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Antioxidants
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Free Radicals, Antioxidants and Melanoma: Where Do We Stand?
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Free Radicals, Antioxidants and Melanoma: Where Do We Stand?

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 December 2022) | Viewed by 17433

Special Issue Editor

Dr. Ana Luisa Kadekaro

E-Mail Website
Guest Editor
Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Interests: melanocyte; melanoma; oxidative stress; DNA damage; ROS

Special Issue Information

Dear Colleagues,

Emerging evidence suggests that oxidative stress is involved in the malignant transformation of normal melanocytes and progression of melanoma. Cutaneous melanomas are characterized by high DNA mutational burdens, a natural consequence of exposure to solar ultraviolet radiation (UVR). Ultraviolet B (UVB)-signature mutations arise from sites of unrepaired cyclobutane pyrimidine dimer (CPD) lesions. There is evidence that the UVA component of solar radiation further increases the DNA burden, not only by generating oxidative DNA damage (i.e., 8-hydroxy-deoxyguanosine (8OhdG)), but also by forming “dark CPDs” or CPDs originated in the absence of UVR. The formation of these CPDs depends on the presence of high levels of pheomelanin (a yellow/reddish pigment) and is mediated by reactive oxygen and reactive nitrogen species (ROS and RNS). In this context, the use of antioxidants could constitute a viable strategy in melanoma prevention, since they could potentially mitigate the additional burden of “dark CPDs” in normal melanocytes. Melanoma cells are apparently well adapted to survive under conditions of elevated ROS by increasing the expression of endogenous antioxidant enzymes. Evidence supporting the role of antioxidants in suppressing melanoma growth, however, remains controversial. This Special Issue intends to provide an update on the current status of the field. This issue will cover a broad range of original articles and reviews on antioxidant use within the context of melanoma.

We invite you to submit your latest research findings or a review article to this Special Issue “Free Radicals, Antioxidants and Melanoma: Where Do We Stand?” We believe this issue will present the most recent advances in preclinical and clinical studies focusing on the central role of oxidative stress in the establishment and progression of melanoma, and current findings with the broad use of antioxidants.

Dr. Ana Luisa Kadekaro
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Melanoma
  • Prevention and progression
  • Antioxidants
  • Sunscreen
  • Diet

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Published Papers (5 papers)

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Research

17 pages, 4151 KiB  
Article
Inhibition of Tumor Growth and Modulation of Antioxidant Activity of Rhodoxanthin Isolated from Taxus baccata Aril against B16F10 Murine Malignant Melanoma
by Daria-Antonia Dumitraş, Alexandra Iulia Dreanca, Emoke Pall, Adrian Florin Gal, Vasile Rus, Andreea Georgiana Morohoschi, Mihaela Cotul, Monica Irina Nan and Sanda Andrei
Antioxidants 2022, 11(11), 2264; https://doi.org/10.3390/antiox11112264 - 16 Nov 2022
Cited by 5 | Viewed by 1995
Abstract
Malignant melanoma is the most aggressive type of skin cancer, and due to the numerous limitations of current treatment methods, there is an urgent need to develop novel approaches for both the prevention and treatment of malignant melanoma, with research-oriented bioactive substances representing [...] Read more.
Malignant melanoma is the most aggressive type of skin cancer, and due to the numerous limitations of current treatment methods, there is an urgent need to develop novel approaches for both the prevention and treatment of malignant melanoma, with research-oriented bioactive substances representing a notable first step. The current study decided to expand on previous rhodoxanthin research by investigating the possible anti-tumor effect as well as the effect on the antioxidant status in the case of murine melanoma in an experimental model. The 21-day study was carried out on female C57BL/6J mice. On the first day of the experiment, they were subcutaneously inoculated with 106 B16F10 cells and were given rhodoxanthin orally until the end of the study. Rhodoxanthin supplementation significantly reduced tumor growth (42.18%) and weight (15.74%). Furthermore, the epidermal growth factor (EGF) activity was reduced and the concentration of 8-OHdG dropped in the treated melanoma-bearing mice compared to the untreated ones, demonstrating the role of rhodoxanthin in slowing tumor growth, one of the mechanisms being the reduction of EGF level and the decrease of DNA oxidation. The administration of rhodoxanthin determined variations in antioxidant enzymes, both at the plasma level and at the tissue level. Full article
(This article belongs to the Special Issue Free Radicals, Antioxidants and Melanoma: Where Do We Stand?)
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18 pages, 2074 KiB  
Article
Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility
by Parth R. Upadhyay, Renny J. Starner, Viki B. Swope, Kazumasa Wakamatsu, Shosuke Ito and Zalfa A. Abdel-Malek
Antioxidants 2022, 11(6), 1204; https://doi.org/10.3390/antiox11061204 - 20 Jun 2022
Cited by 14 | Viewed by 3792
Abstract
Constitutive pigmentation determines the response to sun exposure and the risk for melanoma, an oxidative stress–driven tumor. Using primary cultures of human melanocytes, we compared the effects of constitutive pigmentation on their antioxidant response to solar UV. The quantitation of eumelanin and pheomelanin [...] Read more.
Constitutive pigmentation determines the response to sun exposure and the risk for melanoma, an oxidative stress–driven tumor. Using primary cultures of human melanocytes, we compared the effects of constitutive pigmentation on their antioxidant response to solar UV. The quantitation of eumelanin and pheomelanin showed that the eumelanin content and eumelanin to pheomelanin ratio correlated inversely with the basal levels of reactive oxygen species (ROS). Irradiation with 7 J/cm2 solar UV increased ROS generation without compromising melanocyte viability. Among the antioxidant enzymes tested, the basal levels of heme oxygenase-1 (HO-1) and the glutamate cysteine ligase catalytic subunit and modifier subunit (GCLC and GCLM) correlated directly with the eumelanin and total melanin contents. The levels of HO-1 and GCLM decreased at 6 h but increased at 24 h post–solar UV. Consistent with the GCLC and GCLM levels, the basal glutathione (GSH) content was significantly lower in light than in dark melanocytes. The expression of HMOX1, GCLC, GCLM, and CAT did not correlate with the melanin content and was reduced 3 h after solar UV irradiation, particularly in lightly pigmented melanocytes. Solar UV increased p53 and lipid peroxidation, which correlated inversely with the eumelanin and total melanin contents. These intrinsic differences between light and dark melanocytes should determine their antioxidant response and melanoma risk. Full article
(This article belongs to the Special Issue Free Radicals, Antioxidants and Melanoma: Where Do We Stand?)
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12 pages, 6384 KiB  
Article
Indolium 1 Exerts Activity against Vemurafenib-Resistant Melanoma In Vivo
by Rakan Radi, Christina Huang, Justin Elsey, Yoon H. Jung, Victor G. Corces and Jack L. Arbiser
Antioxidants 2022, 11(5), 798; https://doi.org/10.3390/antiox11050798 - 19 Apr 2022
Cited by 2 | Viewed by 2935
Abstract
The development of targeted therapies (BRAF/MEK inhibitors) and immunotherapy have had a major impact on the treatment of melanoma. However, the majority of patients with advanced melanomas succumb to their disease. The mechanisms of resistance to both targeted therapies and immunotherapies are numerous [...] Read more.
The development of targeted therapies (BRAF/MEK inhibitors) and immunotherapy have had a major impact on the treatment of melanoma. However, the majority of patients with advanced melanomas succumb to their disease. The mechanisms of resistance to both targeted therapies and immunotherapies are numerous and have been well-described. These include the alternative activation of BRAF/MEK signaling, novel compensating mutations in additional oncogenes, and loss of neoantigens. There has been limited development of small molecules that target alternative pathways in melanoma in the last two decades. We have previously identified triphenylmethanes as a class that shows activity against a wide variety of tumors. We have synthesized a novel triphenylmethane, indolium 1, and demonstrated its efficacy against an aggressive vemurafenib-resistant melanoma in vivo. Indolium 1 has a novel mechanism of action against melanoma, in that it results in induction of the tumor-suppressor EPHA3. We believe that pre-IND studies are warranted for this novel compound, given its mechanism of action and ability to inhibit the growth of vemurafenib resistant melanoma in vivo. Full article
(This article belongs to the Special Issue Free Radicals, Antioxidants and Melanoma: Where Do We Stand?)
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34 pages, 13639 KiB  
Article
Redox-Related Proteins in Melanoma Progression
by Larissa A. C. Carvalho, Rodrigo G. Queijo, Alexandre L. B. Baccaro, Ádamo D. D. Siena, Wilson A. Silva, Jr., Tiago Rodrigues and Silvya Stuchi Maria-Engler
Antioxidants 2022, 11(3), 438; https://doi.org/10.3390/antiox11030438 - 22 Feb 2022
Cited by 15 | Viewed by 3600
Abstract
Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis [...] Read more.
Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis and resistance. Redox proteins modulate the disease by controlling ROS/RNS levels in immune response, proliferation, invasion, and relapse. Chemotherapeutics such as BRAF and MEK inhibitors promote oxidative stress, but high ROS/RNS amounts with a robust antioxidant system allow cells to be adaptive and cooperate to non-toxic levels. These proteins could act as biomarkers and possible targets. By understanding the complex mechanisms involved in adaptation and searching for new targets to make cells more susceptible to treatment, the disease might be overcome. Therefore, exploring the role of redox-sensitive proteins and the modulation of redox homeostasis may provide clues to new therapies. This study analyzes information obtained from a public cohort of melanoma patients about the expression of redox-generating and detoxifying proteins in melanoma during the disease stages, genetic alterations, and overall patient survival status. According to our analysis, 66% of the isoforms presented differential expression on melanoma progression: NOS2, SOD1, NOX4, PRX3, PXDN and GPX1 are increased during melanoma progression, while CAT, GPX3, TXNIP, and PRX2 are decreased. Besides, the stage of the disease could influence the result as well. The levels of PRX1, PRX5 and PRX6 can be increased or decreased depending on the stage. We showed that all analyzed isoforms presented some genetic alteration on the gene, most of them (78%) for increased mRNA expression. Interestingly, 34% of all melanoma patients showed genetic alterations on TRX1, most for decreased mRNA expression. Additionally, 15% of the isoforms showed a significant reduction in overall patient survival status for an altered group (PRX3, PRX5, TR2, and GR) and the unaltered group (NOX4). Although no such specific antioxidant therapy is approved for melanoma yet, inhibitors or mimetics of these redox-sensitive proteins have achieved very promising results. We foresee that forthcoming investigations on the modulation of these proteins will bring significant advances for cancer therapy. Full article
(This article belongs to the Special Issue Free Radicals, Antioxidants and Melanoma: Where Do We Stand?)
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19 pages, 2321 KiB  
Article
Triplet-Energy Quenching Functions of Antioxidant Molecules
by Carlos Angelé-Martínez, Leticia Christina Pires Goncalves, Sanjay Premi, Felipe A. Augusto, Meg A. Palmatier, Saroj K. Amar and Douglas E. Brash
Antioxidants 2022, 11(2), 357; https://doi.org/10.3390/antiox11020357 - 11 Feb 2022
Cited by 15 | Viewed by 4049
Abstract
UV-like DNA damage is created in the dark by chemiexcitation, in which UV-activated enzymes generate reactive oxygen and nitrogen species that create a dioxetane on melanin. Thermal cleavage creates an electronically excited triplet-state carbonyl whose high energy transfers to DNA. Screening natural compounds [...] Read more.
UV-like DNA damage is created in the dark by chemiexcitation, in which UV-activated enzymes generate reactive oxygen and nitrogen species that create a dioxetane on melanin. Thermal cleavage creates an electronically excited triplet-state carbonyl whose high energy transfers to DNA. Screening natural compounds for the ability to quench this energy identified polyenes, polyphenols, mycosporine-like amino acids, and related compounds better known as antioxidants. To eliminate false positives such as ROS and RNS scavengers, we then used the generator of triplet-state acetone, tetramethyl-1,2-dioxetane (TMD), to excite the triplet-energy reporter 9,10-dibromoanthracene-2-sulfonate (DBAS). Quenching measured as reduction in DBAS luminescence revealed three clusters of 50% inhibitory concentration, ~50 μM, 200–500 μM, and >600 μM, with the former including sorbate, ferulic acid, and resveratrol. Representative triplet-state quenchers prevented chemiexcitation-induced “dark” cyclobutane pyrimidine dimers (dCPD) in DNA and in UVA-irradiated melanocytes. We conclude that (i) the delocalized pi electron cloud that stabilizes the electron-donating activity of many common antioxidants allows the same molecule to prevent an electronically excited species from transferring its triplet-state energy to targets such as DNA and (ii) the most effective class of triplet-state quenchers appear to operate by energy diversion instead of electron donation and dissipate that energy by isomerization. Full article
(This article belongs to the Special Issue Free Radicals, Antioxidants and Melanoma: Where Do We Stand?)
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