2. Oncodermatology
In the field of oncology, a recent review by Calzari et al. (2023) elucidates the ways in which PLE functions and assesses its applications in oncodermatology, with reference to both in vitro and in vivo research
[8]. However, this review is not the only one, as the trend in recent years has been to publish literature reviews demonstrating the photoprotective effects of PLE, thereby confirming its therapeutic potential against various types of cancerous growths. Alongside these reviews, there have been seven experimental studies, four of which were clinical and three preclinical, which can be found summarized in
Table 1.
Accordingly, a wide range of earlier studies are recognized as crucial references that have significantly advanced our understanding of the potential of Fernblock
® in the field of cancer prevention in both mice and humans. PLE inhibited UVR-mediated DNA damage and mutagenesis through a double mechanism that consisted of prevention of cyclobutane pyrimidine dimer (CPDs) accumulation and reduction of 8-OH-dG and H2Ax, thus preventing oxidative damage
[4]. Also, PLE decreased UVA-dependent mitochondrial DNA damage by reducing common deletions (CD)
[9]. In vitro and in vivo studies suggest that PLE may have a role in the treatment of UV-induced skin inflammation and cancer, probably due to its antioxidant and p53-activating properties
[10]. It is important to note that the extracellular matrix (ECM) provides structural integrity to the tissue and is remodeled during skin aging/photoaging and cancer. In vitro experiments showed that PLE directly inhibited the enzymatic activity and expression of MMPs in melanoma cells and fibroblasts and stimulated the expression of tissue inhibitors of metalloproteinases (TIMPs) in melanoma cells, reducing melanoma cell growth and ECM remodeling
[11][12]. Also, clinical studies shown that PLE reduces epidermal cell proliferation and the number of cyclin D1- and PCNA-positive epidermal cells caused by UVR exposure
[13][14]. In relation to the process of cancerization, previous research has shown that taking oral PLE supplements following PDT can improve AK clearance and reduce recurrence as compared to PDT alone
[15].
However, three recent studies have been conducted to determine the effectiveness of PLE in the context of cancerization not only by oral administration but also by topical administration. The first of them investigated the effectiveness of a new medical device (NMD) in treating the field cancerization in 30 patients with Aks after PDT. The NMD contained a complex of DNA-repair enzymes, UV-filters and Fernblock
®, while the control group received a standard sunscreen (SS). The study utilized clinical, dermoscopic, reflectance confocal microscopy (RCM) and histological evaluations to assess the outcomes and found that after six and twelve months of treatment, the SS group showed a significant increase in the number of AKs compared to the NMD group. The NMD group also showed a significant reduction in the extension and grade of atypia compared to the SS group. Histopathological evaluation showed an improvement in keratinocyte atypia grade in all groups after six months of PDT, but p53 expression was significantly lower in the NMD group at twelve months compared to the SS group. Overall, the NMD was well-tolerated with no serious adverse events reported
[16]. Another recent prospective clinical study evaluated the effectiveness of the same formulation in individuals with AK who underwent cryotherapy. The evaluation involved measuring changes in the AKASI score (Actinic Keratosis Area and Severity Index) and utilized non-invasive line-field confocal-optical coherence tomography (LC-OCT) analysis. The findings revealed that the use of the sunscreen containing DNA-repairing enzymes and PLE significantly reduced the AKASI score after 3 and 12 months treatment compared to the control group. Consequently, the study concluded that the PLE-based sunscreen considerably improved AKASI score among individuals receiving cryotherapy treatment
[17]. Finally, a recent prospective, multicenter, randomized controlled trial was conducted to compare not only the effectiveness of a sunscreen with Fernblock
® vs. one without but also the impact of oral photoprotection for managing AKs in elderly individuals with severe actinic damage. The group that received both topical sunscreen with Fernblock
® and Fernblock
® oral supplementation showed the most significant improvements in AK and field cancerization parameters compared to control group (which used a standard topical sunscreen). These results suggest that combining oral and topical photoprotection leads to superior clinical and anatomical outcomes
[18]. In summary, these studies provide evidence to suggest that both oral and topical PLE could be utilized as an adjuvant treatment option for field cancerization. However, it is necessary to conduct further research in order to validate its effectiveness when compared to established and widely accepted medications considered to be the gold standard.
Regarding melanoma, Aguilera et al. (2013) also investigated the protective role of oral administration of PLE in patients at risk of malignant melanoma (MM) and in the interaction between MC1R polymorphisms and the cyclin-dependent kinase (CDK) inhibitor 2A gene (CDKN2A) status with MED 25–50%. Among patients with familial MM, those individuals with mutations in CDKN2A and/or MC1R had greater differences regarding the response to treatment with PLE
[19]. According to these results, the authors indicated that patients with higher UVR sensitivity (lower basal MED) would benefit the most from oral PLE treatment. These results are intriguing, and thus studies with long-term PLE administration in patients with a high risk of developing MM would be important to expand and confirm these data. No recent clinical studies have been reported in this field that confirm the effectiveness of PLE in preventing melanoma. However, there are new pre-clinical studies which help uncover new mechanisms of action in relation to this matter (
Table 1). Within the scope of the latest in vitro studies, three principal works have been incorporated to the scientific approach. The first one explores the potential of a dietary supplement containing sulforaphane (SFN) and Fernblock
® extract, in terms of its antioxidant, antineoplastic and antiaging properties. The study analyzed the impact of SFN/FB combination on MMPs, ROS production, and IL-1β secretion in human normal keratinocytes. The combination of these actives was found to be more effective than each on its own in inhibiting melanoma cell migration in vitro, MMP-1, -2, -3 and -9 production, inflammasome activation and IL-1β secretion. Moreover, when used in normal keratinocytes with a pro-inflammatory stimulus like TNF-α, SFN/FB was more efficient in inhibiting MMP-1 and -3 production and IL-1β secretion than SFN or FB alone. Based on these results, the authors suggested that SFN/FB-based supplements could be used as potential preventive measures against skin aging and as adjuvants in the treatment of advanced melanoma
[20].
The second work represents an important step forward with respect to understanding the mechanisms involved in DNA damage, and in particular the formation of dark CPDs. Initially discovered by Premi el al (2015), this recent work performed by Portillo-Esnaola et al. (2021) confirms that UVA radiation triggers DNA damage in melanocytes even hours after sun exposure has ended due to increased production of nitrogen reactive species (NO•, O2− and ONOO−), which is linked with the increased formation of CPDs and dark-CPDs. UVA-induced significant dark-CPD formation was observed as soon as 3 h after exposure and the highest peak of dark-CPD formation was obtained 24 h after exposure. However, pre-treatment with Fernblock
® (0.3–0.75 mg/mL) was found to reduce the production of these reactive species and the formation of dark-CPDs due to its antioxidant and scavenging properties. We now understand that PLE not only prevents sunlight-induced DNA damage but also offers protection against it even after exposure to solar irradiation. This suggests that Fernblock
® could be a promising candidate to complement traditional sunscreens in providing long-lasting skin protection against dark-CPD formation formed after irradiation
[21][22].
The third study, performed by Gallego-Rentero et al. (2022) is related to DNA damage induced by photopollution. The interaction of UVA radiation with environmental pollutants, specifically those of a polycyclic aromatic hydrocarbon (PAH) nature such as benzo[a]pyrene (BaP), produces what is known as photopollution. BaP acts as a photosensitizer and upon absorption of UVA radiation it causes increased cell damage in vitro and tumorigenicity in mice even at non-toxic concentrations. Thus, the study evaluated the protective effect of Fernblock
® against the combination of pollution and UVA radiation in human keratinocyte and mouse melanocyte cell lines. This preclinical study demonstrated the efficacy of Fernblock
® in preventing changes in cellular structure, viability, oxidative stress, and DNA damage. These findings provide strong evidence that Fernblock
® induces the priming of cells, rapidly promoting the activation of repair mechanisms and efficient elimination of oxidized derivatives that appear in the nuclear DNA as a result of sequential exposure to BaP and UVA light
[23].
In order to enhance photoprotection, it is crucial to explore innovative methods that move beyond conventional measurements of minimal erythema dose (MED). The first evaluation focuses on demonstrating the clinical impact of assessing the immunomodulatory and preventive effects of DNA damage through in vivo studies. Thus, Schalka and Donato (2019) clinically evaluated the efficacy of an SPF 90 sunscreen with PLE in protecting against sun-induced skin damage vs. the same formulation without PLE. The presence of PLE provided additional protection, further reducing erythema, pigmentation, DNA damage, collagen breakdown and immunosuppression vs. placebo
[24]. One of the most significant findings from this study is the marked reduction of p53 in skin areas protected with SPF 90 sunscreen containing Fernblock
® indicating reduced DNA alteration. These findings were completed by Aguilera et al. (2021), who conducted an in vitro study that analyzed the impact of Fernblock
® as a part of topical sunscreen in protecting the skin from photoimmunosuppression and other detrimental biological effects caused by exposure to UV radiation. In addition to the biological activity demonstrated in previous studies, the UV absorption properties of PLE provide an additional booster effect to topical sunscreens, increasing SPF and UVAPF and enhancing protection against not only erythema and permanent pigment darkening reaction but also against immunosuppression
[25].
Regarding xeroderma pigmentosum (XP), data has shown that PLE reduces UVR-induced COX-2 levels, at least in part through activation of p53, and decreased epidermal cell proliferation induced by UVR in a mouse model
[10]. A case report on XP treatment demonstrated the efficacy of a topical film-forming medical device containing a DNA-repair enzyme, photolyase (Repairsomes
®) and very high protection UV filters in preventing the growth of skin cancer lesions in patients with XP
[26].
Finally, it is worth highlighting the recent findings of Lacerda et al. (2023) in the field of oral cancer prevention. Their study demonstrated that PLE has the ability to suppress oral cancer cell growth in vitro in SCC-9, SCC-15 and SCC-25 cell lines and prevent tumor development in vivo in mice with induced oral carcinogenesis. A decrease in the expression of Ki67 and PCNA proliferating markers as well as in N-cad (Cdh2), Vim and Twist markers related to migration was observed in tongue tissues. Therefore, PLE may have a beneficial effect on immune and inflammatory responses related to oral tumors and could be a promising natural therapeutic approach for preventing and treating oral cancer due its immunomodulatory activity
[27].
Table 1. This table provides a summary of the scientific articles published in the last five years in the field of oncodermatology, specifically highlighting the references to, and conclusions about, PLE treatment.