Chemoprevention Of Skin Cancer Research Articles

Abstract 2985: RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling

Abstract Basal cell carcinoma (BCCs) and Squamous cell carcinoma (SCCs) are the most common skin neoplasms in the Caucasian population. UVB is considered as the most important etiologic factor for these cancers. The molecular mechanism regulating pathogenesis of these neoplasms is not well defined. Similar to humans Ptch+/−/SKH-1 mice develop both BCCs and SCCs, following chronic UVB-irradiation. We used TaqMan-based Open Array platform containing 796 miRNAs (miRs) to profile miRs associated with BCCs and SCCs. Pathway enrichment analysis was performed using miRPathDB databases at https://mpd.bioinf.uni-sb.de/. 81 miRNAs were differentially expressed in BCCs, of which 54 miRs had cumulative frequency of greater than 1 (FC>1) and 78 miRs were differentially expressed in SCCs, out of which 20 miRs had FC>1. miR-721 was highly induced (123.75 fold, P<0.0430) in BCCs followed by miR-2182, miR-21, miR-451, miR-124a, and miR-685 while downmodulated miRs includes miR-1, miR-133a, miR-133b, and miR-196b. Likewise, miR-21 had maximum fold induction (45.94, P<0.007) in SCCs followed by miR-2182, miR-685, miR-1938, miR-2138, and miR-451 while miR-196b, miR196c, and miR-1 were downmodulated. Kegg pathways analysis revealed that altered miRs belong to Hepatitis B, HIF-1, FoxO, chemokine, adipocytokine, NFκB, cholinergic and TLR signaling pathways. WikiPathway database showed alterations in miRs associated with neovascularization process, Notch Signaling, Pregnane X receptor, α6β4, and BDNF-TrkB signaling. To further investigate the importance of pathways associated with tumor progression, we profiled miRs in residual BCCs and SCCs procured from UAB30 treatment groups. The chemopreventive agent UAB30 is an RXR agonist. In BCCs, UAB30 treatment significantly downmodulated UVB-upregulated miRs. These miRs includes miR-210, miR-546, miR-324-3p, miR-706 and miR-1898. However, UAB30 treatment significantly upregulates miR-380-5p which was downmodulated by UVB-alone. These miRs were involved in immune regulation, Fanconi anemia pathways, FoxO signaling, prostate cancer and p53 signaling. In SCCs, UAB30 treatment significantly reversed the expression of various miRs which were downmodulated by UVB. These miRs were miR-24, miR-26a, miR-30c, miR-328, miR-30b, miR-495 and miR-2100. The expression of miR-21a-3p was downmodulated by UAB30 in SCCs of UVB-exposed group relative to SCCs of untreated but UVB-exposed group. These miRs belong to pathways involved in cell cycle progression, p53 signaling, viral carcinogenesis, Hepatitis B, Melanoma, Prostate cancer, FoxO and PI3K-AKT signaling. In summary, this profiling of miRs in UVB-induced BCC and SCC represents the underlying epigenetic mechanisms that regulate various signaling pathways in these cancers. Our data also show the critical role of miRs responsive to UAB30 treatment in cancer chemoprevention. Citation Format: Mahendra P. Kashyap, Rajesh Sinha, Craig A. Elmets, Venkatram R. Atigadda, Mohammad Athar. RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2985.

Betanin Attenuates Epigenetic Mechanisms and UV-Induced DNA Fragmentation in HaCaT Cells: Implications for Skin Cancer Chemoprevention.

Dermal photoaging refers to the skin's response to prolonged and excessive ultraviolet (UV) exposure, resulting in inflammation, changes to the tissue, redness, swelling, and discomfort. Betanin is the primary betacyanin in red beetroot (Beta vulgaris) and has excellent antioxidant properties. Yet, the specific molecular mechanisms of betanin in HaCaT cells have not been fully clarified. The objective of this study was to investigate the activity of betanin and the underlying mechanisms in HaCaT cells; furthermore, in this study, we explored the protective effect of various concentrations of betanin against UVB irradiation on HaCaT cells. Additionally, we assessed its influence on the transcription of various epigenetic effectors, including members of the DNA methyltransferase (DNMT) and histone deacetylase (HDAC) families. Our findings demonstrate a notable downregulation of genes in HaCaT cells, exhibiting diverse patterns upon betanin intake. We considered the involvement of DNMT and HDAC genes in distinct stages of carcinogenesis and the limited exploration of the effects of daily exposure dosages. Our results indicate that betanin may protect the skin from damage caused by UV exposure. Further investigation is essential to explore these potential associations.

Non-Steroidal Anti-Inflammatory Drugs in the Chemoprevention of Non-Melanoma Skin Cancer

Skin cancer, which includes melanoma and non-melanoma cancer types (basal cell and squamous cell carcinomas), is the most common type of neoplasia worldwide with massive calls for exploring chemoprevention strategies. Research suggests that chronic inflammation is a critical component of cancer progression in which over expression of COX-2 has been reported in many cancer studies. Non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit COX enzymes have been investigated for skin cancer chemoprevention both in vitro and in vivo. We have searched the association between NSAIDs and non-melanoma skin cancer in Pub-Med and Embase database in particular for animal, cell lines, and human studies. In animal and skin cancer cell line research studies, NSAIDs have been shown to have a chemoprotective role in non-melanoma skin cancer through various reported mechanisms. However, clinical data results with regards to non-melanoma cancer has been controversial due to the absence of large scale randomised clinical trials. To sustain the idea for NSAIDs role as chemo-preventative agents, further robust investigations with large trial number are required in order to consolidate epidemiological findings with the in vitro data results.

Recent Advances in Clinical Research for Skin Cancer Chemoprevention.

Neoplasm arising from the keratinocytes or melanocytes in the skin is the most prevalent type of cancer in the United States and worldwide. Since ultraviolet (UV) radiation may be a causing factor for several types of skin cancer, effective strategies to manage skin cancer include preventive measures such as minimizing exposure to UV and applying sunscreens. However, the effect of sunscreen in reducing skin cancer incidence remains uncertain. An alternative approach to prevent skin cancer is chemoprevention, which is defined as using either natural products or synthetic compounds to inhibit, delay, or reverse the development of cancer. Preclinical studies have demonstrated the effectiveness of multiple pharmacological agents and dietary supplements. However, whether preclinical findings can be translated into clinical application is unknown. This review evaluates the state of recent clinical trials investigating chemopreventive agents focusing on skin cancer to compare the target populations, interventions, endpoints, and outcomes of these trials. The ClinicalTrials and PubMed databases were searched for their available literature using the key words "skin cancer" and "chemoprevention". The objective of this review is to provide updated information on the effectiveness and side effects of promising chemopreventive agents in human subjects and to identify research gaps.

Transfersome Encapsulated with the R-carvedilol Enantiomer for Skin Cancer Chemoprevention.

The R-carvedilol enantiomer, present in the racemic mixture of the chiral drug carvedilol, does not bind to the β-adrenergic receptors, but exhibits skin cancer preventive activity. For skin delivery, R-carvedilol-loaded transfersomes were prepared using various ratios of drug, lipids, and surfactants, and characterized for particle size, zeta potential, encapsulation efficiency, stability, and morphology. Transfersomes were compared for in vitro drug release and ex vivo skin penetration and retention. Skin irritation was evaluated by viability assay on murine epidermal cells and reconstructed human skin culture. Single-dose and repeated-dose dermal toxicity was determined in SKH-1 hairless mice. Efficacy was evaluated in SKH-1 mice exposed to single or multiple ultraviolet (UV) radiations. Transfersomes released the drug at a slower rate, but significantly increased skin drug permeation and retention compared with the free drug. The transfersome with a drug-lipid-surfactant ratio of 1:3:0.5 (T-RCAR-3) demonstrated the highest skin drug retention and was selected for further studies. T-RCAR-3 at 100 µM did not induce skin irritation in vitro and in vivo. Topical treatment with T-RCAR-3 at 10 µM effectively attenuated acute UV-induced skin inflammation and chronic UV-induced skin carcinogenesis. This study demonstrates feasibility of using R-carvedilol transfersome for preventing UV-induced skin inflammation and cancer.

An update on clinical trials for chemoprevention of human skin cancer.

The pathophysiology of skin cancer is complex, with multiple factors contributing to its development. The proactive treatment of skin cancer has been investigated in the form of chemoprevention of cutaneous malignancies in clinical trials. Chemoprevention is the use of natural or pharmacologic agents that prevent or reverse skin cancer development. Multiple trials have arisen over the past decades to explore the efficacy of specific agents to halt the progression of UV radiation damage. This comprehensive review article aims to assess clinical trials performed with chemopreventive agents for melanoma and nonmelanoma skin cancers. The following compounds were most often used in these trials: nicotinamide, retinoids, polyphenolic antioxidants, COX-2 selective inhibitors, non-steroidal anti-inflammatory drugs, difluoromethylornithine, and 5-fluorouracil. Many agents show promise in their ability to prevent nonmelanoma skin cancer formation, with few melanoma trials demonstrating efficacy. The chemoprevention efforts aimed at skin cancer are complex; current and future trials will be instrumental in identifying therapeutic agents that pose efficacy in halting cancer development and assessing whether long-term administration is tolerable.

Sieve estimation of semiparametric accelerated mean models with panel count data

A widely adopted semiparametric model for analyzing panel count data is a proportional mean model, which may be deemed inappropriate when the proportionality assumption is violated. Motivated by the popular accelerated failure time model that relaxes such assumption, we investigate accelerated mean models for semiparametric regression analysis of panel count data. For estimation of bundled parameters, we develop a sieve least squares estimation procedure, which is robust in the sense that no distributional assumption is required for the underlying recurrent event process. Overcoming the theoretical challenges from bundled parameters, we establish the consistency and convergence rate of the proposed estimators, and derive the asymptotic normality of both the finite-dimensional estimator and the functionals of the infinite-dimensional estimator. Simulation studies demonstrate promising performances of the proposed approach, and an application to a skin cancer chemoprevention trial yields some new findings.

Abstract A022: Limonene as a vehicle in topical delivery of carvedilol for skin cancer chemoprevention

Abstract Skin cancer is currently one of the most common cancers and is defined as an abnormal growth of the skin cells. The goal of this study is to develop a topical delivery system of carvedilol with limonene as the vehicle. Limonene is a major component found in the rinds of citrus fruits and other herbs. It is one of many natural compounds that have demonstrated inhibitory activity in different types of cancers such as breast, lung, and stomach cancer. Furthermore, limonene has shown to increase skin permeation of drugs including carvedilol. The soft agar colony formation assay was used to evaluate anchorage-independent growth of JB6 mouse epidermal cells. This assay tested concentrations of carvedilol (0.1, 1.0 and 10 μM); limonene (1.0, 10, 100 and 1000 μM); and a combination of carvedilol (1.0 μM) and limonene (1.0, 10 or 100 μM). Results demonstrated that carvedilol and limonene as single treatment inhibited colony formation. The combination of carvedilol and limonene showed higher colony inhibition than single treatment, although not statistically significant. Franz diffusion cell was used to test for permeation of the drug. The device has two chambers separated by a membrane, which in this case is rat skin. The drugs, in vehicles of 40% polyethylene glycol (PEG) 400 in PBS or 40% PEG400 in PBS plus 5% limonene were applied into the donor chamber while the samples are collected through the receptor chamber as the drug permeates through the skin. The samples were collected at 16 hours, 20 hours, and 24 hours. Results showed that limonene significantly increased permeation. Therefore, our data indicate that limonene was able to increase skin permeation and the chemopreventive activity of carvedilol. This new formulation will be further examined in animal models for its efficacy against UV-induced skin cancer. Citation Format: Janell Wang, Lawrence Chao, Steven Yeung, Ying Huang. Limonene as a vehicle in topical delivery of carvedilol for skin cancer chemoprevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A022.

Promising Phyto-Antioxidant Methanolic Extract from Canarium Odontophyllum Miq. (Dabai) Leaves against UVB Induced B164A5 Melanoma Cells as a Potential Skin Chemoprevention Agent

The high incidence and mortality of skin cancer along with the development of chemotherapy resistance have urged researchers to look into alternative strategies to combat cancer. Chemoprevention is one of the well-researched strategies using natural products. Canarium odontophyllum Miq. (dabai) is a local seasonal fruit that is mainly found in Sarawak, Malaysia. The leaves of the fruit harbor many medicinal useful phytochemicals that provide a new insight for chemoprevention. The present research has been planned to study the chemopreventive activity of methanolic extract of C. odontophyllum Miq. leaves on UVB induced B164A5 melanoma cells through its antioxidant profiles. The extract displayed statistically significant (p<0.05) antioxidant activity by enhancing superoxide dismutase, SOD (1023.02 ± 106.74 U/mg protein) and catalase (0.12 ± 0.003 U/mg protein) activities compared to negative control. Low oxidative damage was also observed whereby the protein carbonyl and malondialdehyde levels were significantly reduced (p<0.05), 1.69 ± 0.296 nmol/mg protein and 1.181 ± 0.03 nmol/mg protein respectively. In conclusion, the extract exhibited a promising skin cancer chemoprevention activity through its significant antioxidant activities. These findings evidently pave the path for further investigations in chemoprevention strategy.

Is 5-fluorouracil the best candidate for topical chemoprevention of skin cancers in organ transplant recipients?

Abstract Linked Article: Hasan et al. Br J Dermatol 2022; 187:324–337.

Recent Advances in Phenolic Metabolites and Skin Cancer.

Skin cancer represents any tumor development from the cutaneous structures within the epidermis, dermis or subcutaneous tissue, and is considered to be the most prevalent type of cancer. Compared to other types of cancer, skin cancer is proven to have a positive growth rate of prevalence and mortality. There are available various treatments, including chemotherapy, immunotherapy, radiotherapy and targeted therapy, but because of the multidrug resistance development, a low success has been registered. By this, the importance of studying naturally occurring compounds that are both safe and effective in the chemoprevention of skin cancer is emphasized. This review focuses on melanoma because it is the deadliest form of skin cancer, with a significantly increasing incidence in the last decades. As chemopreventive agents, we present polyphenols and their antioxidant activity, anti-inflammatory effect, their ability to balance the cell cycle and to induce apoptosis and their various other effects on skin melanoma. Besides chemoprevention, studies suggest that polyphenols can have treating abilities in some conditions. The limitations of using polyphenols are also pointed out, which are related to their poor bioavailability and stability, but as the technology is well developed, it is possible to augment the efficacy of polyphenols in the case of melanoma.

Oral nicotinamide: The role in skin cancer chemoprevention.

The incidence of skin cancer has gradually increased in the last years and exposition to ultraviolet radiation remains the main risk factor. We performed a comprehensive review on the role of nicotinamide (NAM) in the chemoprevention of skin cancers. NAM, a water-soluble form of vitamin B3, interferes with skin carcinogenesis as it regulates immunosuppressor genes such as p53 and sirtuins and restores intracellular level of NAD+, a co-enzyme essential for energy production. Efficacy and safety of NAM was evaluated in a Phase III double-blinded control-placebo study (ONTRAC), thus demonstrating that the incidence of actinic keratoses and non-melanoma skin cancers was lower in the nicotinamide group than in placebo group. Further studies showed the efficacy of NAM also in transplanted patients and among inhabitants living in arsenic contamination areas. Despite the quick response to NAM supplementation, its intake need to be carried on chronically as the efficacy seems to vanish rapidly.

Topical Delivery of Carvedilol Loaded Nano-Transfersomes for Skin Cancer Chemoprevention.

The β-blocker carvedilol has been shown to prevent skin carcinogenesis in vitro and in vivo. Since systemic absorption of the β-blocker may cause cardiovascular disturbance, we developed a carvedilol loaded transfersome for skin-targeted delivery. Transfersomes were prepared using phospholipids and surfactants at various ratios and characterized. One formulation (F18) selected for further analysis was composed of carvedilol, soy phosphatidylcholine, and Tween-80 at a ratio of 1:3:0.5, which had a particle size of 115.6 ± 8.7 nm, a zeta potential of 11.34 ± 0.67 mV, and an encapsulation efficiency of 93.7 ± 5.1%. F18 inhibited EGF-induced neoplastic transformation of mouse epidermal JB6 P+ cells at non-toxic concentrations, while only high concentrations induced cytotoxicity in JB6 P+ and human keratinocytes HaCaT. Compared to the free drug, F18 released through the dialysis membrane and permeated through the porcine ear skin at a slower rate, but similarly depositing the drug in the epidermis and dermis of the skin. Consistently, surface application of F18 on reconstructed full-thickness human skin showed slower drug permeation, while it suppressed ultraviolet-induced DNA damage, inflammatory gene expression, and apoptosis. These data indicate that transfersome is a promising topical delivery system of carvedilol for preventing ultraviolet-induced skin damage and carcinogenesis.

Nonparametric inference for panel count data with competing risks

In survival and reliability studies, panel count data arise when we investigate a recurrent event process and each study subject is observed only at discrete time points. If recurrent events of several types are possible, we obtain panel count data with competing risks. Such data arise frequently from transversal studies on recurrent events in demography, epidemiology and reliability experiments where the individuals cannot be observed continuously. In the present paper, we propose an isotonic regression estimator for the cause specific mean function of the underlying recurrent event process of a competing risks panel count data. Further, a nonparametric test is proposed to compare the cause specific mean functions of the panel count competing risks data. Asymptotic properties of the proposed estimator and test statistic are studied. A simulation study is conducted to assess the finite sample behaviour of the proposed estimator and test statistic. Finally, the procedures developed are applied to a real data arising from skin cancer chemo prevention trial.

Chemoprevention of keratinocyte carcinoma and actinic keratosis in solid-organ transplant recipients: Systematic review and meta-analyses

To the Editor: Skin cancers account for 40% of malignancies in solid-organ transplant recipients (SOTRs), who have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC). Systemic chemoprevention is one method to mitigate this amplified risk. Acitretin, for instance, has been used to prevent keratinocyte carcinomas (KC) and actinic keratoses (AK) in SOTRs since 1995,1Bavinck J.N. Tieben L.M. Van der Woude F.J. et al.Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.J Clin Oncol. 1995; 13: 1933-1938Crossref PubMed Google Scholar but its adverse effects include mucositis, liver and lipid abnormalities, and teratogenicity.2George R. Weightman W. Russ G.R. et al.Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients.Australas J Dermatol. 2002; 43: 269-273Crossref PubMed Scopus (130) Google Scholar Nicotinamide, an amide form of vitamin B3, is a newer chemoprophylaxis with fewer adverse effects.3Chen A.C. Martin A.J. Dalziell R.A. et al.A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.Br J Dermatol. 2016; 175: 1073-1075Crossref PubMed Scopus (61) Google Scholar Here we report results of a pairwise and network meta-analyses to summarize the current evidence regarding chemoprevention. We selected studies that analyzed the efficacy of systemic chemoprevention to prevent KC/AK in patients who are SOTRs or have a history of 2 or more KCs, or both. We limited our search to placebo-controlled, randomized control trials (RCTs) that reported the number of new KC/AK in both arms. Two authors (L.Y.T., S.Y.C.T.) independently conducted the literature search, screened titles and abstracts for eligibility, and extracted data. Statistical synthesis was performed with RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). After the literature search, 6 RCTs with 734 patients were included in the quantitative synthesis (Appendix A, available via Mendeley at https://doi.org/10.17632/m6z2fzkkxn.2). Of the 6 RCTs, 3 studies with 580 patients (range, 17-192 patients) compared nicotinamide to placebo, and 3 studies with 154 patients (range, 19-35 patients) compared acitretin to placebo. Pairwise meta-analysis of all 6 RCTs using a random-effects model demonstrated a significant risk reduction with chemoprevention (Fig 1). The overall mean difference was 0.855 (95% confidence interval, 0.365-1.345; P < .001). In addition, acitretin and nicotinamide were both efficacious, with a combined mean difference of 0.792 (95% confidence interval, 0.298-1.286; P = .00168) for acitretin and a combined mean difference of 4.239 (95% confidence interval, 0.611-7.866; P = .0220) for nicotinamide. A network meta-analysis comparing nicotinamide and acitretin found no significant difference between the 2 treatments (Fig 2, Appendix B).Fig 1Forest plot of the pairwise meta-analysis of randomized controlled trials. The squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The horizontal lines represent the 95% confidence interval (CI). The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated 95% CI.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 2Network graph and league table of the network meta-analysis. Mean differences and 95% confidence intervals are calculated using a random-effects model. A mean difference >1 means the top-left treatment is better.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This meta-analysis does not address the optimal dosages of the drugs or the frequency of adverse effects. In addition, owing to the limited numbers of eligible RCTs, we are unable to investigate how chemoprevention is influenced by the duration or type of transplantation, duration of systemic chemoprevention, or existing immunosuppressive regimens. Moving forward, topical chemoprevention may be a suitable alternative to systemic chemoprophylaxis in SOTRs. Notably, large RCTs have evaluated topical chemoprevention for actinic keratosis. For instance, the Veterans Affairs Keratinocyte Carcinoma Chemoprevention trial found that topical 5% 5-fluorouracil cream resulted in a 49% relative risk reduction in the number of AK after 6 months and reduced the risk of SCC requiring surgery by 75% after 1 year but did not lower the risk of BCC.4Hyemin P. Hogan D. Eilers D. et al.Long-term efficacy of topical fluorouracil cream 5% for treating actinic keratosis: a randomized clinical trial.JAMA Dermatol. 2015; 151: 952-960Crossref PubMed Scopus (69) Google Scholar,5Weinstock M.A. Thwin S.S. Siegel J.A. et al.Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial.JAMA Dermatol. 2018; 154: 167-174Crossref PubMed Scopus (54) Google Scholar To our knowledge, this is the first meta-analysis that statistically integrates the current evidence regarding chemoprevention of KC/AK. This study demonstrates that systemic chemoprevention with nicotinamide or acitretin is effective in lowering the risk of KC/AK. Yet, even with the advent of better chemoprevention, regular physician surveillance and sun protection are still key basic strategies that should be practiced by all SOTRs.

The Role of Nicotinamide in Cancer Chemoprevention and Therapy.

Nicotinamide (NAM) is a water-soluble form of Vitamin B3 (niacin) and a precursor of nicotinamide-adenine dinucleotide (NAD+) which regulates cellular energy metabolism. Except for its role in the production of adenosine triphosphate (ATP), NAD+ acts as a substrate for several enzymes including sirtuin 1 (SIRT1) and poly ADP-ribose polymerase 1 (PARP1). Notably, NAM is an inhibitor of both SIRT1 and PARP1. Accumulating evidence suggests that NAM plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention or as an adjunct to radiotherapy against head and neck, laryngeal, and urinary bladder cancers. Evidence for other cancers has mostly been collected through preclinical research and, in its majority, is not yet evidence-based. NAM has potential as a safe, well-tolerated, and cost-effective agent to be used in cancer chemoprevention and therapy. However, more preclinical studies and clinical trials are needed to fully unravel its value.

A comparative ex vivo permeation evaluation of a novel 5-Fluorocuracil nanoemulsion-gel by topically applied in the different excised rat, goat, and cow skin.

Aim of the study5-Fluorouracil (5-FU) can’t be given orally because of very low bioavailability and produces serious adverse effects. Therefore, the main objective of this research is to develop, evaluate, and comparative effects by different nanoformulations of topical application on chemoprevention of skin cancer in different types of skin.Material and methodsCastor oil (oil), Transcutol HP (surfactant), and Polyethylene glycol (PEG)–400 (co-surfactant) have taken on the basis of nonionic property and highest nanoemulsion (NE)-region. Aqueous micro titration method with ultra-sonication method (based on high energy) was used for the preparation of 5-FU-NE. Optimized-5-FU-NE was stable thermodynamically, and their characterizations was performed on the basis of globule size, zeta potential, refractive index, and viscosity. Optimized-NE has been converted into 5-FU-NE-Gel with the help of Carbopol® 934 and also performed their permeation studies in the different skins (cow, goat, and rat, ex vivo) using Logan transdermal diffusion cell (DHC-6T). Optimized-5-FU-NE and 5-FU-NE-Gel were evaluated cytotoxic studies (in vitro) on the melanoma cell lines.ResultsThe permeation of 5-FU from 5-FU-NE-Gel nanoformulation for rat skin model was 1.56 times higher than the 5-FU-NE and 12.51 times higher than the 5-FU-S for the cow and goat skin model. The values of steady state flux and permeability coefficient for 5-FU-NE-Gel of rat skin were higher i.e. 12.0244 ± 1.12 µgcm−2h−1 and 1.2024 ± 0.073 × 10−2 µg cm−2h−1, respectively. Optimized-5-FU-NE and 5-FU-NE-Gel nanoformulation were found to be physically stable. SK-MEL-5 cancer cells have showed the results based on cytotoxicity studies (in vitro) that 5-FU as Optimized-5-FU-NE-Gel is much more efficacious than 5-FU-NE followed by free 5-FU. Localization of 5-FU from 5-FU-NE-Gel was higher with higher permeation in rat skin.Conclusion5-FU-NE-Gel is found to be for the better to treatment of cutaneous malignancies. It can be developed 5-FU-NE-Gel could be a promising vehicle for the skin cancer chemoprevention.

Nicotinamide for skin cancer chemoprevention: effects of nicotinamide on melanoma in vitro and in vivo

Nicotinamide (NAM), an amide form of vitamin B3, replenishes cellular energy after ultraviolet radiation (UVR) exposure, thereby enhancing DNA repair and reducing UVR's immunosuppressive effects. NAM reduces actinic keratoses and new keratinocyte cancers in high risk individuals, but its effects on melanoma are unknown. Melanomas arising on NAM or placebo within the ONTRAC skin cancer chemoprevention trial (Oral Nicotinamide To Reduce Actinic Cancer) were examined by immunohistochemistry. The effects of NAM (50 μM, 5 mM and 20 mM) on the viability, proliferation and invasiveness of four human melanoma cell lines and on the viability and proliferation of two human melanocyte lines, with and without UV irradiation were also investigated. 50 μM NAM did not affect viability, proliferation or invasion of melanoma or melanocyte cell lines, whereas concentrations too high to be achievable in vivo reduced viability and proliferation. Nicotinamide did not enhance melanoma viability, proliferation or invasiveness in vitro, providing additional confidence in its safety for use in clinical trials in high risk patients. Peritumoral and tumour infiltrating CD4+ and CD8+ lymphocytes were significantly increased in melanomas arising on NAM compared to those arising on placebo. Given the chemopreventive activity of nicotinamide against keratinocyte cancers, its DNA repair enhancing effects in melanocytes and now its potential enhancement of tumour-infiltrating lymphocytes and lack of adverse effects on melanoma cell growth and proliferation, clinical trials of nicotinamide for melanoma chemoprevention are now indicated.

Hyperoside exerts potent anticancer activity in skin cancer.

Quercetin-3-O-β-D-galactopyranoside, is a hyperoside flavonol glycoside with anti-cancer, anti-inflammatory, and anti-oxidant activities that is derived from Hypericum and Crataegus plants. To this end, we examined the effect of this hyperoside in skin cancer cells lines and in DMBA/TPA induced skin tumors in vivo. In vitro treatment of cancer cells with hyperoside significantly inhibited phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p38 MAPK axis, concomitantly activated the 5'AMP-activated protein kinase (AMPK) signaling, inhibited proliferation, and induced apoptosis and autophagy. Hyperoside markedly inhibited diffuse epidermal hyperplasia and significantly reduced the changes in phosphorylated levels of PI3K, AKT, mTOR and AMPK while reducing p38 phosphorylation as well as of tumor burden in vivo in DMBA/TPA induced skin tumors. These data suggest that hyperoside might be of therapeutic value in chemoprevention of skin cancer.

The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ=290-400nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ=290-320nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.