Treatment of actinic keratosis through inhibition of cyclooxygenase-2: Potential mechanism of action of diclofenac sodium 3% in hyaluronic acid 2.5.
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SUBMITTER: Thomas GJ
PROVIDER: S-EPMC6767532 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Treatment of actinic keratosis through inhibition of cyclooxygenase-2: Potential mechanism of action of diclofenac sodium 3% in hyaluronic acid 2.5.
Thomas Gareth J GJ Herranz Pedro P Cruz Susana Balta SB Parodi Aurora A
Dermatologic therapy 20190409 3
Cyclooxygenase-2 (COX-2) and its metabolic product prostaglandin E<sub>2</sub> (PGE<sub>2</sub> ) are induced in response to growth factors, inflammatory cytokines, tumor promoters, activated oncogenes, and, in the skin, ultraviolet (UV) radiation. Accumulating evidence suggests a role for the COX-2/PGE<sub>2</sub> pathway in tumorigenesis in various tissue types including cutaneous squamous cell carcinoma. There is also strong evidence for a role in the development of actinic keratoses (AKs) - ...[more]
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Project description:Background: Melanoma and squamous cell carcinoma of the skin are characterized by an altered glucose metabolism, but little is known about metabolic changes in precancerous skin lesions such as actinic keratosis (AK). Here, we studied the central carbon metabolism and immune cell infiltrate of actinic keratosis lesions before, under, and 4 weeks after treatment with topical diclofenac (Solaraze®). Methods: This study was designed as a prospective, randomized, controlled, monocentric investigation (ClinicalTrials.gov Identifier: NCT01935531). Myeloid and T cell infiltration was analyzed in skin biopsies from 28 patients by immunohistochemistry. Furthermore, immune cell activation was determined via quantitative real-time PCR (IFN-γ, IL-10, CSF1, TGF-β, IL-6). Glucose, amino acid and Krebs' cycle metabolism was studied by mass spectrometry prior, during and after treatment with topical diclofenac. Biopsies from sun-exposed, untreated, healthy skin served as controls. Results: Increased lactate and decreased glucose levels suggested accelerated glycolysis in pre-treatment AK. Further, levels of Krebs' cycle intermediates other than citrate and amino acids were elevated. Analysis of the immune infiltrate revealed less epidermal CD1a+ cells but increased frequencies of dermal CD8+ T cells in AK. Treatment with diclofenac reduced lactate and amino acid levels in AK, especially in responding lesions, and induced an infiltration of dermal CD8+ T cells accompanied by high IFN-γ mRNA expression, suggesting improved T cell function. Discussion: Our study clearly demonstrated that not only cancers but also pre-malignant skin lesions, like AK, exhibit profound changes in metabolism, correlating with an altered immune infiltrate. Diclofenac normalizes metabolism, immune cell infiltration and function in AK lesions, suggesting a novel mechanism of action.
| S-EPMC6619385 | biostudies-literature
Project description:In this work, hybrid compounds 1-4 obtained by conjugation of the non-steroidal anti-inflammatory drug diclofenac, with natural molecules endowed with antioxidant and antiproliferative activity were prepared. The antiproliferative activity of these hybrids was evaluated on immortalized human keratinocyte (HaCaT) cells stimulated with epidermal growth factor (EGF), an actinic keratosis (AK) model, and on human squamous cell carcinoma (SCC) cells (A431). Hybrid 1 presented the best activity in both cell models. Self-assembling surfactant nanomicelles have been chosen as the carrier to drive the hybrid 1 into the skin; the in vitro permeation through and penetration into pig ear skin have been evaluated. Among the nanostructured formulations tested, Nano3Hybrid20 showed a higher tendency of the hybrid 1 to be retained in the skin rather than permeating it, with a desirable topical and non-systemic action. On these bases, hybrid 1 may represent an attractive lead scaffold for the development of new treatments for AK and SCC.
| S-EPMC6539072 | biostudies-literature
Project description:Actinic keratoses (AKs) are common skin lesions heralding an increased risk of developing squamous cell carcinoma (SCC) and other skin malignancies, arising principally due to excessive ultraviolet (UV) exposure. They are predominantly found in fair-skinned individuals, and increasingly, are a problem of the immunosuppressed. AKs may regress spontaneously, remain stable or transform to invasive SCC. The risk of SCC increases for those with more than 5 AKs, and the majority of SCCs arise from AKs. The main mechanisms of AK formation are inflammation, oxidative stress, immunosuppression, impaired apoptosis, mutagenesis, dysregulation of cell growth and proliferation, and tissue remodeling. Human papilloma virus has also been implicated in the formation of some AKs. Understanding these mechanisms guides the rationale behind the current available treatments for AKs. One of the main principles underpinning the management of AKs is that of field cancerization. Wide areas of skin are exposed to increasing amounts of UV light and other environmental insults as we age. This is especially true for the head, neck and forearms. These insults do not target only the skin where individual lesions develop, but also large areas where crops of AKs may appear. The skin between lesions is exposed to the same insults and is likely to contain as-yet undetectable preclinical lesions or areas of dysplastic cells. The whole affected area is known as the 'field'. Management is therefore divided into lesion-directed and field-directed therapies. Current therapies include lesion-directed cryotherapy and/or excision, and topical field-directed creams: 5-fluorouracil, imiquimod, diclofenac, photodynamic therapy and ingenol mebutate. Combining lesion- and field-directed therapies has yielded good results and several novel therapies are under investigation. Treatment is variable and tailored to the individual making a gold standard management algorithm difficult to design. This literature review article aims to describe the rationale behind the best available therapies for AKs in light of current understanding of pathophysiology and epidemiology. A PubMed and MEDLINE search of literature was performed between January 1, 2000 and September 18, 2013. Where appropriate, articles published prior to this have been referenced. This is not a systematic review or meta-analysis, but aims to highlight the most up to date understanding of AK disease and its management.
| S-EPMC4065271 | biostudies-literature
Project description:Actinic keratoses (AKs) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression from normal skin to skin with AK to skin with invasive cSCC is challenging because of the massive UVR-induced mutational burden characteristic at all stages of this progression. In this study, we report the largest AK whole-exome sequencing study to date and perform a mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AKs from both immunosuppressed and immunocompetent patients that there are significant similarities between AKs and cSCC in terms of mutational burden, copy number alterations, mutational signatures, and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in cSCC. We identify azathioprine mutational signature in all AKs from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. cSCCs differ from AKs in having higher levels of intrasample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGFβ signaling significantly more mutated in cSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGFβ signaling may represent an important event in AK‒cSCC progression.
| S-EPMC8221374 | biostudies-literature
Project description:ImportanceActinic keratosis (AK), a skin growth induced by ultraviolet light exposure, requires chronic management because a small proportion can progress into squamous cell skin cancer. Spending for AK management was more than $1 billion in 2004. Investigating geographic variation in AK spending presents an opportunity to decrease waste or recoup excess spending.ObjectiveTo evaluate geographic variation in health care cost for management of AKs and the association with patient-related and health-related factors.Design, setting, and participantsThis retrospective cohort study was performed using data from the MarketScan medical claims database of 488 324 continuously enrolled members with 2 or more claims for AK. Data from January 1, 2008, to December 31, 2012, was used.Main outcomes and measuresAnnual costs of care were calculated for outpatient visits, AK destruction, and medications for AKs, and the total of these components. Costs were adjusted for inflation to 2014 US dollars. To display cost variation, we calculated the ratio of mean cost in the highest quintile (Q5) relative to the mean in the lowest quintile (Q1), or the Q5:Q1 ratio; Q5:Q1 ratios were adjusted based on age, sex, history of nonmelanoma skin cancer, US geographic region, and population density (metropolitan statistical area).ResultsOverall, data from 488 324 continuously enrolled members (mean [SD] age, 53.1 [7.5] years; 243 662 women) with 2 or more claims for AK were included. Overall, patients had 1 085 985 claims related to AK, and dermatologists accounted for 71.0% of claims. The 2-year total cost was $111.5 million, with $52.4 million in 2011 and $59.1 million in 2012. The unadjusted Q5:Q1 ratios for total annual cost per patient ranged from 9.49 to 15.10. Adjusted ratios ranged from 1.72 to 1.80.Conclusions and relevanceThere is variation in AK management cost within and between regions. This is not fully explained by differences in patient characteristics such as age, sex, or comorbidities. The annual cost for 10 common conditions from Medicare had lower Q5:Q1 ratios that ranged from 1.33 (joint degeneration of back/neck) to 1.69 (chronic sinusitis) when compared with 1.72 to 1.80 for AKs. This suggests an opportunity to investigate and improve the value of health care delivery in the management of AKs.
| S-EPMC5470414 | biostudies-literature
Project description:BackgroundActinic keratoses (AK) are pre-malignant cutaneous lesions caused by prolonged exposure to ultraviolet radiation. As AKs lesions are generally accepted to be the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC), AK lesions have to be treated. They are also the second most common reason for visits to the dermatologist. Several treatments are available but their efficacy still needs to be improved. The UV-B-induced KA lesion mouse model is used in preclinical studies to assess the efficacy of novel molecules, even though it is often more representative of advanced AK or SCC.ObjectivesHere we report on a translational study, comparing the various stages of AK development in humans and in the UV-B irradiated mouse model, as well as the optimization of photograph acquisition of AK lesions on mouse skin.MethodsHuman and mouse skin lesions were analysed by histology and immunohistochemistry. Mouse lesions were also assessed using a digital dermatoscope.ResultsAn histological and phenotypic analysis, including p53, Ki67 and CD3 expression detection, performed on human and mouse AK lesions, shows that overall AK modelling in mice is relevant in the clinical situation. Some differences are observed, such as disorganization of keratinocytes of the basal layer and a number of atypical nuclei which are more numerous in human AK, whereas much more pronounced acanthosis is observed in skin lesion in mice. Thanks to this translational study, we are able to select appropriate experimental conditions for establishing either early or advanced stage AK or an SCC model. Furthermore, we optimized photograph acquisition of AK lesions on mouse skin by using a digital dermatoscope which is also used in clinics and allows reproducible photograph acquisition for further reliable assessment of mouse lesions. Use of this camera is illustrated through a pharmacological study assessing the activity of CARAC®.ConclusionThese data demonstrate that this mouse model of UV-B-induced skin lesions is predictive for the identification of novel therapeutic treatments for both early and advanced stages of the disease.
| S-EPMC5491107 | biostudies-literature
Project description:BACKGROUND: As evidenced by epidemiological and etiological studies, the development of varicose veins is driven by risk-factors which support the development of venous hypertension and thus chronically augment circumferential stress of the venous wall (e.g. dysfunctional venous valves, pregnancy or obesity). We have previously verified the relevance of this biomechanical stimulus for the activation of venous endothelial as well as smooth muscle cells and the subsequent detrimental structural remodeling of the vein wall in experimental mouse models. METHODS: Here, transcriptome analyses revealed an increase in the expression of cyclooxygenase 2 (COX-2) in human venous endothelial cells upon exposure to biomechanical stress. Subsequently, we investigated the impact of diclofenac – a cyclooxygenase inhibitor – on responses of isolated mouse veins to augmented wall stress in vitro and on varicose-like venous remodeling in vivo. RESULTS: Diclofenac treatment decreased COX-2 protein abundance in mouse veins but had no significant impact on the expression of corresponding transcripts. Short-term exposure to elevated pressure levels stimulated the activity of matrix-metalloproteinase-2 (MMP-2) and mitogen activated protein kinases ERK1/2. Diclofenac decreased the level of activated MMP-2 and ERK1/2 in pressure-exposed mouse veins. Varikose-like remodeling of veins in the mouse auricle was significantly inhibited by transdermal application of diclofenac-containing phospholipid-micelles. This effect was associated with decreased COX-2 and MMP-2 abundance as well as cell proliferation. CONCLUSION: The cyclooxygenase inhibitor diclofenac interferes with short term activation of MAP-kinases and matrix-metalloproteinases in cells of the wall stress-exposed venous wall while attenuating venous remodeling in vivo. Thus, nonsteroidal anti-inflammatory drugs may be suitable to interfere with processes promoting the progression of varicose vein development and biomechanical activation of venous cells.
2021-01-12 | GSE121557 | GEO
Project description:OBJECTIVE:To compare the repetitive DNA patterns of human actinic keratoses and squamous cell carcinomas to determine the genetic alterations that are associated with malignant transformation. INTRODUCTION:Cancer cells are prone to genomic instability, which is often due to DNA polymerase slippage during the replication of repetitive DNA and to mutations in the DNA repair genes. The progression of benign actinic keratoses to malignant squamous cell carcinomas has been proposed by several authors. MATERIAL AND METHODS:Eight actinic keratoses and 24 squamous cell carcinomas (SCC), which were pair-matched to adjacent skin tissues and/or leucocytes, were studied. The presence of microsatellite instability (MSI) and the loss of heterozygosity (LOH) in chromosomes 6 and 9 were investigated using nine PCR primer pairs. Random Amplified Polymorphic DNA patterns were also evaluated using eight primers. RESULTS:MSI was detected in two (D6S251, D9S50) of the eight actinic keratosis patients. Among the 8 patients who had squamous cell carcinoma-I and provided informative results, a single patient exhibited two LOH (D6S251, D9S287) and two instances of MSI (D9S180, D9S280). Two LOH and one example of MSI (D6S251) were detected in three out of the 10 patients with squamous cell carcinoma-II. Among the four patients with squamous cell carcinoma-III, one patient displayed three MSIs (D6S251, D6S252, and D9S180) and another patient exhibited an MSI (D9S280). The altered random amplified polymorphic DNA ranged from 70% actinic keratoses, 76% squamous cell carcinoma-I, and 90% squamous cell carcinoma-II, to 100% squamous cell carcinoma-III. DISCUSSION:The increased levels of alterations in the microsatellites, particularly in D6S251, and the random amplified polymorphic DNA fingerprints were statistically significant in squamous cell carcinomas, compared with actinic keratoses. CONCLUSION:The overall alterations that were observed in the repetitive DNA of actinic keratoses and squamous cell carcinomas indicate the presence of a spectrum of malignant progression.
| S-EPMC3093780 | biostudies-literature
Project description:IntroductionCost-utility assessment of first-line actinic keratosis (AK) treatments for max 25 cm2 AK field.MethodsA probabilistic, 2-year decision tree model was used to assess costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratio (ICER), cost-effectiveness efficiency frontier, cost-effectiveness acceptability frontier (CEAF), and expected value of perfect information (EVPI) of AK treatments from the Finnish health care payer perspective with 3% discounting per annum. In the model, the first-line AK treatment resulted in complete clearance (CC) or non-CC with or without local skin responses (LSR), or AK recurrence. Non-CC AK was treated with methyl aminolevulinate+photodynamic therapy (MAL+PDT), and AK recurrence was retreated with the previous effective treatment. Costs included primary and secondary health care, outpatient drugs, and LSR management. QALYs were assessed with the EuroQol (EQ-5D-3L). Result robustness was assessed with sensitivity analyses.ResultsThe mean simulated per patient QALYs (costs) were 1.526 (€982) for MAL+PDT, 1.524 (€794) for ingenol mebutate gel (IngMeb) 0.015% (3 days), 1.522 (€869) for IngMeb 0.05% (2 days), 1.520 (€1062) for diclofenac 3% (12 weeks), 1.518 (€885) for imiquimod 3.75% (6 weeks), 1.517 (€781) for imiquimod 5% (4/8 weeks), and 1.514 (€1114) for cryosurgery when treating AK affecting any body part. IngMeb 0.015% was less costly and more effective (dominating) than other AK treatments indicated for face and scalp area with the exception of imiquimod 5% for which the ICER was estimated at €1933/QALY gained and MAL+PDT, which had an ICER of €82,607/QALY gained against IngMeb 0.015%. With willingness-to-pay €2526-18,809/QALY gained, IngMeb 0.015% had >50% probability for cost-effectiveness on the CEAF. IngMeb 0.05% dominated AK treatments indicated for trunk and extremities. EVPIs for face and scalp (trunk and extremities) analyses were €26 (€0), €86 (€58), and €250 (€169) per patient with the willingness-to-pay of €0, €15,000, and €30,000 per QALY gained, respectively.ConclusionIngMebs were cost-effective AK treatments in Finland.FundingLEO Pharma.
| S-EPMC4449383 | biostudies-literature
Project description:BackgroundActinic keratosis (AK) is a common premalignant skin lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Microwave therapy is an established cancer treatment and has been used for plantar viral warts.ObjectivesTo evaluate the efficacy and feasibility of microwave as a treatment for AK.MethodsStage I was a dose-setting study, in which seven participants had the dielectric properties of 12 thick and 22 thin AKs assessed for optimization of the microwave dose used for treatment in Stage II. Stage II was a randomized, internally controlled trial evaluating 179 AKs in 11 patients (93 treated, 86 untreated controls) on the scalp/forehead or dorsal hand. Participants received one treatment initially and a repeat treatment to unresolved AKs at week 4. The response was assessed at six visits over 4 months. The primary outcome was partial or complete resolution of the treated AKs.ResultsA significantly higher proportion of treated AK areas responded than untreated (90% vs. 15%; P < 0·001). Thin AKs were more responsive than thick AKs. The site did not affect efficacy. Pain was severe, but brief (80% reported pain lasting 'a few seconds only'). Adverse effects were minimal (erythema, n = 6; flaking, n = 3; itch, n = 3). All participants who would chose microwave therapy over their current treatment cited the shorter discomfort period.ConclusionsMicrowave therapy is a portable, safe and effective treatment for AK. An easy-to-deliver, acceptable therapy for AK is attractive as a prevention strategy. While these results are promising, a larger randomized controlled trial is needed against an effective comparator to confirm clinical efficacy and patient acceptability. What is already known about this topic? Actinic keratoses (AKs) are common precancerous skin lesions. Successful treatment of AK can prevent cutaneous squamous cell carcinoma (cSCC). Most topical therapies for AK require repeated application over weeks and drive local skin inflammation, leading to poor compliance. An easy-to-deliver and effective treatment for AK, suitable for use in primary care, could reduce cSCC. What does this study add? Microwave therapy is a feasible, effective treatment for AK. Ninety per cent of treated AKs showed full or partial resolution at 120 days post-treatment. Microwave therapy was painful, but the pain was short-lived (seconds) and this short discomfort period was cited as the main reason that microwave was preferred to their current treatment.
| S-EPMC7496712 | biostudies-literature