Eleven studies reported on the administration of polyphenolic compounds for the treatment of AKs, BCC and SCC and actinic ageing, as well as prevention of UVB-induced damage to the skin (CPDs formation, erythema, etc.). Five out of the 11 were clinical trials and 6 were preclinical studies.

Regarding clinical trials, Polypodium leucotomos extract (PLE), polyphenols from black tea, and a combination of rosemary and grapefruit polyphenols were administered as dietary supplements for the prevention of AKs, UV-induced erythema and lipid peroxidation, the improvement of signs of photoaging, and the reduction of incidence of BCCs and SCCs. Overall, these studies included a total of 1595 patients, with a mean age of 51.7 years, ranging from 28 to 85 years. Data showed that 54.4% (n=867 women/1595) of participants were women.

Preclinical experimentation included the evaluation of PLE, flavonols (quercetin, kaempferol and galangin), and extracts obtained from the leaves of Hamamelis virginiana and lotus to prevent genomic UV-induced damage and formation of CPDs, to inhibit actinic aging and progression of AKs and to suppress neoplastic transformation.

A recent clinical trial analyzed the effect of PLE, orally administered in combination with topical sun protection SPF100, in subjects with severe photoaging and history of at least three AKs. The combination of topical and oral PLE at a daily dose of 240mg led to an improvement in AKASI and AK-FAS parameters and reduced the number of new AKs and the need for additional intervention to a greater degree than in the case of topical treatment alone.21 Thus, combination of topical and oral photoprotection with PLE can help prevent the onset of further lesions in sun-exposed areas of the skin.21

Additionally, this extract has not only demonstrated the effectiveness of skin cancer prevention but also skin cancer treatment. A clinical trial assessed whether PLE could improve the effectiveness of PDT in decreasing the recurrence of Aks.25 For this purpose, patients with at least two visible AKs on the scalp were categorized into two groups: one receiving two sessions of MAL-PDT alone, and the other receiving the same two PDT sessions along with oral PLE supplementation (daily doses of 480mg, starting 1-week after last session) for 6 months. Clinical, dermoscopic, and fluorescent image data showed that at the 6-month follow-up, PDT plus oral PLE resulted in a higher clearance rate than PDT alone. Thus, PLE supplementation appears to enhance long-term PDT effectiveness, significantly reducing the number of Aks.25

A recent study performed by Gandarillas et al. using primary human epidermal keratinocytes suggests that PLE has the capacity to induce the repair of genomic damage induced by UV light.26 Treatment with PLE promotes the expression of H2AX and p53 – triggering DNA repair machinery – and slows down the progression of keratinocytes through G2/M transition (favoring the G2/M checkpoint control). The authors observed that PLE treatment extended the duration of DNA repair phase in stem cells, enhancing their ability to regenerate. Additionally, increasing the DNA repair signal should decrease the number of cells undergoing differentiation after cell division. Premature differentiation of keratinocytes is a factor in skin aging. Nevertheless, cells treated with PLE showed greater resilience vs aging, maintaining a higher potential for self-renewal and proliferation after treatment. Thus, this boost to DNA repair signaling could prolong the renewal capacity of stem cells and diminish the proportion of cells undergoing differentiation post-mitotically.26

Regarding the importance to evaluate the impact of DNA damage, Torricelli et al. also evaluated the preventive role of PLE vs UV-induced damage.27 Their preclinical trial was performed in a model of reconstructed human epidermis (RHE) exposed to UVB and showed that treatment with PLE reduces the expression of p53 and p21, which correlated with the reduction of sunburn cells formation, and prevents the upregulation of proliferating proteins (EFG, Ki67) and formation of CPDs.27 In connection with the formation of CPDs, Portillo-Esnaola et al.28 analyzed the role of Fernblock® (FB; the standardized hydrophilic extract from the leaves of P. leucotomos) in preventing the formation of these photoproducts in UVA-exposed murine melanocytes. Results indicated that treatment with FB decreases levels of both reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus reducing the formation of dark-CPDs. Both antioxidant and scavenging properties shown by FB make this compound an optimal candidate to be included in sunscreens formulations.28

A prospective study explored whether there is a relationship between drinking black tea and the occurrence of BCC and SCC. The study estimated black tea consumption in 1325 volunteers from 1992, 1994 and 1996 and recorded all skin cancers diagnosed in these volunteers from 1997 through 2007. Despite this comprehensive analysis, results showed no significant association between black tea consumption and the incidence of BCC or SCC. Therefore, black tea consumption cannot be considered as part of a preventive strategy to reduce the risk of skin cancer.29

Additional polyphenol sources have been investigated in various studies to explore their role in preventing UV-induced skin damage, offering promising avenues for skin protection and cancer prevention. Pérez-Sánchez et al.,30 demonstrated that a combination of rosemary and citrus bioflavonoids from grapefruit (Nutroxsun®) increased cell survival, reduced intracellular ROS, prevented DNA damage, and decreased chromosomal aberrations in UVB-exposed human keratinocytes. Moreover, oral administration of this combination to human volunteers resulted in a significant increase in minimal erythema dose (MED), suggesting its potential as an oral photoprotection strategy.30 Similarly, the clinical trial conducted by Nobile et al.31 indicated that intake of the same combination of rosemary and grapefruit (Nutroxsun®) by volunteers with clinical signs of photoaging also lead to a decrease in skin redness and peroxidation of basal lipids and an increase in MED, as well as a decrease of wrinkle depth and an increase in skin elasticity.31 In another study, Maini et al.32 revealed the effectiveness of quercetin, kaempferol, and galangin in preventing UVR-induced CPD formation in artificial skin. Additionally, quercetin significantly reduced the secretion of MMP-1 and TNF-α. These findings suggest that these flavonols, traditionally considered antioxidants, could serve as a promising tool to prevent DNA damage associated with AK progression.32 Regarding skin elastosis, characterized by the accumulation of abnormal elastic fibers in the skin, Pain et al.33 evaluated the capacity of a leaf extract from H. virginiana to counteract the elastin/lysyl oxidase (LOXL1) enzyme imbalance and elafin synthesis, a marker of elastotic aggregates, triggered by UV light exposure. This imbalance contributes to the accumulation of nonfunctional elastin fiber aggregates, leading to actinic aging. For that purpose, they measured LOXL1 and elafin expression in both human fibroblasts and human skin biopsies that were exposed to UVA radiation and treated with H. virginiana extract. The extract increased LOXL1 expression and decreased elafin synthesis, resulting in a decrease in aggregates and restoration of functional elastic fibers.33 Phytochemicals in the diet possess chemopreventive properties that can hinder or delay the process of carcinogenesis. The lotus leaf, a traditional medicinal plant rich in numerous polyphenols, is a notable example. Lotus leaf extract, rich in phenolics and quercetin, showed strong potential in inhibiting skin carcinogenesis in murine skin JB6 P+ cells. It activated the NRF2 pathway, boosting antioxidant and detoxification enzymes like HO-1, NQO1, and UGT1A1, while also reducing DNA methylation levels. This suggests that this extract may hinder neoplastic transformation by regulating the NRF2 pathway and epigenetic processes.34

Thus, the exploration of polyphenolic compounds, conducted through both clinical and preclinical studies, reveals their potential in preventing and treating various skin conditions, including AKs, BCCs, SCCs, and actinic aging. Clinical trials have demonstrated the efficacy of supplements such as Polypodium leucotomos extract (PLE), in improving skin health and reducing the risk of skin cancers. Preclinical experiments highlight the role of polyphenols in inhibiting DNA damage, suppressing neoplastic transformation, and protecting against UV-induced skin damage. However, not all polyphenols exhibit significant protective effects, as evidenced by the lack of association between black tea consumption and the incidence of BCC or SCC. Despite this, research into polyphenols from sources like rosemary, citrus bioflavonoids, lotus leaf extract, and H. virginiana extract offers promising avenues for developing effective photoprotective and chemopreventive strategies vs skin cancer and actinic aging.

The selected studies provide valuable insights into the potential of nicotinamide (NAM) as a preventive and therapeutic agent for skin cancer. In 2015,35 Chen et al. conducted a clinical trial with 386 high-risk patients with a past medical history of at least two NMSCs in the previous 5 years. Participants were randomized to receive oral NAM (500mg) or placebo twice daily for 12 months. The evaluation by dermatologists revealed promising results, with a 20% lower rate of BCCs, a 30% lower rate of new SCCs, and a 13% lower rate of new AKs in the NAM group vs the placebo group.35 In another clinical trial, Chen et al.36 explored the safety and efficacy profile of NAM in preventing the appearance of BCCs and SCCs in immunosuppressed renal transplant recipients with a history of at least two NMSCs in the previous 12 months. Patients were randomized to receive oral NAM (500mg) or placebo and skin lesions (AKs, BCCs, and SCCs) were recorded twice monthly up to 6 months by dermatologists. In this study, a reduction of BCC and SCC (35%) and of AKs (16%) were observed in the NAM vs the placebo group, yet results were not statistically significant.36 In 2023, Allen et al.,37 also explored the efficacy of NAM in skin cancer chemoprevention in OTR patients. A total of 158 adults who had had at least two histologically confirmed keratinocyte cancers in the past 5 years and had undergone kidney, liver, or heart or lung transplantation at least 12 months previously were enrolled. These participants randomly received oral NAM (500mg) or matched placebo twice daily for 12 months. Evaluation by dermatologists revealed no significant differences in SCC, BCC and AK counts between the NAM and placebo group, concluding that oral NAM did not prevent the appearance of new keratinocyte cancers or AKs in immunosuppressed solid OTR.37 Camillo et al. in 2022,38 also analyzed the potential role of NAM as chemopreventive agent from a preclinical viewpoint. They obtained skin biopsies from 30 patients with precancerous skin lesions, dysplastic nevi, NMSCs, and/or cutaneous melanoma. From these biopsies, they isolated field cancerization human primary keratinocytes (FC-HPKs) for further study. Their findings demonstrated that NAM efficiently decreased ROS levels and the expression of oxoguanine glycosylase (OGG)1 (responsible for 8-oxoG excision) in UVB-exposed FC-HPKs, thus protecting from oxidative stress and DNA damage induced by UVB irradiation. Furthermore, NAM prevented UVB-induced inflammation via modulation of the expression of proinflammatory cytokines (especially IL1b and TNFα). These results suggest that NAM could be a useful molecule for chemoprevention of NMSCs and the treatment of field cancerization.38

All these contrasting findings about NAM highlight the complexity of the role of this compound in skin cancer prevention and underscore the need for further research to elucidate its mechanisms of action and potential therapeutic applications.

Another derivative of B vitamin is folate (vitamin B9). A prospective study performed by Donnenfeld et al.,39 aimed to investigate the impact of dietary folate intake on the risk of developing skin cancer. During the study period spanning from 1994 through 2002, 5880 volunteers completed a dietary record every 2 months, detailing all foods and beverages consumed within 24-h periods. Throughout the trial, all diagnosed skin cancer lesions were meticulously documented. At the end of trial, a total of 144 incident skin cancer cases were diagnosed (20 melanoma, 18 SCC, and 106 BCC). Based on these results and on erythrocyte folate analyses – which were performed on all participants at years 2 and 5 – it was concluded that dietary folate intake was associated with an increased risk of BCC skin cancer. This association was more specifically observed in women.39

Freitas et al.,40 conducted a study with two phases to investigate the effects of an antioxidant therapy (consisting of a complex with vitamin C, vitamin E and zinc) in the oxidative stress status of patients with a past medical history of NMSC. In phase I, plasma concentrations of several oxidative biomarkers were analyzed in 60 NMSC patients (previously treated with surgery) and 24 healthy volunteers. Results showed that NMSC patients had higher levels of all assessed oxidative markers vs healthy volunteers. In phase II, NMSC patients were randomized to receive oral antioxidant complex or placebo once daily for 2 months. In this case, evaluation of stress biomarkers after supplementation period did not reveal significant differences across groups. In conclusion, antioxidant therapy based on these vitamins did not significantly reduce levels of oxidative stress biomarkers.40 Another in vitro study performed by Lin et al.41 explored the role of vitamin C on UV-induced apoptosis in cells from a human epidermoid carcinoma and p16/p21-knockout fibroblasts. As results showed, vitamin C effectively antagonized UV-induced apoptosis in skin cancer cells by promoting DNA demethylation and subsequently reactivating the activation of tumor suppressor genes p16 and p21.41

Regarding vitamin D, Passarelli et al. in 2020,42 examined the effect of daily oral vitamin D or calcium supplementation on the risk of developing BCC or invasive cutaneous SCC. They enrolled a total of 2259 patients diagnosed with a colorectal adenoma in this clinical trial. Participants were randomized to receive 1 of these 4 groups: (1) 1000IU/day of vitamin D3; (2) 1200mg/day of calcium carbonate; (3) both vitamin D3 and calcium carbonate; (4) placebo. Supplementation period was 3 or 5 years, and during that period the incidence of BCC or SCC was reported. Results indicated that while BCC incidence was not related to the supplementation administered, calcium carbonate supplementation – alone or in combination with vitamin D – seemed to reduce the incidence of SCC, suggesting the preventive role of calcium in the development of SCC.42

Therefore, the investigation into vitamin supplementation for the prevention and treatment of various skin conditions presents diverse findings and implications. Clinical trials have explored the potential benefits of NAM, folate (vitamin B9), antioxidant complexes, and vitamin D3 in reducing the risk of precancerous lesions, NMSCs, and melanocytic lesions. Conflicting results from these trials highlight the complexity of the role of such vitamins in skin cancer prevention, particularly evident in the case of NAM, where its efficacy varies across different studies. Preclinical studies further elucidate the mechanisms underlying the protective effects of these vitamins, such as NAM's ability to reduce oxidative stress and inflammation and folate's association with an increased risk of skin cancer, especially in women. Additionally, vitamin C shows promise in modulating UV-induced apoptosis and promoting DNA demethylation in skin cancer cells. The role of vitamin D supplementation, particularly calcium carbonate, appears to have a preventive effect on the incidence of invasive cutaneous SCC. Overall, these findings underscore the importance of continued research to better understand the mechanisms of action and optimize the therapeutic potential of vitamin supplementation in skin cancer prevention and treatment.