Keratinocyte Carcinoma and Photoprevention:The Protective Actions of Repurposed Pharmaceuticals, Phytochemicals and Vitamins

SIMPLE SUMMARY: Keratinocyte carcinoma is the most common type of cancer. Sun exposure and ultraviolet radiation are significant contributors to the development of carcinogenesis, mediated by DNA damage, increased oxidative stress, inflammation, immunosuppression and dysregulated signal transduction. Photoprevention involves using different compounds to delay or prevent ultraviolet radiation-induced skin cancer. In this review, we look at new avenues for systemic photoprevention that are based on pharmaceuticals, plant-derived phytochemicals and vitamins. We also investigate the mechanisms underlying these strategies for preventing the onset of carcinogenesis. ABSTRACT: Ultraviolet radiation (UVR) arising from sun exposure represents a major risk factor in the development of keratinocyte carcinomas (KCs). UVR exposure induces dysregulated signal transduction, oxidative stress, inflammation, immunosuppression and DNA damage, all of which promote the induction and development of photocarcinogenesis. Because the incidence of KCs is increasing, better prevention strategies are necessary. In the concept of photoprevention, protective compounds are administered either topically or systemically to prevent the effects of UVR and the development of skin cancer. In this review, we provide descriptions of the pathways underlying photocarcinogenesis and an overview of selected photoprotective compounds, such as repurposed pharmaceuticals, plant-derived phytochemicals and vitamins. We discuss the protective potential of these compounds and their effects in pre-clinical and human trials, summarising the mechanisms of action involved in preventing photocarcinogenesis

miR-122 Regulates p53/Akt Signalling and the Chemotherapy-Induced Apoptosis in Cutaneous T-Cell Lymphoma

Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by γ-secretase inhibitors (GSIs), we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sézary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL

Photocarcinogenicity of selected topically applied dermatological drugs: calcineurin inhibitors, corticosteroids, and vitamin D analogs

Topical therapies constitute the mainstay of dermatological treatments for skin disorders, such as atopic dermatitis, contact dermatitis, psoriasis, or acne. Since some of these diseases are often chronic, treatment duration may last for years and may even last the patient’s entire lifetime. Obviously, such long-term therapy may raise safety concerns, which also include the potential photocarcinogenic effect. Most patients are exposed to ultraviolet radiation (UVR) during leisure, work, vacations, or in tanning beds. Additionally, the patients may receive UVR via UVB phototherapy or psoralens plus UVA radiation (PUVA). The use of immunosuppressant’s, such as corticosteroids and calcineurin inhibitors, has markedly increased. Patients with skin diseases have benefited from both systemic and topical treatment of both new and established drugs. The issue of a black box warning by the US Food and Drug Administration has increased concerns about photocarcinogenesis, which raises the question: “Are these drugs safe?” This review focuses on the mechanism of action and photocarcinogenic potential of commonly used topical treatments, such as corticosteroids, calcineurin inhibitors, and vitamin D analogs

Oral administration of quercetin and fisetin potentiates photocarcinogenesis in UVR-exposed hairless mice

Background: Phytochemicals have demonstrated great potential as photoprotectants. Apple-derived compounds such as quercetin, fisetin, and rutin are reported to provide topical photoprotection, but oral delivery has not been explored. Purpose: To determine the photoprotective effects of oral administration of quercetin, fisetin, and rutin, and their accumulation in skin assessed through mass spectrometry imaging. Study design: Groups of 25 hairless mice (n = 125 mice) received in the daily feed 100 mg/kg quercetin, fisetin, or rutin, 600 mg/kg nicotinamide in water as a positive control, or no supplementation as the UV control. The animals were exposed to ultraviolet radiation (UVR) equivalent to 3.5 standard erythema doses thrice weekly. Method: Mass spectroemetry imaging was used to assess local skin accumulation. Results: Oral administration of quercetin and fisetin reduced the time to tumour onset (Quercetin: second and third tumour [p &lt; 0.045]; fisetin: third tumour [p &lt; 0.021]), with no observed effect for rutin. Nicotinamide delayed the onset of all three recorded tumours (p &lt; 0.0082). Results were supported by accelerated tumour growth following quercetin treatment (p &lt; 0.0069), whereas nicotinamide reduced tumour growth (p &lt; 0.00015). Skin accumulation of the compounds could not be demonstrated, suggesting other mechanisms must be explored to explain these effects on UVR-induced carcinogenesis. Conclusion: Oral administration of quercetin and fisetin to hairless mice increased UVR-induced tumour development. These results indicate a need for caution when selecting candidates for photoprotectants.</p

Anti-PD-1 immunotherapy with adjuvant ablative fractional laser displays increased tumour clearance of squamous cell carcinoma, a murine study

PD-1 checkpoint inhibitors are used as systemic immunotherapy for locally advanced and metastatic cutaneous squamous cell carcinoma (SCC); however, improved treatment efficacy is urgently needed. In this study, we aimed to investigate the effect of combining systemic anti-PD-1 treatment with adjuvant ablative fractional laser (AFL) in a spontaneous SCC mouse model. Tumours induced by ultraviolet radiation in the strain C3.Cg-Hrhr/TifBomTac were divided into four groups: anti-PD-1-antibody+AFL (n = 33), AFL alone (n = 22) anti-PD-1-antibody alone (n = 31) and untreated controls (n = 46). AFL was given at Day 0 (100 mJ/mb, 5% density), while anti-PD-1-antibody (ip, 200 μg) at Days 0, 2, 4, 6 and 8. Response to treatment was evaluated by tumour growth, survival time and by dividing response to treatment into complete responders (clinically cleared tumours), partial responders (reduced tumour growth rate compared to untreated controls) and non-responders (no decrease in tumour growth rate compared to untreated controls). The strongest tumour response was observed following the combination of systemic anti-PD-1 treatment combined with laser exposure, resulting in the highest percentage of complete responders (24%) compared with untreated controls (0%, p &lt; 0.01), AFL monotherapy (13%, p &gt; 0.05) and anti-PD-1-antibody monotherapy (3%, p &gt; 0.05). Moreover, all three treatment interventions demonstrated significantly reduced tumour growth rates compared with untreated controls (p &lt; 0.01), and the mice had significantly longer survival times (p &lt; 0.01). In conclusion, the combination treatment revealed an improved treatment effect that significantly enhanced the complete tumour clearance not observed with the monotherapies, indicating a possible additive effect of anti-PD-1 with adjuvant AFL in treatment of SCC.</p

A Skin Cancer Prophylaxis Study in Hairless Mice Using Methylene Blue, Riboflavin, and Methyl Aminolevulinate as Photosensitizing Agents in Photodynamic Therapy

The high incidence of sunlight-induced human skin cancers reveals a need for more effective photosensitizing agents. In this study, we compared the efficacy of prophylactic photodynamic therapy (PDT) when methylene blue (MB), riboflavin (RF), or methyl aminolevulinate (MAL) were used as photosensitizers. All mice in four groups of female C3.Cg/TifBomTac hairless immunocompetent mice (N = 100) were irradiated with three standard erythema doses of solar-simulated ultraviolet radiation (UVR) thrice weekly. Three groups received 2 × 2 prophylactic PDT treatments (days 45 + 52 and 90 + 97). The PDT treatments consisted of topical administration of 16% MAL, 20% MB, or 20% RF, and subsequent illumination that matched the photosensitizers’ absorption spectra. Control mice received no PDT. We recorded when the first, second, and third skin tumors developed. The pattern of tumor development after MB-PDT or RF-PDT was similar to that observed in irradiated control mice (p &gt; 0.05). However, the median times until the first, second, and third skin tumors developed in mice given MAL-PDT were significantly delayed, compared with control mice (256, 265, and 272 vs. 215, 222, and 230 days, respectively; p &lt; 0.001). Only MAL-PDT was an effective prophylactic treatment against UVR-induced skin tumors in hairless mice