RESUMEN
Susceptibility to photoimmune suppression and photocarcinogenesis is greater in male than in female humans and mice and is exacerbated in female estrogen receptor-beta knockout (ER-ß-/-) mice. We previously reported that the active vitamin D hormone, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), applied topically protects against the ultraviolet radiation (UV) induction of cutaneous cyclobutane pyrimidine dimers (CPDs) and the suppression of contact hypersensitivity (CHS) in female mice. Here, we compare these responses in female versus male Skh:hr1 mice, in ER-ß-/-/-- versus wild-type C57BL/6 mice, and in female ER-blockaded Skh:hr1 mice. The induction of CPDs was significantly greater in male than female Skh:hr1 mice and was more effectively reduced by 1,25(OH)2D in female Skh:hr1 and C57BL/6 mice than in male Skh:hr1 or ER-ß-/- mice, respectively. This correlated with the reduced sunburn inflammation due to 1,25(OH)2D in female but not male Skh:hr1 mice. Furthermore, although 1,25(OH)2D alone dose-dependently suppressed basal CHS responses in male Skh:hr1 and ER-ß-/- mice, UV-induced immunosuppression was universally observed. In female Skh:hr1 and C57BL/6 mice, the immunosuppression was decreased by 1,25(OH)2D dose-dependently, but not in male Skh:hr1, ER-ß-/-, or ER-blockaded mice. These results reveal a sex bias in genetic, inflammatory, and immune photoprotection by 1,25(OH)2D favoring female mice that is dependent on the presence of ER-ß.
Asunto(s)
Calcitriol/administración & dosificación , Receptor beta de Estrógeno/metabolismo , Transducción de Señal/efectos de la radiación , Quemadura Solar/tratamiento farmacológico , Quemadura Solar/metabolismo , Protectores Solares/administración & dosificación , Rayos Ultravioleta , Administración Cutánea , Animales , Dermatitis por Contacto/tratamiento farmacológico , Modelos Animales de Enfermedad , Receptor beta de Estrógeno/genética , Femenino , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/efectos de la radiación , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dímeros de Pirimidina/metabolismo , Dímeros de Pirimidina/efectos de la radiación , Factores Sexuales , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Neoplasias Cutáneas/prevención & control , Quemadura Solar/prevención & controlRESUMEN
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.
Asunto(s)
Melanoma/patología , Niacinamida/farmacología , Neoplasias Cutáneas/patología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Melanoma/tratamiento farmacológico , Melanoma/prevención & control , Niacinamida/química , Niacinamida/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Rayos UltravioletaAsunto(s)
Linfocitos B/inmunología , Inmunoterapia , Queratinocitos/patología , Metástasis Linfática/prevención & control , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Supervivencia Celular , Daño del ADN , Femenino , Ratones , Ratones Endogámicos C57BL , Rituximab/uso terapéutico , Neoplasias Cutáneas/patología , Rayos UltravioletaRESUMEN
Nicotinamide (vitamin B3) has photoprotective effects and reduces skin cancer incidence in high risk patients. Nicotinamide also improves cognition in animal models. As part of the ONTRAC (Oral Nicotinamide To Reduce Actinic Cancer) phase III placebo-controlled, randomized trial to assess nicotinamide's efficacy in skin cancer prevention, we included clinical neurocognitive function and patient-reported quality of life assessments at baseline and after 12 months of intervention in individuals with previous skin cancer in order to assess any effect of oral nicotinamide (500 mg po twice daily) on cognitive function and quality of life. In our sample of 310 participants who completed neurocognitive function testing at baseline and at 12 months, we were not able to detect any significant effect of oral nicotinamide on cognitive function nor on quality of life. Further studies of nicotinamide's effects on cognition in humans might include individuals with pre-existing mild cognitive impairment, and it may be that higher doses of nicotinamide are required to significantly influence cognitive function compared to doses required to reduce skin cancer.
RESUMEN
Nicotinamide is a water-soluble vitamin B3 derivative that has many roles in medicine. This review examines the role of nicotinamide in dermatology and its actions in preventing photoageing and skin cancers in humans. Nicotinamide prevents ultraviolet radiation (UV) from reducing ATP levels and inhibiting glycolysis, thus preventing the UV radiation-induced energy crisis. This enhances DNA repair and reduces UV-induced suppression of immunity. Randomised controlled clinical trials have also shown that nicotinamide reduces transepidermal water loss and the development of new non-melanoma skin cancers in high-risk humans. This review also examines nicotinamide's safety profile.
Asunto(s)
Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Envejecimiento de la Piel/efectos de los fármacos , Neoplasias Cutáneas/prevención & control , Adenosina Trifosfato/metabolismo , Animales , Antiinflamatorios , Quimioprevención , Daño del ADN , Reparación del ADN , Dermatología/métodos , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Glucólisis , Humanos , Inflamación , Queratosis Actínica/metabolismo , Fallo Renal Crónico/complicaciones , Hígado/efectos de los fármacos , Leche Humana/efectos de los fármacos , Seguridad del Paciente , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Envejecimiento de la Piel/efectos de la radiación , Rayos Ultravioleta , Complejo Vitamínico B/farmacologíaAsunto(s)
Carcinoma Basocelular/prevención & control , Carcinoma de Células Escamosas/prevención & control , Macrófagos/efectos de los fármacos , Niacinamida/farmacología , Neoplasias Cutáneas/prevención & control , Carcinogénesis/efectos de los fármacos , Carcinoma Basocelular/epidemiología , Carcinoma Basocelular/inmunología , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/inmunología , Recuento de Células , Humanos , Incidencia , Macrófagos/inmunología , Niacinamida/uso terapéutico , Piel/citología , Piel/inmunología , Piel/patología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/inmunologíaRESUMEN
BACKGROUND: Ultraviolet radiation (UVR) is the principal cause of keratinocyte skin cancers. Previous work found that levels of the chromatin remodelling protein, Brahma (Brm), are diminished during the progression from actinic keratoses to cutaneous squamous cell carcinomas in humans, and its loss in UV-irradiated mouse skin causes epidermal hyperplasia and increased tumour incidence. METHODS: The skins of mice and mouse and human keratinocytes deficient in Brm were exposed to UVR and evaluated for cell cycle progression and DNA damage response. OBJECTIVE: To identify the mechanisms by which loss of Brm contributes to UVR-induced skin carcinogenesis. RESULTS: In both mouse keratinocytes and HaCaT cells, Brm deficiency led to an increased cell population growth following UVR exposure compared to cells with normal levels of Brm. Cell cycle analysis using a novel assay showed that Brm-deficient keratinocytes entered cell cycle arrest normally, but escaped from cell cycle arrest faster, enabling them to begin proliferating earlier. In mouse keratinocytes, Brm primarily affected accumulation in G0/G1-phase, whereas in HaCaT cells, which lack normal p53, accumulation in G2/M-phase was affected. Brm-deficient keratinocytes in mouse skin and human cell cultures also had higher levels of UVR-induced cyclobutane pyrimidine dimer photolesions. These effects occurred without any compensatory increase in DNA repair or cell death to remove photolesions or the cells that harbor them from the keratinocyte population. CONCLUSION: The loss of Brm in keratinocytes exposed to UVR enables them to resume proliferation while harboring DNA photolesions, leading to an increased fixation of mutations and, consequently, increased carcinogenesis.
Asunto(s)
Carcinogénesis/genética , Neoplasias Cutáneas/genética , Factores de Transcripción/deficiencia , Rayos Ultravioleta/efectos adversos , Animales , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/efectos de la radiación , Línea Celular , Daño del ADN/efectos de la radiación , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Noqueados , MicroARNs/metabolismo , Cultivo Primario de Células , Dímeros de Pirimidina/efectos de la radiación , Piel/citología , Piel/patología , Neoplasias Cutáneas/patología , Factores de Transcripción/genéticaRESUMEN
Melanoma incidence is increasing worldwide, and although drugs such as BRAF/MEK small-molecule inhibitors and immune checkpoint antibodies improve patient outcomes, most patients ultimately fail these therapies and alternative treatment strategies are urgently needed. DNAzymes have recently undergone clinical trials with signs of efficacy and no serious adverse events attributable to the DNAzyme. Here we investigated c-Jun expression in human primary and metastatic melanoma. We also explored the role of T cell immunity in DNAzyme inhibition of primary melanoma growth and the prevention of growth in non-treated tumors after the cessation of treatment in a mouse model. c-Jun was expressed in 80% of melanoma cells in human primary melanomas (n = 17) and in 83% of metastatic melanoma cells (n = 38). In contrast, c-Jun was expressed in only 11% of melanocytes in benign nevi (n = 24). Dz13, a DNAzyme targeting c-Jun/AP-1, suppressed both Dz13-injected and untreated B16F10 melanoma growth in the same mice, an abscopal effect relieved in each case by administration of anti-CD4/anti-CD8 antibodies. Dz13 increased levels of cleaved caspase-3 within the tumors. New, untreated melanomas grew poorly in mice previously treated with Dz13. Administration of anti-CD4/anti-CD8 antibodies ablated this inhibitory effect and the tumors grew rapidly. Dz13 inhibited c-Jun expression, reduced intratumoral vascularity (vascular lumina area defined by CD31 staining), and increased CD4+ cells within the tumors. This study provides the first demonstration of an abscopal effect of a DNAzyme on tumor growth and shows that Dz13 treatment prevents growth of subsequent new tumors in the same animal. Dz13 may be useful clinically as a therapeutic antitumor agent by preventing tumor relapse through adaptive immunity.
Asunto(s)
ADN Catalítico/genética , Melanoma/genética , Animales , Antígenos CD4/genética , Antígenos CD8/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-jun/genéticaRESUMEN
Ultraviolet radiation (UVR) causes DNA damage in melanocytes by producing photolesions such as cyclobutane pyrimidine dimers and 8-oxo-7-hydrodeoxyguanosine. The production of reactive oxygen species by UVR also induces inflammatory cytokines that, together with the inherent immunosuppressive properties of UVR, propagate carcinogenesis. Nicotinamide (Vitamin B3 ) enhances DNA repair, modulates the inflammatory environment produced by UVR, and reduces UV-induced immunosuppression. As nicotinamide reduces the incidence of actinic keratoses and nonmelanoma skin cancers in high-risk individuals and enhances repair of DNA damage in melanocytes, it is a promising agent for the chemoprevention of melanoma in high-risk populations.
Asunto(s)
Carcinoma Basocelular/prevención & control , Carcinoma de Células Escamosas/prevención & control , Melanoma/prevención & control , Niacinamida/uso terapéutico , Neoplasias Cutáneas/prevención & control , Complejo Vitamínico B/uso terapéutico , Animales , Reparación del ADN/efectos de los fármacos , Humanos , Inmunomodulación/efectos de los fármacos , Niacinamida/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Complejo Vitamínico B/farmacologíaRESUMEN
The cornea sits at the anterior aspect of the eye and, like the skin, is highly exposed to ultraviolet radiation (UVR). The cornea blocks a significant proportion of UVB from reaching the posterior structures of the eye. However, UVA can penetrate the full thickness of the cornea, even reaching the anterior portion of the lens. Epidemiological data indicate that UVR is a contributing factor for a multitude of diseases of the cornea including pterygium, photokeratitis, climatic droplet keratopathy and ocular surface squamous neoplasia (OSSN), although the pathogenic mechanisms of each require further elucidation. UVR is a well-known genotoxic agent, and its effects have been well characterized in organs such as the skin. However, we are only beginning to identify its effects on the cornea, such as the UVR signature C â T and CC â TT transversions identified by sequencing and increased proliferative and shedding rates in response to UVR exposure. Alarmingly, a single low-dose exposure of UVR to the cornea is sufficient to elicit genetic, molecular and cellular changes, supporting the consideration of using protective measures, such as wearing sunglasses when outdoors. The aim of this review was to describe the adverse effects of UVR on the cornea.
Asunto(s)
Córnea/efectos de la radiación , Luz Solar/efectos adversos , Rayos Ultravioleta/efectos adversos , Córnea/inmunología , Córnea/metabolismo , Córnea/patología , Enfermedades de la Córnea/etiología , Daño del ADN , Humanos , Exposición a la Radiación , Traumatismos por Radiación/etiologíaRESUMEN
Maintaining the structure of the cornea is essential for high-quality vision. In adult mammals, corneal epithelial cells emanate from stem cells in the limbus, driven by an unknown mechanism towards the centre of the cornea as cohesive clonal groups. Here we use complementary mathematical and biological models to show that corneal epithelial cells can self-organize into a cohesive, centripetal growth pattern in the absence of external physiological cues. Three conditions are required: a circumferential location of stem cells, a limited number of cell divisions and mobility in response to population pressure. We have used these complementary models to provide explanations for the increased rate of centripetal migration caused by wounding and the potential for stem cell leakage to account for stable transplants derived from central corneal tissue, despite the predominantly limbal location of stem cells.
Asunto(s)
Movimiento Celular , Señales (Psicología) , Epitelio Corneal/citología , Animales , Linaje de la Célula , Movimiento Celular/efectos de la radiación , Células Clonales , Epitelio Corneal/efectos de la radiación , Limbo de la Córnea/citología , Ratones , Modelos Biológicos , Células Madre/citología , Células Madre/metabolismo , Rayos UltravioletaRESUMEN
The ultraviolet (UV) radiation contained in sunlight is a powerful immune suppressant. While exposure to UV is associated with protection from the development of autoimmune diseases, particularly multiple sclerosis, the precise mechanism by which UV achieves this protection is not currently well understood. Regulatory B cells play an important role in preventing autoimmunity and activation of B cells is a major way in which UV suppresses adaptive immune responses. Whether UV-protection from autoimmunity is mediated by the activation of regulatory B cells has never been considered before. When C57BL/6 mice were exposed to low, physiologically relevant doses of UV, a unique population of B cells was activated in the skin draining lymph nodes. As determined by flow cytometry, CD1d(low)CD5(-)MHC-II(hi)B220(hi) UV-activated B cells expressed significantly higher levels of CD19, CD21/35, CD25, CD210 and CD268 as well as the co-stimulatory molecules CD80, CD86, CD274 and CD275. Experimental autoimmune encephalomyelitis (EAE) in mice immunized with MOG/CFA was reduced by exposure to UV. UV significantly inhibited demyelination and infiltration of inflammatory cells into the spinal cord. Consequently, UV-exposed groups showed elevated IL-10 levels in secondary lymphoid organs, delayed EAE onset, reduced peak EAE score and significantly suppressed overall disease incidence and burden. Importantly, protection from EAE could be adoptively transferred using B cells isolated from UV-exposed, but not unirradiated hosts. Indeed, UV-protection from EAE was dependent on UV activation of lymph node B cells because UV could not protect mice from EAE who were pharmacologically depleted of B cells using antibodies. Thus, UV maintenance of a pool of unique regulatory B cells in peripheral lymph nodes appears to be essential to prevent an autoimmune attack on the central nervous system.
Asunto(s)
Autoinmunidad/efectos de la radiación , Linfocitos B Reguladores/efectos de la radiación , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Activación de Linfocitos/efectos de la radiación , Luz Solar , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Antígenos CD/metabolismo , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II/metabolismo , Inyecciones Intraperitoneales , Interleucina-10/metabolismo , Interleucina-10/efectos de la radiación , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidadRESUMEN
BACKGROUND: Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses. METHODS: In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide. RESULTS: At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued. CONCLUSIONS: Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.).
Asunto(s)
Carcinoma Basocelular/prevención & control , Carcinoma de Células Escamosas/prevención & control , Queratosis Actínica/prevención & control , Niacinamida/uso terapéutico , Neoplasias Cutáneas/prevención & control , Complejo Vitamínico B/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Método Doble Ciego , Femenino , Humanos , Queratosis Actínica/epidemiología , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Prevención Secundaria , Neoplasias Cutáneas/epidemiología , Complejo Vitamínico B/efectos adversosRESUMEN
Ultraviolet (UV) wavelengths in sunlight are the prime cause of skin cancer in humans with both the UVA and UVB wavebands making a contribution to photocarcinogenesis. UV has many different biological effects on the skin that contribute to carcinogenesis, including suppression of adaptive immunity, sunburn and altering the migration of mast cells into and away from irradiated skin. Many molecular mechanisms have been identified as contributing to skin responses to UV. Recently, using gene set enrichment analysis of microarray data, we identified the alternative complement pathway with a central role for factor B (fB) in UVA-induced immunosuppression. In the current study we used mice genetically deficient in fB (fB-/- mice) to study the functional role of the alternative complement pathway in skin responses to UV. We found that fB is required for not only UVA but also UVB-induced immunosuppression and solar-simulated UV induction of the oedemal component of sunburn. Factor B-/- mice had a larger number of resident skin mast cells than control mice, but unlike the controls did not respond to UV by increasing mast cell infiltration into the skin. This study provides evidence for a function role for fB in skin responses to UV radiation. Factor B regulates UVA and UVB induced immunosuppression, UV induced oedema and mast cell infiltration into the skin. The alternative complement pathway is therefore an important regulator of skin responses to UV.
Asunto(s)
Factor B del Complemento/metabolismo , Edema/fisiopatología , Hipersensibilidad Tardía/fisiopatología , Mastocitos/efectos de la radiación , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Animales , Movimiento Celular/fisiología , Movimiento Celular/efectos de la radiación , Factor B del Complemento/genética , Modelos Animales de Enfermedad , Edema/etiología , Femenino , Hipersensibilidad Tardía/etiología , Masculino , Mastocitos/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Piel/fisiopatología , Quemadura Solar/etiología , Quemadura Solar/fisiopatologíaRESUMEN
Arsenic-induced skin cancer is a significant global health burden. In areas with arsenic contamination of water sources, such as China, Pakistan, Myanmar, Cambodia and especially Bangladesh and West Bengal, large populations are at risk of arsenic-induced skin cancer. Arsenic acts as a co-carcinogen with ultraviolet (UV) radiation and affects DNA damage and repair. Nicotinamide (vitamin B3) reduces premalignant keratoses in sun-damaged skin, likely by prevention of UV-induced cellular energy depletion and enhancement of DNA repair. We investigated whether nicotinamide modifies DNA repair following exposure to UV radiation and sodium arsenite. HaCaT keratinocytes and ex vivo human skin were exposed to 2µM sodium arsenite and low dose (2J/cm2) solar-simulated UV, with and without nicotinamide supplementation. DNA photolesions in the form of 8-oxo-7,8-dihydro-2'-deoxyguanosine and cyclobutane pyrimidine dimers were detected by immunofluorescence. Arsenic exposure significantly increased levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in irradiated cells. Nicotinamide reduced both types of photolesions in HaCaT keratinocytes and in ex vivo human skin, likely by enhancing DNA repair. These results demonstrate a reduction of two different photolesions over time in two different models in UV and arsenic exposed cells. Nicotinamide is a nontoxic, inexpensive agent with potential for chemoprevention of arsenic induced skin cancer.
Asunto(s)
Arsenitos/farmacología , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Niacinamida/farmacología , Piel/efectos de los fármacos , Compuestos de Sodio/farmacología , Rayos Ultravioleta , Línea Celular , Daño del ADN/efectos de la radiación , Humanos , Queratinocitos/efectos de la radiación , Piel/efectos de la radiación , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Ultraviolet (UV) radiation is likely to drive the initiation and progression of skin cancer from actinic keratosis to squamous cell carcinoma. Signs of photodamage occur at multiple steps. UV radiation damages many cellular constituents, including lipids, proteins and DNA, all of which are likely to contribute to UV-induced skin cancer. Two biological events culminating from photodamage are mutations in the genes critical to the control of cell division, differentiation and invasion and immunosuppression. DNA photodamage, if unrepaired prior to cell division, can result in the incorporation of an incorrect nucleotide into newly synthesised DNA. Mutations in critical genes contribute to carcinogenesis. Photodamage to proteins such as those involved in DNA repair or proteins or lipids involved in cellular signalling can interfere with this repair process and contribute to mutagenesis. Mutations in key genes, including TP53, BRM, PTCH1, and HRAS, contribute to skin carcinogenesis. UV also damages immunity. Photodamage to DNA and signalling lipids as well as other molecular changes are detrimental to the key cells that regulate immunity. Photodamaged dendritic cells and altered responses by mast cells lead to the activation of T and B regulatory cells that suppress immunity to the protein products of UV-mutated genes. This stops the immune response from its protective function of destroying mutated cells, enabling the transformed cells to progress to skin cancer. UV appears to play a pivotal role at each of these steps, and therefore, signs of photodamage point to the development of skin cancer.
Asunto(s)
Carcinoma de Células Escamosas/etiología , Queratosis Actínica/etiología , Neoplasias Inducidas por Radiación , Neoplasias Cutáneas/etiología , Rayos Ultravioleta/efectos adversos , Carcinogénesis/genética , Carcinogénesis/inmunología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Humanos , Inmunidad Celular/efectos de la radiación , Queratosis Actínica/genética , Queratosis Actínica/inmunología , Mutación , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Nicotinamide has shown potential as a safe and effective intervention for the prevention of malignant and premalignant skin lesions. Recent studies have shown that nicotinamide, in both oral and topical forms, is able to prevent ultraviolet-induced immunosuppression in humans [1,2,3] and mice [4,5]. Immunosuppression is a known factor for the progression of premalignant lesions, such as actinic keratosis [6]. Murine studies have shown that nicotinamide is also able to protect against photocarcinogenesis [4,5]. Preliminary human studies suggest that nicotinamide may help prevent skin cancers and enhance the regression of actinic keratoses.
Asunto(s)
Antineoplásicos/administración & dosificación , Suplementos Dietéticos , Queratosis Actínica/tratamiento farmacológico , Niacinamida/administración & dosificación , Administración Oral , Animales , Reparación del ADN/efectos de los fármacos , Humanos , Inmunidad Celular/efectos de los fármacos , Ratones , Neoplasias Cutáneas/prevención & control , Rayos UltravioletaRESUMEN
Topical 1,25-dihydroxyvitamin D (1,25D) and other vitamin D compounds have been shown to protect skin from damage by ultraviolet radiation (UVR) in a process that requires the vitamin D receptor. Yet, while mice which do not express the vitamin D receptor are more susceptible to photocarcinogenesis, mice unable to 1α-hydroxylate 25-hydroxyvitamin D to form 1,25D do not show increased susceptibility to UVR-induced skin tumors. A possible explanation is that an alternative pathway, which does not involve 1α-hydroxylation, may produce photoprotective compounds from vitamin D. The cholesterol side chain cleavage enzyme CYP11A1 is expressed in skin and produces 20-hydroxyvitamin D3 (20OHD) as a major product of vitamin D3. We examined whether topical 20OHD would affect UVR-induced DNA damage, inflammatory edema or immune suppression produced in Skh:hr1 mice. Photoprotection by 20OHD at 23 or 46pmol/cm(2) against cyclobutane pyrimidine dimers (DNA lesions) after UVR in mice was highly effective, up to 98±0.8%, (p<0.001) and comparable to that of 1,25D. Sunburn edema measured as skinfold thickness 24h after UVR was also significantly reduced by 20OHD (p<0.001). In studies of contact hypersensitivity (CHS), which is suppressed by UVR, topical application of 20OHD to mice protected against UVR-induced immunosuppression (p<0.05), similar to the effect of 1,25D at similar doses (46±0.6% protection with 20OHD, 44±0.5% with 1,25D). Both UVR-induced DNA damage and immunosuppression contribute to increased susceptibility to UVR-induced skin tumors. This study indicates a potentially anti-photocarcinogenic role of the naturally occurring vitamin D metabolite, 20OHD, which does not depend on 1α-hydroxylation for generation. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
Asunto(s)
Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Neoplasias Cutáneas/prevención & control , Piel/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Vitamina D/farmacología , Vitaminas/farmacología , Animales , Humanos , Ratones , Piel/citología , Piel/enzimología , Piel/efectos de la radiación , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patologíaRESUMEN
Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm-/-, Trp53+/-, and particularly the Brm-/- Trp53+/- mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm-/- Trp53+/+ and Brm-/- Trp53+/- mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm-/- mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis.
Asunto(s)
Epitelio Corneal/citología , Epitelio Corneal/efectos de la radiación , Queratinocitos/citología , Queratinocitos/efectos de la radiación , Factores de Transcripción/metabolismo , Rayos Ultravioleta/efectos adversos , Alelos , Animales , División Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Epitelio Corneal/metabolismo , Humanos , Queratinocitos/metabolismo , Antígeno Ki-67/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/deficiencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
UVR has deleterious and beneficial effects on human health. In this issue, Liu et al. (2014) show that UVA decreases blood pressure and increases blood flow and heart rate in humans, which is beneficial to the cardiovascular system. This is likely mediated by UVA causing release of nitric oxide (NO) from skin stores. This mediator may have additional effects on human health.