Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma.

To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), we combined single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging from a series of human cSCCs and matched normal skin. cSCC exhibited four tumor subpopulations, three recapitulating normal epidermal states, and a tumor-specific keratinocyte (TSK) population unique to cancer, which localized to a fibrovascular niche. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing TSK cells as a hub for intercellular communication. Multiple features of potential immunosuppression were observed, including T regulatory cell (Treg) co-localization with CD8 T cells in compartmentalized tumor stroma. Finally, single-cell characterization of human tumor xenografts and in vivo CRISPR screens identified essential roles for specific tumor subpopulation-enriched gene networks in tumorigenesis. These data define cSCC tumor and stromal cell subpopulations, the spatial niches where they interact, and the communicating gene networks that they engage in cancer.

Topically Applied therapies for the treatment of skin disease : Past Present and Future.

The purpose of this review is to summarize essential biological, pharmaceutical and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin, routes of drug absorption and their limitations is then provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory, microbial infections, skin cancers and genetic skin diseases. The complexity of topical product development through to large scale manufacture along with recommended risk mitigation approaches is then highlighted. As such topical treatments are applied externally patient preferences along with the challenges they invoke are then described and finally the future of this field of drug delivery is discussed with the emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. Significance Statement This review of the key aspects the skin, its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient populations preferences and limitations and the future with regards to new skin diseases and topical medicine approaches.

Functional heterogeneity of human skin-resident memory T cells in health and disease.

The human skin is populated by a diverse pool of memory T cells, which can act rapidly in response to pathogens and cancer antigens. Tissue-resident memory T cells (TRM ) have been implicated in range of allergic, autoimmune and inflammatory skin diseases. Clonal expansion of cells with TRM properties is also known to contribute to cutaneous T-cell lymphoma. Here, we review the heterogeneous phenotypes, transcriptional programs, and effector functions of skin TRM . We summarize recent studies on TRM formation, longevity, plasticity, and retrograde migration and contextualize the findings to skin TRM and their role in maintaining skin homeostasis and altered functions in skin disease.

CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma.

Somatic mutations in DNA-binding sites for CCCTC-binding factor (CTCF) are significantly elevated in many cancers. Prior analysis has suggested that elevated mutation rates at CTCF-binding sites in skin cancers are a consequence of the CTCF-cohesin complex inhibiting repair of UV damage. Here, we show that CTCF binding modulates the formation of UV damage to induce mutation hot spots. Analysis of genome-wide CPD-seq data in UV-irradiated human cells indicates that formation of UV-induced cyclobutane pyrimidine dimers (CPDs) is primarily suppressed by CTCF binding but elevated at specific locations within the CTCF motif. Locations of CPD hot spots in the CTCF-binding motif coincide with mutation hot spots in melanoma. A similar pattern of damage formation is observed at CTCF-binding sites in vitro, indicating that UV damage modulation is a direct consequence of CTCF binding. We show that CTCF interacts with binding sites containing UV damage and inhibits repair by a model repair enzyme in vitro. Structural analysis and molecular dynamic simulations reveal the molecular mechanism for how CTCF binding modulates CPD formation.

Nuclear IL-33/SMAD signaling axis promotes cancer development in chronic inflammation.

Interleukin (IL)-33 cytokine plays a critical role in allergic diseases and cancer. IL-33 also has a nuclear localization signal. However, the nuclear function of IL-33 and its impact on cancer is unknown. Here, we demonstrate that nuclear IL-33-mediated activation of SMAD signaling pathway in epithelial cells is essential for cancer development in chronic inflammation. Using RNA and ChIP sequencing, we found that nuclear IL-33 repressed the expression of an inhibitory SMAD, Smad6, by interacting with its transcription factor, RUNX2. IL-33 was highly expressed in the skin and pancreatic epithelial cells in chronic inflammation, leading to a markedly repressed Smad6 expression as well as dramatically upregulated p-SMAD2/3 and p-SMAD1/5 in the epithelial cells. Blocking TGF-ß/SMAD signaling attenuated the IL-33-induced cell proliferation in vitro and inhibited IL-33-dependent epidermal hyperplasia and skin cancer development in vivo. IL-33 and SMAD signaling were upregulated in human skin cancer, pancreatitis, and pancreatitis-associated pancreatic cancer. Collectively, our findings reveal that nuclear IL-33/SMAD signaling is a cell-autonomous tumor-promoting axis in chronic inflammation, which can be targeted by small-molecule inhibitors for cancer treatment and prevention.

Artificial intelligence in digital pathology of cutaneous lymphomas: A review of the current state and future perspectives.

Primary cutaneous lymphomas (CLs) represent a heterogeneous group of T-cell lymphomas and B-cell lymphomas that present in the skin without evidence of extracutaneous involvement at time of diagnosis. CLs are largely distinct from their systemic counterparts in clinical presentation, histopathology, and biological behavior and, therefore, require different therapeutic management. Additional diagnostic burden is added by the fact that several benign inflammatory dermatoses mimic CL subtypes, requiring clinicopathological correlation for definitive diagnosis. Due to the heterogeneity and rarity of CL, adjunct diagnostic tools are welcomed, especially by pathologists without expertise in this field or with limited access to a centralized specialist panel. The transition into digital pathology workflows enables artificial intelligence (AI)-based analysis of patients' whole-slide pathology images (WSIs). AI can be used to automate manual processes in histopathology but, more importantly, can be applied to complex diagnostic tasks, especially suitable for rare disease like CL. To date, AI-based applications for CL have been minimally explored in literature. However, in other skin cancers and systemic lymphomas, disciplines that are recognized here as the building blocks for CLs, several studies demonstrated promising results using AI for disease diagnosis and subclassification, cancer detection, specimen triaging, and outcome prediction. Additionally, AI allows discovery of novel biomarkers or may help to quantify established biomarkers. This review summarizes and blends applications of AI in pathology of skin cancer and lymphoma and proposes how these findings can be applied to diagnostics of CL.

Arsenic and UVR co-exposure results in unique gene expression profile identifying key co-carcinogenic mechanisms.

Changes in gene expression underlie many pathogenic endpoints including carcinogenesis. Metals, like arsenic, alter gene expression; however, the consequences of co-exposures of metals with other stressors are less understood. Although arsenic acts as a co-carcinogen by enhancing the development of UVR skin cancers, changes in gene expression in arsenic UVR co-carcinogenesis have not been investigated. We performed RNA-sequencing analysis to profile changes in gene expression distinct from arsenic or UVR exposures alone. A large number of differentially expressed genes (DEGs) were identified after arsenic exposure alone, while after UVR exposure alone fewer genes were changed. A distinct increase in the number of DEGs was identified after exposure to combined arsenic and UVR exposure that was synergistic rather than additive. In addition, a majority of these DEGs were unique from arsenic or UVR alone suggesting a distinct response to combined arsenic-UVR exposure. Globally, arsenic alone and arsenic plus UVR exposure caused a global downregulation of genes while fewer genes were upregulated. Gene Ontology analysis using the DEGs revealed cellular processes related to chromosome instability, cell cycle, cellular transformation, and signaling were targeted by combined arsenic and UVR exposure, distinct from UVR alone and arsenic alone, while others were related to epigenetic mechanisms such as the modification of histones. This result suggests the cellular functions we identified in this study may be key in understanding how arsenic enhances UVR carcinogenesis and that arsenic-enhanced gene expression changes may drive co-carcinogenesis of UVR exposure.

Bioactive C-phycocyanin exerts immunomodulatory and antitumor activity in mice with induced melanoma.

Melanoma is the most aggressive and deadly skin cancer. The difficulty in its treatment arises from its ability to suppress the immune system, making it crucial to find a substance that increases anti-tumor immunity. C-phycocyanin (C-PC) appears as a promising bioactive, with multifaceted effects against several cancers, but its efficacy against melanoma has only been tested in vitro. Therefore, we investigated C-PC's the anti-tumor and immunomodulatory action in a murine melanoma model. The tumor was subcutaneously induced in C57BL/6 mice by injecting B16F10 cells. The animals were injected subcutaneously with C-PC for three consecutive days. After euthanasia, the tumor was weighed and measured. The inguinal lymph node was removed, and the cells were stained with antibodies and analyzed by flow cytometry. The heart, brain and lung were analyzed by histopathology. C-PC increased the B cell population of the inguinal lymph node in percentage and absolute number. The absolute number of T lymphocytes and myeloid cells were also increased in the groups treated with C-PC. Thus, C-PC showed a positive immunomodulatory effect both animals with and without tumor. However, this effect was more pronounced in the presence of the tumor. Positive immune system modulation may be associated with a reduction in tumor growth in animals treated with C-PC. Administration of C-PC subcutaneously did not cause organ damage. Our findings demonstrate C-PC's immunomodulatory and anti-melanoma action, paving the way for clinical research with this bioactive.

Protein therapeutics as an emerging strategy to deal with skin cancer: A short review.

Cancer has turned into a global menace with an exponential increase in the rate of death every year. Amongst all forms of cancers, skin cancer is the one becoming more common day by day because of the increased exposure to ultraviolet rays, chemicals, pollutants, etc. Skin cancer is of three types namely basal cell, squamous cell and melanoma which is one of the most aggressive forms of cancer with a low survival rate and easy relapse. Melanoma is also notorious for being multi-drug resistant which accounts for its low survival rates in it. Many kinds of therapeutics are been practiced in the contemporary world, but among them, protein therapeutics is been emerging as a promising field with multiple molecular pathway targets that have revolutionized the science of oncology. Proteins acts as small-molecule targets for cancer cells by binding to the cell surface receptors. Proteins including bromodomain and extra-terminal domain (BET) and some toxin proteins are been tried on for dealing with melanoma targeting the major pathways including MAPK, NF-κB and PI3K/AKT. The protein therapeutics also targets the tumour microenvironment including myofibrils, lymphatic vessels etc., thus inducing tumour cell death. In the review, several kinds of proteins and their function toward cell death will be highlighted in the context of skin cancer. In addition to this, the review will look into the inhibition of the function of other inflammatory pathways by inflammasomes and cytokines, both of which have a role in preventing cancer.

Utilizing systems genetics to enhance understanding into molecular targets of skin cancer.

Despite progress made with immune checkpoint inhibitors and targeted therapies, skin cancer remains a significant public health concern in the United States. The intricacies of the disease, encompassing genetics, immune responses, and external factors, call for a comprehensive approach. Techniques in systems genetics, including transcriptional correlation analysis, functional pathway enrichment analysis, and protein-protein interaction network analysis, prove valuable in deciphering intricate molecular mechanisms and identifying potential diagnostic and therapeutic targets for skin cancer. Recent studies demonstrate the efficacy of these techniques in uncovering molecular processes and pinpointing diagnostic markers for various skin cancer types, highlighting the potential of systems genetics in advancing innovative therapies. While certain limitations exist, such as generalizability and contextualization of external factors, the ongoing progress in AI technologies provides hope in overcoming these challenges. By providing protocols and a practical example involving Braf, we aim to inspire early-career experimental dermatologists to adopt these tools and seamlessly integrate these techniques into their skin cancer research, positioning them at the forefront of innovative approaches in combating this devastating disease.

From decision to reflection: understanding the experiences and unmet care needs of patients treated with immunotherapy for melanoma in the adjuvant or metastatic setting.

BACKGROUND: Despite increased use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma, little is known about patient experiences during this treatment. This study aimed to gain an in-depth understanding of experiences and unmet care needs of patients treated in the adjuvant or metastatic setting for advanced melanoma regarding their ICI treatment trajectory. METHODS: Interviews and focus groups were conducted among 35 patients treated with ICIs in the adjuvant setting for completely resected stage III (n = 14), or in the metastatic setting for irresectable stage IV (n = 21) melanoma. A thorough thematic content analysis was conducted. RESULTS: Three main themes were identified. When (1) dealing with uncertainty in the decision-making process, adjuvant patients explored the pros and cons, whereas metastatic patients considered immunotherapy their only viable option. Both groups expressed the need for additional guidance. In (2) navigating the immunotherapy course, both perceived the trajectory as intense, experienced a major impact on their and their (close) relatives' lives, and felt the need to (re)gain control. When (3) looking back on the immunotherapy experience, metastatic patients generally felt relieved, while among adjuvant patients, feelings of doubt regarding their choice for ICIs were also reported. CONCLUSIONS: ICI treatment is perceived as intensive for both patient groups, facing both comparable and distinct challenges throughout the treatment trajectory, underscoring the need for stage-specific, individualised guidance. Options regarding flexible follow-ups, low-threshold contact and psychosocial support throughout the treatment trajectory should be explored.

Glucagon like peptide-1 receptor agonists and the risk of skin cancer among patients with type 2 diabetes: Population-based cohort study.

AIMS: The objective of this study was to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink (2007-2019), we assembled two new-user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP-1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP-1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. RESULTS: Compared with sulfonylureas, GLP-1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person-years, respectively; HR 0.96, 95% CI 0.53-1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person-years, respectively; HR 1.03, 95% CI 0.80-1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. CONCLUSIONS: In this population-based cohort study, GLP-1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas.

Role of Insulin Use and Social Determinants of Health on Non-melanoma Skin Cancer: Results From the Behavioral Risk Factor Surveillance System.

BACKGROUND: Non-melanoma skin cancer (NMSC) is a frequent type of malignancy with a steadily increasing incidence rate worldwide. Although NMSC was shown to be associated with diabetes, no studies have addressed the extent to which insulin use influences the risk of NMSC in light of social determinants of health (SDOH). We conducted a quantitative study that examined the interplay between insulin use, SDOH, additional covariates, and NMSC among individuals with diabetes. METHODS: We based our analysis on the 2020 Behavioral Risk Factor Surveillance System (BRFSS), a national survey conducted yearly in the US. We performed weighted chi-squared test, logistic regression, and survival analyses on 8685 eligible participants with diabetes enrolled in the BRFSS. RESULTS: Kaplan Meier survival curves showed higher probability of NMSC event-free survival for participants with diabetes using insulin compared to participants with diabetes not using insulin (log-rank test P < .001). Significant associations were detected between insulin use and reduced odds of NMSC (OR .56; 95% CI: .38-.82), and decreased hazard (HR .36; 95% CI: .21-.62), along with indices of SDOH. CONCLUSIONS: Our findings suggest that socioeconomic differences related to the healthcare system and behavioral patterns are linked to discrepancies in the use of insulin and the development of NMSC.

Exploring the role of cancer fatalism and engagement with skin cancer genetic information in diverse primary care patients.

OBJECTIVE: To broaden the currently limited reach of genomic innovations, research is needed to understand how psychosocial and cultural factors influence reactions to genetic testing in diverse subgroups. Cancer fatalism is important in cancer prevention and deserves theoretical and empirical attention in the context of genomics and behavior change. METHODS: The current study employed data from a randomized controlled trial (N = 593) offering skin cancer genetic testing (using the melanocortin-1 receptor [MC1R] gene) in primary care in Albuquerque, New Mexico, USA. We examined interrelations of cancer fatalism with demographics, general health beliefs, perceived risk, perceived control, sun protection and skin screening behaviors and cancer worry in the skin cancer context stratified across Hispanic versus non-Hispanic ethnicity, and examined cancer fatalism as a moderator of intervention effects on study primary outcomes, including 3-month sun protection, cancer worry and perceived risk. RESULTS: Cancer fatalism was significantly related to the perception of control over skin cancer risk behaviors (ps ≤ 0.01) and demographics (ethnicity, education, health literacy; ps < 0.05), but not consistently related to general health beliefs or risk perception. Cancer fatalism did not moderate intervention effects on primary outcomes, except those with higher cancer fatalism randomized to intervention had higher levels of 3-month cancer worry (p = 0.019). CONCLUSIONS: These findings will guide future work considering the role of cancer fatalism in use of genomic technologies in the general population. This work anticipates strategies required to address cancer fatalism as translational genomics becomes more commonly available to diverse general population subgroups.

Single-Photon Emission Computed Tomography/Computed Tomography Utilization for Extremity Melanomas at a High-Volume Center.

INTRODUCTION: Planar lymphoscintigraphy (PL) is commonly used in mapping before sentinel lymph node biopsy (SLNB) for invasive cutaneous melanoma. Recently, single-photon emission computed tomography (SPECT)/ computed tomography (CT) has been utilized, in addition to PL, for detailed anatomic information and detection of sentinel lymph nodes (SLNs) outside of the primary nodal basin in truncal and head and neck melanoma. Following a protocol change due to COVID-19, our institution began routinely obtaining both PL and SPECT-CT imaging for all melanoma SLN mapping. We hypothesized that SPECT-CT is associated with higher instances of SLNBs from "nontraditional" nodal basins (NTNB) for extremity melanomas. METHODS: Patients with extremity melanoma (2017-2022) who underwent SLNB were grouped into SPECT-CT with PL versus PL alone. Outcomes were total SLNs removed, + or-SLN status, total NTNB sampled, and postoperative complication rate. Poisson regression and logistic regression models were used to assess association of SPECT-CT with patient outcomes. RESULTS: Of 380 patients with extremity melanoma, 42.11% had SPECT-CT. There were no differences between the groups with regards to age at diagnosis or sex. From 2020 to 2022, all patients underwent SPECT-CT. SPECT-CT was associated with increased odds of SLNB from an NTNB, (odds ratio = 2.39 [95% confidence interval: 1.25-4.67]). There was no difference in odds of number of SLNs sampled, SLN positivity rate, or postoperative complication rate with SPECT-CT. CONCLUSIONS: Routine SPECT-CT was associated with higher incidence of SLNB in NTNB but did not increase number of SLNs removed or SLN positivity rate. The added value of routine SPECT-CT in cutaneous melanoma of the extremities remains to be defined.

Natural dyes developed by microbial-nanosilver to produce antimicrobial and anticancer textiles.

Developing special textiles (for patients in hospitals for example) properties, special antimicrobial and anticancer, was the main objective of the current work. The developed textiles were produced after dyeing by the novel formula of natural (non-environmental toxic) pigments (melanin amended by microbial-AgNPs). Streptomyces torulosus isolate OSh10 with accession number KX753680.1 was selected as a superior producer for brown natural pigment. By optimization processes, some different pigment colors were observed after growing the tested strain on the 3 media. Dextrose and malt extract enhanced the bacteria to produce a reddish-black color. However, glycerol as the main carbon source and NaNO3 and asparagine as a nitrogen source were noted as the best for the production of brown pigment. In another case, starch as a polysaccharide was the best carbon for the production of deep green pigment. Peptone and NaNO3 are the best nitrogen sources for the production of deep green pigment. Microbial-AgNPs were produced by Fusarium oxysporum with a size of 7-21 nm, and the shape was spherical. These nanoparticles were used to produce pigments-nanocomposite to improve their promising properties. The antimicrobial of nanoparticles and textiles dyeing by nanocomposites was recorded against multidrug-resistant pathogens. The new nanocomposite improved pigments' dyeing action and textile properties. The produced textiles had anticancer activity against skin cancer cells with non-cytotoxicity detectable action against normal skin cells. The obtained results indicate to application of these textiles in hospital patients' clothes.

Curcumin modulates purinergic signaling and inflammatory response in cutaneous metastatic melanoma cells.

Cutaneous melanoma (CM) poses a therapeutic challenge due to its aggressive nature and often limited response to conventional treatments. Exploring novel therapeutic targets is essential, and natural compounds have emerged as potential candidates. This study aimed to elucidate the impact of curcumin, a natural compound known for its anti-inflammatory, antioxidant, and anti-tumor properties, on metastatic melanoma cells, focusing on the purinergic system and immune responses. Human melanoma cell line SK-Mel-28 were exposed to different curcumin concentrations for either 6 or 24 h, after which we assessed components related to the purinergic system and the inflammatory cascade. Using RT-qPCR, we assessed the gene expression of CD39 and CD73 ectonucleotidases, as well as adenosine deaminase (ADA). Curcumin effectively downregulated CD39, CD73, and ADA gene expression. Flow cytometry analysis revealed that curcumin significantly reduced CD39 and CD73 protein expression at specific concentrations. Moreover, the A2A receptor's protein expression decreased across all concentrations. Enzymatic activity assays demonstrated that curcumin modulated CD39, CD73, and ADA activities, with effects dependent on concentration and duration of treatment. Extracellular ATP levels increased after 24 h of curcumin treatment, emphasizing its role in modulating hydrolytic activity. Curcumin also displayed anti-inflammatory properties by reducing NLRP3 gene expression and impacting the levels of key inflammatory cytokines. In conclusion, this study unveils the potential of curcumin as a promising adjuvant in CM treatment. Curcumin modulates the expression and activity of crucial components of the purinergic system and exhibits anti-inflammatory effects, indicating its potential therapeutic role in combating CM. These findings underscore curcumin's promise and warrant further investigation in preclinical and clinical settings for melanoma management.

Rural-urban differences in meeting of physical activity recommendations by sun exposure and protection behaviors in the United States.

OBJECTIVE: To examine associations between sun protection behaviors and physical activity (PA) by rural and urban residence in the United States. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (2013-2018), restricting to participants ages 20-59 with sun behavior data. Sunburns, sun exposure, and sun protection measures were dichotomized (yes/no): ≥1 sunburn in the past year, 2+ hour outside during workdays or non-workdays, and never/rarely/sometimes using sunscreen, wearing long sleeves, and staying in the shade. Meeting PA recommendations (yes/no) was defined as ≥150 min of vigorous/moderate or ≥ 75 min vigorous PA per week. Associations between sun behaviors and PA were analyzed using logistic regression models, which accounted for survey-weights and potential confounders, and stratified by rural-urban status. RESULTS: Rural and urban individuals meeting PA recommendations had greater odds of spending 2+ hour outside during workdays (OR: 2.26 [1.88, 2.74] and 3.95 [2.72, 5.73]) and non-workdays (OR: 2.06 [1.78, 2.38] and 3.33 [2.47, 4.46]). Among urban residents, odds of staying in the shade were lower among those who met PA recommendations (OR: 0.78 [0.66, 0.92]). We did not observe differences in sunburns or other sun behaviors by PA status, regardless of rurality. CONCLUSIONS: Meeting PA recommendations was associated with greater sun exposure in both rural and urban populations. Additional exercise location (indoors/outside) data is needed to inform PA and skin cancer prevention interventions to reduce unintended increases in sun exposure and reductions in PA, respectively, especially among rural populations.

Oral intake of bucillamine, carvedilol, metformin, or phenformin does not protect against UVR-induced squamous cell carcinomas in hairless mice.

Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral photoprotection aims to reduce incidence rates through oral intake of photoprotective compounds. Recently, drug repurposing has gained traction as an interesting source of chemoprevention. Because of their reported photoprotective properties, we investigated the potential of bucillamine, carvedilol, metformin, and phenformin as photoprotective compounds following oral intake in UVR-exposed hairless mice. Tumour development was observed in all groups in response to UVR, with only the positive control (Nicotinamide) demonstrating a reduction in tumour incidence (23.8%). No change in tumour development was observed in the four repurposed drug groups compared to the UV control group, whereas nicotinamide significantly reduced carcinogenesis (P = 0.00012). Metformin treatment significantly reduced UVR-induced erythema (P = 0.012), bucillamine and phenformin increased dorsal pigmentation (P = 0.0013, and P = 0.0005), but no other photoprotective effect was observed across the repurposed groups. This study demonstrates that oral supplementation with bucillamine, carvedilol, metformin, or phenformin does not affect UVR-induced carcinogenesis in hairless mice.

Cyclic AMP-regulatory element-binding protein: a novel UV-targeted transcription factor in skin cancer.

Common therapeutics in relation to melanoma and non-melanoma cancers include the use of kinase inhibitors. The long-term benefits of kinases, however, are limited by development of drug resistance. An alternative approach for treatment would be to focus on transcription factors. Cyclic AMP-regulatory element-binding protein (CREB) is a transcription factor that is commonly overactivated or overexpressed in many different cancers including skin cancer. Ultraviolet radiation (UVR), one of the main causes of skin cancer, can activate CREB in both melanocytes and keratinocytes. In addition, CREB has been found to be activated in skin cancers. Considering the prominent role that CREB plays in skin cancers, the studies reviewed herein raise the possibility of CREB as a potential prognostic and diagnostic marker of skin cancer and a novel target for therapeutic intervention.