoma: A Case-control Study
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Morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results.
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Anticancer response to disulfiram may be enhanced by co-treatment with MEK inhibitor or oxaliplatin: modulation by tetrathiomolybdate, KRAS/BRAF mutations and c-MYC/p53 status
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Enhancement of melphalan activity by buthionine sulfoximine and electroporation in melanoma cells
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miRNA-200b Signature in the Prevention of Skin Cancer Stem Cells by Polyphenol-enriched Blueberry Preparation
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Ultraviolet-B-induced Inactivation of Human OGG1, the Repair Enzyme for Removal of 8-Oxoguanine in DNA†¶
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Malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously: A case report
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Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130 · see citing works
Antioxidant Therapy in Cancer: Rationale and Progress
Luo, M., Zhou, L., Huang, Z., Li, B., Nice, E. C., Xu, J., & Huang, C. (2022) · Antioxidants · doi:10.3390/antiox11061128 · Cited by 201 · see citing works
Chitosan‐Based Hydrogels as Antibacterial/Antioxidant/Anti‐Inflammation Multifunctional Dressings for Chronic Wound Healing
Xu, J., Chang, L., Xiong, Y., & Peng, Q. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202401490 · Cited by 151 · see citing works
Role of oxidative stress in the relationship between periodontitis and systemic diseases
Shang, J., Liu, H., Zheng, Y., & Zhang, Z. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1210449 · Cited by 132 · see citing works
Oxidative Stress, Genomic Integrity, and Liver Diseases
Sadasivam, N., Kim, Y., Radhakrishnan, K., & Kim, D. (2022) · Molecules · doi:10.3390/molecules27103159 · Cited by 129 · see citing works
SCDNet: A Deep Learning-Based Framework for the Multiclassification of Skin Cancer Using Dermoscopy Images
Naeem, A., Anees, T., Fiza, M., Naqvi, R. A., & Lee, S. W. (2022) · Sensors · doi:10.3390/s22155652 · Cited by 128 · see citing works
Modulation of NRF2/KEAP1 Signaling in Preeclampsia
Tossetta, G., Fantone, S., Piani, F., Crescimanno, C., Ciavattini, A., Giannubilo, S. R., & Marzioni, D. (2023) · Cells · doi:10.3390/cells12111545 · Cited by 130 · see citing works
Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway
Tossetta, G., & Marzioni, D. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106365 · Cited by 115 · see citing works
Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer?
Wang, R., Liang, L., Matsumoto, M., Iwata, K., Umemura, A., & He, F. (2023) · Biomolecules · doi:10.3390/biom13020353 · Cited by 105 · see citing works
Role of SLC7A11/xCT in Ovarian Cancer
Fantone, S., Piani, F., Olivieri, F., Rippo, M. R., Sirico, A., Simone, N. D., Marzioni, D., & Tossetta, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25010587 · Cited by 100 · see citing works
The Role of NQO1 in Ovarian Cancer
Tossetta, G., Fantone, S., Goteri, G., Giannubilo, S. R., Ciavattini, A., & Marzioni, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097839 · Cited by 90 · see citing works
Carotenoids in Human Skin In Vivo: Antioxidant and Photo-Protectant Role against External and Internal Stressors
Darvin, M. E., Lademann, J. M., von Hagen, J., Lohan, S. B., Kolmar, H., Meinke, M. C., & Jung, S. (2022) · Antioxidants · doi:10.3390/antiox11081451 · Cited by 89 · see citing works
Role of CD93 in Health and Disease
Tossetta, G., Piani, F., Borghi, C., & Marzioni, D. (2023) · Cells · doi:10.3390/cells12131778 · Cited by 80 · see citing works
Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers
Tossetta, G., & Marzioni, D. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175503 · Cited by 79 · see citing works
Metformin Improves Ovarian Cancer Sensitivity to Paclitaxel and Platinum-Based Drugs: A Review of In Vitro Findings
Tossetta, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112893 · Cited by 67 · see citing works
Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer
Tossetta, G., Fantone, S., Marzioni, D., & Roberta Mazzucchelli, A. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2807143 · Cited by 65 · see citing works
Modulation of NRF2/KEAP1 Signaling by Phytotherapeutics in Periodontitis
Tossetta, G., Fantone, S., Togni, L., Santarelli, A., Olivieri, F., Marzioni, D., & Rippo, M. R. (2024) · Antioxidants · doi:10.3390/antiox13101270 · Cited by 57 · see citing works
pH Switchable Nanozyme Platform for Healing Skin Tumor Wound Infected with Drug‐Resistant Bacteria
Yan, Y., Wang, M., Zhao, M., Zhang, J., Liu, Y., & Gao, X. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202301375 · Cited by 55 · see citing works
SBXception: A Shallower and Broader Xception Architecture for Efficient Classification of Skin Lesions
Mehmood, A., Gulzar, Y., Ilyas, Q. M., Jabbari, A. M. A., Ahmad, M., & Iqbal, S. (2023) · Cancers · doi:10.3390/cancers15143604 · Cited by 47 · see citing works
Nrf2 Signaling in Renal Cell Carcinoma: A Potential Candidate for the Development of Novel Therapeutic Strategies
Schiavoni, V., Emanuelli, M., Milanese, G., Galosi, A. B., Pompei, V., Salvolini, E., & Campagna, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413239 · Cited by 49 · see citing works
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NRF2 modulation in TRAMP mice: an in vivo model of prostate cancer
Marzioni, D., Roberta Mazzucchelli, A., Fantone, S., & Tossetta, G. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-08052-2 · Cited by 48 · see citing works
Oxidative Stress in Melanoma: Beneficial Antioxidant and Pro-Oxidant Therapeutic Strategies
Becker, A. L., & Indra, A. K. (2023) · Cancers · doi:10.3390/cancers15113038 · Cited by 51 · see citing works
Mitochondrial dysfunction and oxidative stress in Alzheimer's disease–A step towards mitochondria based therapeutic strategies
Aran, K. R., & Singh, S. (2023) · Aging and Health Research · doi:10.1016/j.ahr.2023.100169 · Cited by 48 · see citing works
The KEAP1-NRF2 System and Esophageal Cancer
Hirose, W., Oshikiri, H., Taguchi, K., & Yamamoto, M. P. (2022) · Cancers · doi:10.3390/cancers14194702 · Cited by 46 · see citing works
Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer
Criscuolo, D., Avolio, R., Parri, M., Romano, S., Chiarugi, P., Matassa, D. S., & Esposito, F. (2022) · Antioxidants · doi:10.3390/antiox11081544 · Cited by 41 · see citing works
Paraoxonase-2 is upregulated in triple negative breast cancer and contributes to tumor progression and chemoresistance
Campagna, R., Pozzi, V., Giorgini, S., Morichetti, D., Goteri, G., Sartini, D., Serritelli, E. N., & Emanuelli, M. (2023) · Human Cell · doi:10.1007/s13577-023-00892-9 · Cited by 38 · see citing works
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Additive Interactions between Betulinic Acid and Two Taxanes in In Vitro Tests against Four Human Malignant Melanoma Cell Lines
Wróblewska-Łuczka, P., Cabaj, J., Bąk, W., Bargieł, J., Grabarska, A., Góralczyk, A., & Łuszczki, J. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179641 · Cited by 38 · see citing works
Microbiota, Oxidative Stress, and Skin Cancer: An Unexpected Triangle
Azzimonti, B., Ballacchino, C., Zanetta, P., Cucci, M. A., Monge, C., Grattarola, M., Dianzani, C., Barrera, G., & Pizzimenti, S. (2023) · Antioxidants · doi:10.3390/antiox12030546 · Cited by 38 · see citing works
Oxidative Stress and Immune Response in Melanoma: Ion Channels as Targets of Therapy
Remigante, A., Spinelli, S., Marino, A., Pusch, M., Morabito, R., & Dossena, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010887 · Cited by 32 · see citing works
Effect of natural compounds on NRF2/KEAP1 signaling in periodontitis: a potential use to prevent age-related disorders
Tossetta, G., Fantone, S., Olivieri, F., Roberta Mazzucchelli, A., Togni, L., Santarelli, A., Marzioni, D., & Rippo, M. R. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10878-5 · Cited by 31 · see citing works
Exosomes as novel biomarkers in sepsis and sepsis related organ failure
Yuan, Y., Xiao, Y., Zhao, J., Zhang, L., Li, M., Luo, L., Jia, Y., Wang, K., Chen, Y., Wang, P., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05817-0 · Cited by 27 · see citing works
Mechanisms underlying the anti-aging activity of bergamot (Citrus bergamia) extract in human red blood cells
Remigante, A., Spinelli, S., Straface, E., Gambardella, L., Russo, M., Cafeo, G., Caruso, D., Falliti, G., Dugo, P., Dossena, S., et al. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1225552 · Cited by 27 · see citing works
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Authors: Emanuelli, M., Sartini, D., Molinelli, E., Campagna, R., Pozzi, V., Salvolini, E., Simonetti, O., Campanati, A., & Offidani, A.
Affiliations: Marche Polytechnic University (IT)
Corresponding author: Campagna, Roberto
ORCID: Emanuelli, Monica
Sartini, Davide
Molinelli, Elisa
Campagna, Roberto
Pozzi, Valentina
Salvolini, Eleonora
Simonetti, Oriana
Campanati, Anna
Offidani, Annamaria
Venue: Antioxidants
Publisher: MDPI AG
Published: 2022-03-23
Volume: 11
Issue: 4
Pages: 612
ISSN: 2076-3921 (ISSN-L)
DOI: 10.3390/antiox11040612
PMC: PMC9027913
OpenAlex: W4224323967
Cited by: 132
References: 131
Citations by year: 2026: 17 · 2025: 48 · 2024: 27 · 2023: 20 · 2022: 20
FWCI: 2.99
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Antioxidants (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
Keywords: oxidative stress, melanoma, skin damage, reactive oxygen species, melanocytes, melanogenesis, ultraviolet radiation, antioxidant defense, melanoma progression, metastasis, chemoresistance

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The Double-Edged Sword of Oxidative Stress in Skin Damage and Melanoma: From Physiopathology to Therapeutical Approaches

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