ascorbic-acid and Skin-Neoplasms

Melanoma is the most serious form of skin cancer affecting mostly people of Caucasian origin and is associated with high exposure to solar ultraviolet (UV) radiation. Antioxidants in the diet are thought to prevent UV-induced DNA damage and oxidative stress and laboratory-based studies have shown that high antioxidant intakes inhibit melanoma development. Corresponding epidemiological evidence is inconsistent, however. We therefore reviewed results from prospective observational studies and randomized controlled trials (RCTs) to clarify whether consumption of antioxidant vitamin C, E (tocopherol), and A (retinol), carotenoids and selenium, as food, supplements, or both, or high fruit and vegetable intake, reduce the incidence of cutaneous melanoma. A total of 9 studies (2 cohort, 1 nested case-control, 6 RCTs) were included. Neither antioxidant nutrients, individually or combined, nor fruit and vegetable intake showed any strong and significant associations with melanoma, though the number of relevant studies was limited and several had methodological shortcomings. In particular, melanoma was not a primary disease outcome in any of the RCTs and therefore, none adequately accounted for potential confounding by sun exposure. In conclusion, available evidence is currently inadequate to assess possible beneficial effects of antioxidant intake on melanoma risk.

Topics: Antioxidants; Ascorbic Acid; Carotenoids; Databases, Factual; Dietary Supplements; DNA Damage; Fruit; Humans; Melanoma; Melanoma, Cutaneous Malignant; Observational Studies as Topic; Oxidative Stress; Randomized Controlled Trials as Topic; Selenium; Skin Neoplasms; Vegetables; Vitamin A; Vitamin E

Skin cells are constantly exposed to reactive oxygen species (ROS) and oxidative stress from exogenous and endogenous sources. UV radiation is the most important environmental factor in the development of skin cancer and skin aging. The primary products caused by UV exposure are generally direct DNA oxidation or generation of free radicals which form and decompose extremely quickly but can produce effects that can last for hours, days, or even years. UV-induced generation of ROS in the skin develops oxidative stress when their formation exceeds the antioxidant defense ability. The reduction of oxidative stress can be achieved on two levels: by lowering exposure to UVR and/or by increasing levels of antioxidant defense in order to scavenge ROS. The only endogenous protection of our skin is melanin and enzymatic antioxidants. Melanin, the pigment deposited by melanocytes, is the first line of defense against DNA damage at the surface of the skin, but it cannot totally prevent skin damage. A second category of defense is repair processes, which remove the damaged biomolecules before they can accumulate and before their presence results in altered cell metabolism. Additional UV protection includes avoidance of sun exposure, usage of sunscreens, protective clothes, and antioxidant supplements.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Glutathione; Humans; Reactive Oxygen Species; Retinoids; Skin Neoplasms; Ultraviolet Rays; Vitamin E

Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human neoplasms, representing one third of all new malignancies diagnosed in the US. The number of new cases diagnosed per year in the US alone is approaching one million and continues to rise. Ultraviolet (UV) radiation from the sun is a major cause of non-melanoma skin cancer in humans. Aside from the mutagenic effects of UV radiation, there are suggestions from clinical studies and evidence in animal models that the immune system plays an important role in preventing skin cancer development and progression, and is suppressed by cutaneous exposure to UV radiation. In this article, we review the research on new and existing agents that are being developed to protect the skin immune response from suppression by UV radiation. We also discuss the current state of knowledge regarding their mechanism of action in humans as well as animal models of photosuppression, and their efficacy in cancer prevention.

Topics: Aloe; Animals; Antioxidants; Ascorbic Acid; Carcinoma, Basal Cell; Flavonoids; Humans; Immune System; Phenols; Phytotherapy; Polyphenols; Skin Neoplasms; Ultraviolet Rays; Vitamin E

Experimental animal studies have unambiguously demonstrated that topical sunscreens can prevent squamous cell carcinoma and photoaging (damage of collagen and elastic fibers of the skin). Although data from clinical studies and surrogate markers also indicate such photoprotective effects in man, there is a lack of controlled, prospective clinical trials to provide definite evidence in man. Because of inadequate data, no definite conclusions can be drawn about the cancer-preventive activity of topical use of sunscreens against basal cell carcinoma and malignant melanoma.

Topics: Administration, Topical; Adult; Animals; Antioxidants; Ascorbic Acid; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Disease Models, Animal; Humans; Melanoma; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Prospective Studies; Randomized Controlled Trials as Topic; Skin Aging; Skin Neoplasms; Sunscreening Agents; Time Factors; Ultraviolet Rays; Vitamin E

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; beta Carotene; Carotenoids; Case-Control Studies; Cell Transformation, Neoplastic; Diet; Free Radicals; Guinea Pigs; Humans; Incidence; Lung Neoplasms; Melanoma; Mice; Mice, Hairless; Models, Chemical; Neoplasms; Neoplasms, Radiation-Induced; Oxygen; Partial Pressure; Prospective Studies; Reactive Oxygen Species; Retrospective Studies; Selenium; Singlet Oxygen; Skin Neoplasms; Smoking; Structure-Activity Relationship; Ultraviolet Rays; Vegetables; Vitamin E

Human studies have convincingly demonstrated pronounced photoprotective effects of 'natural' and synthetic antioxidants when applied topically before UVR exposure. Particularly with respect to UVB-induced skin damage such as erythema formation, the photoprotective effects of antioxidants are significant when applied in distinct mixtures in appropriate vehicles. Topical application of such combinations may result in a sustained antioxidant capacity of the skin, possibly due to antioxidant synergisms. And, since UVA-induced skin alterations are believed to be largely determined by oxidative processes [26], topical administration of antioxidants might be particularly promising [27, 28]. In fact, topical application of antioxidants or antioxidant mixtures resulted in a remarkable increase in the minimal dose to induce immediate pigment darkening after UVA exposure [18, 23] and diminished the severity of UVA-induced photodermatoses [22] in humans. In conclusion, regular application of skin care products containing antioxidants may be of the utmost benefit in efficiently preparing our skin against exogenous oxidative stressors occurring during daily life. Furthermore, sunscreening agents may also benefit from combination with antioxidants resulting in increased safety and efficacy of such photoprotective products [11, 29].

Topics: Administration, Cutaneous; Administration, Topical; Air Pollutants; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Drug Administration Schedule; Flavonoids; Humans; Neoplasms, Radiation-Induced; Ozone; Radiation-Protective Agents; Reactive Oxygen Species; Skin Aging; Skin Neoplasms; Sunscreening Agents; Swine; Ultraviolet Rays; Vitamin E

Skin carcinogenesis can be operationally and mechanistically divided into at least three stages; tumor initiation, stage I and stage II of promotion. Current information suggests that reactive intermediates of skin tumor initiators are mutagenic and bind convalently to DNA of epidermal stem cells (dark basal keratinocytes) leading to some irreversible alteration in the differentiation capacity of these cells. Inhibitors of skin tumor initiation by polycyclic aromatic hydrocarbons (PAH) decrease the level of the PAH diol-epoxide bound to specific DNA adducts. The tumor promoters have been shown to have many cellular and biochemical effects in the skin. Recent data suggests that free radicals may be important in skin tumor promotion. The first stage of promotion is partially irreversible and can be accomplished by a single treatment of a tumor promoter such as TPA or by non-promoting agents such as 4-0-methyl-TPA, calcium ionophore A23187, and hydrogen peroxide, as well as wounding. These agents increase the number of dark basal keratinocytes, which suggest that these cells are important in the first stage of promotion. Prostaglandin E2 was found to specifically enhance stage I of promotion whereas the protease inhibitor tosyl phenylalanine chloromethylketone (TPCK) specially inhibited stage I of promotion and the TPA-induced dark basal keratinocytes. The second stage of promotion is initially reversible but later becomes irreversible. The weak promoting agent mezerein is an effective stage II promoter. Polyamines and epidermal cell proliferation appear to be important events in stage II of promotion. Putrescine was found to specifically enhance stage II, whereas retinoic acid (RA), diflouromethylornithine (DFMO), and butylated hydroxyanisole (BHA) specially inhibited stage II of promotion and the mezerein-induced polyamine levels. Floucinolone acetonide (FA) was found to inhibit both stages but was more effective in counteracting stage I of promotion. Although, TPA can cause a decrease in the number of glucocorticoid receptors during promotion, FA can effectively prevent this loss. Recent data suggest that skin tumor promotion can be effectively inhibited by a combination of stage I and II inhibitors. Furthermore, skin carcinogenesis can be counteracted by a combination of low and nontoxic doses of BHA, TPCK, DFMO and vitamin E.

Topics: Animals; Ascorbic Acid; Carcinogens; Disease Models, Animal; Humans; Neoplasms; Phorbol Esters; Selenium; Skin Neoplasms; Vitamin E

Topics: Amino Acids; Animals; Ascorbic Acid; Cell Division; Cricetinae; Dietary Fats; Dietary Proteins; Humans; Melanoma; Mice; Nucleosides; Nutritional Physiological Phenomena; Pyridoxine; Skin Neoplasms; Trace Elements; Vitamin A; Vitamin D; Vitamin K

Topics: Ammonia; Animal Nutritional Physiological Phenomena; Animals; Ascorbic Acid; Colonic Neoplasms; Copper; Cricetinae; Dietary Fats; Dietary Fiber; Dietary Proteins; Energy Intake; Female; Humans; Iodine; Lipotropic Agents; Liver Neoplasms; Mammary Neoplasms, Experimental; Mice; Neoplasms; Neoplasms, Experimental; Nutritional Physiological Phenomena; Rats; Riboflavin; Selenium; Skin Neoplasms; Vitamin A; Vitamin B Complex; Zinc

Nonspecific enhancers of resistance may include (1) viral interference, (2) interferon, (3) interferon inducers, (4) bacterial interference, (5) bacterial products such as Coley's "toxins," endotoxins, or staphylococcal, BCG, and Corynebacterium parvum vaccines, (6) transfer factor, and (7) well-defined chemicals such as dinitrochlorbenzene, levamisole, and vitamin C. These are discussed only as they have been applied to man to learn whether or not they have enhanced his ability to resist infections and growth of tumors. Preliminary studies suggest that a variety of relatively safe and effective nonspecific enhancers may soon be available for clinical use.

Topics: Adjuvants, Immunologic; Animals; Ascorbic Acid; Bacteria; BCG Vaccine; Dinitrochlorobenzene; Endotoxins; Humans; Immunity; Immunity, Cellular; Interferon Inducers; Interferons; Levamisole; Melanoma; Mice; Propionibacterium acnes; Rats; Respiratory Tract Infections; Skin Neoplasms; Staphylococcal Vaccines; Transfer Factor; Viral Interference

Skin cancer is the most common cancer in the United States and among Caucasians worldwide, with more people diagnosed each year than all other cancers combined. Basal cell cancer is the most common form with an estimated 4.3 million cases diagnosed annually, and treatment costs estimated at $4.8 billion. The objective of this study was to compare efficacy of a topical solution consisting of 30% ascorbic acid in 95% dimethylsulfoxide with topical imiquimod in the treatment of basal cell carcinoma. Twenty-five patients with 29 biopsy confirmed basal cell carcinomas were randomly assigned to receive either the topically applied ascorbic acid treatment twice daily for 8 weeks or topical imiquimod, a standard and well characterized topical treatment. After 8 weeks, post-treatment biopsy of lesions showed complete resolution of 13/15 (86.7%) in the ascorbic acid group, while 8/14 (57.1%) lesions in the IMQ group were resolved (p < 0.05 Chi Square). Topical ascorbic acid was superior at 8 weeks, and non-inferior at 12 weeks to topical imiquimod in the treatment of low risk nodular and superficial lesions. In addition, ascorbic acid was associated with fewer adverse effects than imiquimod. 70% of patients in the imiquinod group showed residual hypopigmentation at 30mo follow up versus 0% in the ascorbate group.

Topics: Administration, Topical; Aminoquinolines; Antineoplastic Agents; Ascorbic Acid; Carcinoma, Basal Cell; Dimethyl Sulfoxide; Humans; Imiquimod; Skin Neoplasms; Treatment Outcome

Phase I of this study was aimed at comparing the profiles of oxidative stress biomarkers in patients with history of nonmelanoma skin cancer (NMSC), previously treated with surgery, to the healthy subjects. Phase II aimed to evaluate the effects of supplementary antioxidant therapy on the levels of biomarkers in the case group.. In Phase I, oxidative stress biomarkers were measured in blood samples obtained from 24 healthy subjects and 60 patients with history of NMSC previously treated with surgery. In Phase II, the 60 patients with history of NMSC were randomized into two subgroups, one receiving placebo (n = 34) and the other (n = 26) receiving vitamin C, vitamin E, and zinc supplementation for 8 weeks, followed by reevaluation of biomarkers.. In Phase I, patients with history of NMSC showed increased plasma concentrations of all biomarkers, but only 15-F2t-isoprostane was significantly higher than in the healthy subjects. Risk of NMSC increased by 4% for each additional 1 pg/mL increase in 15-F2t-isoprostane. In Phase II, supplementation did not significantly reduce levels of oxidative stress biomarkers.. Patients with history of NMSC had significantly high 15-F2t-isoprostane plasma levels; supplementation did not result in significant reduction of oxidative stress biomarkers. This trial was registered with ClinicalTrials.gov (ID NCT02248584).

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Biomarkers, Tumor; Dietary Supplements; Dinoprost; Female; Humans; Isoprostanes; Male; Middle Aged; Oxidative Stress; Skin Neoplasms; Vitamin E; Zinc

Skin cancer and photoaging changes result from ultraviolet (UV)-induced oxidative stress. Topical antioxidants may protect skin from these effects.. We sought to determine whether a stable topical formulation of 15% L-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid (CEFer) could protect human skin in vivo from substantial amounts of solar-simulated UV radiation.. CEFer and its vehicle were applied to separate patches of normal-appearing human skin for 4 days. Each patch was irradiated with solar-simulated UV, 2 to 10 minimal erythema doses, at 2-minimal erythema dose intervals. One day later, skin was evaluated for erythema and sunburn cells, and immunohistochemically for thymine dimers and p53. UV-induced cytokine formation, including interleukin (IL)-1alpha, IL-6, IL-8, and IL-10, and tumor necrosis factor-alpha, were evaluated by real-time polymerase chain reaction.. CEFer provided significant and meaningful photoprotection for skin by all methods of evaluation.. The number of patients evaluated was relatively small.. CEFer provided substantial UV photoprotection for skin. It is particularly effective for reducing thymine dimer mutations known to be associated with skin cancer. Its mechanism of action is different from sunscreens and would be expected to supplement the sun protection provided by sunscreens.

Topics: Administration, Cutaneous; Adult; alpha-Tocopherol; Antioxidants; Ascorbic Acid; Coumaric Acids; Cytokines; DNA Damage; DNA Primers; Drug Combinations; Erythema; Humans; Immunohistochemistry; Polymerase Chain Reaction; Pyrimidine Dimers; Radiation Dosage; RNA, Messenger; Skin; Skin Neoplasms; Statistics, Nonparametric; Sunburn; Tumor Suppressor Protein p53; Ultraviolet Rays

We conducted a single institution phase II trial to evaluate the tolerability and effectiveness of therapy with arsenic trioxide (ATO) and ascorbic acid (AA) with temozolomide (TMZ) in patients with advanced melanoma. Planned enrollment was for 40 patients. Eligible patients were required to have metastatic melanoma with or without brain metastases, an ECOG performance status of 0-2, and adequate organ function. The primary endpoints were overall response rate and degree of grade 4 toxicity. ATO was administered as a loading dose at 0.25 mg/kg/day for 5 days during week 0, and then twice weekly at 0.35 mg/kg during an 8-week cycle. Each infusion of ATO was followed by an infusion of 1000 mg of AA. TMZ was given at the standard dose of 200 mg/m for 5 days during weeks 1 and 5 of each cycle. Eleven patients were enrolled with 10 evaluable for response, five with central nervous system disease. No responses were seen among the first 10 patients and on the basis of a predetermined stopping rule, the trial was terminated. Common grade 1 and 2 side effects included nausea and vomiting (10), fatigue (six), edema (six), rash (six), and elevated AST or ALT (six). Grade 3 and 4 side effects included nausea and vomiting (three), elevated AST or ALT (two), seizure (one), and renal failure (one). This is the first trial combining ATO with chemotherapy in a solid tumor. ATO and AA were administered in the outpatient setting with TMZ in 11 patients with an acceptable side effect profile. No responses were seen in the first 10 evaluable patients leading to early closure of the study. Further studies using ATO and AA with TMZ with this dosing schedule in advanced melanoma are not warranted.

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Brain Neoplasms; Dacarbazine; Female; Humans; Male; Melanoma; Middle Aged; Oxides; Skin Neoplasms; Temozolomide

Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFAs) protect against photocarcinogenesis in animals, but prospective human studies are scarce. The mechanism(s) underlying the photoprotection are uncertain, although omega-3 PUFAs may influence oxidative stress. We examined the effect of supplementation on a range of indicators of ultraviolet radiation (UVR)-induced DNA damage in humans, and assessed effect on basal and post-UVR oxidative status. In a double-blind randomized study, 42 healthy subjects took 4 g daily of purified omega-3 PUFA, eicosapentaenoic acid (EPA), or monounsaturated, oleic acid (OA), for 3 months. EPA was bioavailable; the skin content at 3 months showing an 8-fold rise from baseline, P < 0.01. No consistent pattern of alteration in basal and UVR-exposed skin content of the antioxidants glutathione, vitamins E and C or lipid peroxidation, was seen on supplementation. Sunburn sensitivity was reduced on EPA, the UVR-induced erythemal threshold rising from a mean of 36 (SD 10) mJ/cm(2) at baseline to 49 (16) mJ/cm(2) after supplementation, P < 0.01. Moreover, UVR-induced skin p53 expression, assessed immunohistochemically at 24 h post-UVR exposure, fell from a mean of 16 (SD 5) positive cells/100 epidermal cells at baseline to 8 (4) after EPA supplementation, P < 0.01. Peripheral blood lymphocytes (PBL) sampled on 3 successive days both pre- and post-supplementation, showed no change with respect to basal DNA single-strand breaks or oxidative base modification (8-oxo-dG). However, when susceptibility of PBL to ex vivo UVR was examined using the comet assay, this revealed a reduction in tail moment from 84.4 (SD 3.4) at baseline to 69.4 (3.1) after EPA, P = 0.03. No significant changes were seen in any of the above parameters following OA supplementation. Reduction in this range of early markers, i.e. sunburn, UVR-induced p53 in skin and strand breaks in PBL, indicate protection by dietary EPA against acute UVR-induced genotoxicity; longer-term supplementation might reduce skin cancer in humans.

Topics: Adult; Aged; Ascorbic Acid; Biological Availability; Dietary Supplements; DNA; DNA Damage; DNA Repair; Double-Blind Method; Eicosapentaenoic Acid; Female; Genetic Markers; Glutathione; Humans; Lipid Peroxidation; Lymphocytes; Male; Middle Aged; Neoplasms, Radiation-Induced; Oleic Acid; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays; Vitamin E

Arsenic trioxide (As2O3) displays apoptogenic properties against various types of hematopoietic malignancies. We investigated the effects of As2O3 on the viability of the cutaneous T cell lymphoma cell lines HuT-78, SeAx, and Myla, and of peripheral blood mononuclear cells from patients with Sézary syndrome, by using propidium iodide and annexin-V staining, terminal deoxyuridine triphosphate nick end labeling (TUNEL), cell cycle analysis, mitochondrial transmembrane potential (delta psi(m)) alterations, cytochrome c release, and detection of processed caspase-3. We also report in vivo effects of As2O3 in two patients with cutaneous T cell lymphoma. The results show that As2O3 induces apoptosis of cutaneous T cell lymphoma lines and of Sézary cells from patients in a time- and concentration-dependent manner in vitro, as demonstrated by annexin-V staining, mitochondrial depolarization, and DNA fragmentation. Ascorbic acid 100 microM potentiated As2O3-induced Sézary cell death, whereas interferon-alpha had no synergistic effect. As2O3-induced Sézary cell death involves activation of caspase-3, cleavage of poly(ADP-ribose)polymerase, and cytochrome c release, but was only partially inhibited by the pancaspase inhibitor Z-VAD.fluoromethylketone. Finally, As2O3 was administered to two patients with cutaneous T cell lymphoma, allowing us to obtain a partial response in one case, whereas stability was observed in the second patient. These results demonstrate that As2O3 synergizes with ascorbic acid to induce Sézary cell death at clinically achievable concentrations, through a caspase-partially independent pathway, and provide a rationale for further in vivo studies addressing the therapeutic efficacy of As2O3 in cutaneous T cell lymphoma patients.

Topics: Aged; Antineoplastic Agents; Antioxidants; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Caspases; Cell Division; Cell Line, Tumor; Clone Cells; Drug Synergism; Humans; Leukocytes, Mononuclear; Lymphoma, T-Cell, Cutaneous; Middle Aged; Mitochondria; Oxides; Skin Neoplasms

Longitudinal studies are often concerned with estimating the recurrence rate of a non-fatal event. In many cases, only the total number of events occurring during successive time intervals is known. We compared a mixed Poisson-gamma regression method proposed by Thall and a quasi-likelihood method proposed by Zeger and Liang for the analysis of such data, in the case where the mean was correctly specified, using simulation techniques with large samples. Both methods produced similar standard errors in most situations, except in the case of time-dependent covariates with non-Poisson-gamma data where they were seriously underestimated by the Thall method. A simple method for discriminating between the variance forms of the two methods is described. The findings are applied to the analyses of clinical trials of non-melanoma skin cancer and familial polyposis. This study extends the findings of Breslow concerning variance misspecification in overdispersed Poisson and quasi-likelihood models to the longitudinal setting.

Topics: Adenomatous Polyposis Coli; Adjuvants, Immunologic; Ascorbic Acid; beta Carotene; Carotenoids; Combined Modality Therapy; Data Interpretation, Statistical; Dietary Fiber; Double-Blind Method; Female; Humans; Likelihood Functions; Longitudinal Studies; Male; Models, Statistical; Morbidity; Poisson Distribution; Risk Factors; Skin Neoplasms; Vitamin E

Topics: Ascorbic Acid; Carcinoma, Squamous Cell; Humans; Risk Factors; Skin Neoplasms

Topics: Animals; Ascorbic Acid; Itraconazole; Mice; Skin Absorption; Skin Neoplasms

Whereas the prevalence of several cancer types is decreasing, skin malignancies are growing more common every year. Malignant melanoma is the most aggressive form of skin cancer with high metastatic capacity. In most cases, malignant melanoma shows acquired therapy resistance. We evaluated the ability of Ocoxin, a natural compound-based antioxidant and anti-inflammatory nutritional complement, to exert an antitumor effect in melanoma. To do so, the cytotoxicity of Ocoxin in a panel of BRAF-mutated murine and human melanoma cell lines was tested alone and in combination with BRAF inhibitor Vemurafenib. Our results revealed a potent cytotoxic effect of Ocoxin against melanoma cells and a synergic effect when combined with Vemurafenib, reducing viability and increasing apoptosis. Besides, Ocoxin interferes with the cell cycle, impairs the inherent and fibroblast-mediated melanoma cell migration, and reduces resistance to BRAF inhibition. Proteomic analysis revealed reduced tumor secretion of inflammatory factors Galectin-1, Osteopontin, CCL5, and CCL9 upon treatment with Ocoxin. Moreover, RNASeq showed that Ocoxin downregulated the cell cycle and proliferation-related genes. In vivo, Ocoxin reduced the number of lung metastasis of YUMM-1.7 melanoma cells. Therefore, Ocoxin arises as a good candidate for clinical trials analyzing the beneficial effects in patients suffering from this cutaneous malignancy.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Cancer-Associated Fibroblasts; Cell Line, Tumor; Drug Resistance, Neoplasm; Folic Acid; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Pantothenic Acid; Plant Extracts; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib; Vitamin B 12; Vitamin B 6; Zinc Sulfate

The incidence of skin cancers such as non-melanoma skin cancer and malignant melanoma has increased in the last few years mainly because of chronic exposure to ultraviolet (UV) radiation. Sunscreens protect the skin against harmful UV radiations; however, some limitations of these products justify the discovery of new UV filters. Novel 1,3,5-triazine derivatives (12a-h) obtained by the optimization of prototype resveratrol were synthesized and characterized. All compounds exhibited sun protection factor (SPF) and UVA protection factor (UVAPF) in the range of 3-17 and 3-13, respectively. These values were superior to resveratrol and the UV filter ethylhexyl triazone (EHT) currently available on the market. In addition, all compounds demonstrated in vitro antioxidant activity and thermal stability with the decomposition at temperatures above 236 °C. In conclusion, the novel 1,3,5-triazine derivatives have emerged as new UV filters with antioxidant effect useful to prevent skin cancer.

Topics: Antioxidants; Humans; Skin Neoplasms; Sunscreening Agents; Triazines

Vitamin C has been used in complementary and alternative medicine for cancers regardless of its ineffectiveness in clinical trials and the paradoxical effects antioxidants have on cancer. Vitamin C was found to induce cytotoxicity against cancers. However, the mechanisms of action have not been fully elucidated, and the effects of vitamin C on human malignant melanoma have not been examined. This study revealed that vitamin C at millimolar concentrations significantly reduced the cell viability as well as invasiveness, and induced apoptosis in human malignant melanoma cells. Vitamin C displayed stronger cytotoxicity against the Vemurafenib-resistance cell line A2058 compared with SK-MEL-28. In contrast, vitamin C at micromolar concentrations promoted cell growth, migration and cell cycle progression, and protected against mitochondrial stress. Vemurafenib paradoxically activated the RAS-RAF-MEK-ERK signaling pathway in the Vemurafenib-resistant A2058, however, vitamin C abolished the activations. Vitamin C displayed synergistic cytotoxicity with Vemurafenib against the Vemurafenib-resistant A2058. In vivo assay suggested that lower dosage (equivalent to 0.5 g/70 kg) of vitamin C administered orally increased the melanoma growth. Therefore, vitamin C may exert pro- or anti-melanoma effect depending on concentration. The combination of vitamin C at high dosage and Vemurafenib is promising in overcoming the action of drug resistance.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cell Cycle; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Drug Synergism; Humans; Indoles; Male; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Skin; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents; Ascorbic Acid; Carcinoma, Basal Cell; Female; Humans; Male; Neoplasm Recurrence, Local; Skin Neoplasms; Treatment Outcome

Lichens are considered a great bio-resource because they produce large numbers of secondary metabolites with many biological activities; however, they have not been cultivated under artificial conditions to date. As a result, lichen substances from natural sources are limited and have not been widely utilized in commercial applications. Accordingly, interest in lichen-associated fungi, especially endogenic fungi, has increased. Ultraviolet (UV) radiation in sunlight is harmful to human health, resulting in demand for effective UV filtering agents for use in sunscreen. In this study, we purified (3

Topics: Animals; Anti-Infective Agents; Antioxidants; Ascorbic Acid; Biphenyl Compounds; Butylated Hydroxyanisole; Candida albicans; Cell Line; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Isocoumarins; Keratinocytes; Lichens; Lipid Peroxidation; Melanins; Melanoma, Experimental; Mice; Picrates; Saccharomycetales; Skin Neoplasms; Sunscreening Agents; Superoxides

Low-molecular-weight antioxidants are some of the most efficient agents of the skin defense mechanism against environmental factors, such as cosmic rays, smoke, and pollutants. The total skin concentrations of hydrophilic ascorbic and uric acids, as well as lipophilic α-tocopherol, β-carotene, and ubiquinol-10 antioxidants were determined by an HPLC-EC detector from 18 biopsies of human nonmelanoma skin carcinomas and 18 biopsies from skin areas adjacent to carcinomas. No significant differences in the concentrations of lipophilic antioxidants in both carcinomas and normal-looking skin areas adjacent to carcinomas were observed. On the contrary, ascorbic and uric acid concentrations were found to be 18 and 36% lower in carcinomas than in normal-looking skin areas, respectively. No statistical significance was observed between antioxidant concentrations and age, sex, phototype, profession, site of tumor, frequency, and time of UV light exposure either. Accordingly the antioxidant concentrations in both cancerous skin and adjacent normal-looking areas were found to be much higher than in normal skin, in contrast to literature data.

Topics: Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Male; Middle Aged; Molecular Weight; Skin; Skin Neoplasms; Ubiquinone; Uric Acid

Alpha-tocopheryl succinate (αTOS), vitamin K3 (VK3) and vitamin C (ascorbic acid, AA) were previously shown to synergistically promote different death pathways in carcinoma cells, depending on their concentrations and combinations. Similar effects were observed herein in melanoma cells, although αTOS behaved as an antagonist. Interestingly, suboptimal cell death-inducing concentrations (1.5 μM αTOS/20 μM AA/0.2 μM VK3) effectively up-regulated activating Natural Killer (NK) cell ligands, including MICA (the stress-signaling ligand of the NKG2D receptor), and/or the ligands of at least one of the natural cytotoxicity receptors (NKp30, NKp44 and NKp46) in 5/6 melanoma cell lines. Only an isolated MICA down-regulation was seen. HLA class I, HLA class II, ULBP1, ULBP2, ULBP3, Nectin-2, and PVR displayed little, if any, change in expression. Ligand up-regulation resulted in improved lysis by polyclonal NK cells armed with the corresponding activating receptors. These results provide the first evidence for concerted induction of cell death by cell-autonomous and extrinsic (immune) mechanisms. Alarming the immune system much below the cell damage threshold may have evolved as a sensitive readout of neoplastic transformation and oxidative stress. Cocktails of vitamin analogues at slightly supra-physiological dosages may find application as mild complements of melanoma treatment, and in chemoprevention.

Topics: alpha-Tocopherol; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Drug Synergism; Humans; Killer Cells, Natural; Melanoma; Oxidants; Oxidative Stress; Signal Transduction; Skin Neoplasms; Vitamin K 3; Vitamins

Chronic ultraviolet (UV) radiation exposure is a major cause of skin cancer. A novel series of hybrid derivatives (I-VIII) for use in sunscreen formulations were synthesized by molecular hybridization of t-resveratrol, avobenzone, and octyl methoxycinnamate, and were characterized. The antioxidant activity values for VIII were comparable than to those of t-resveratrol. Compounds I-III and VI demonstrated Sun Protector Factor superior to that of t-resveratrol. Compounds I and IV-VIII were identified as new, broad-spectrum UVA filters while II-III were UVB filters. In conclusion, novel hybrid derivatives with antioxidant effects have emerged as novel photoprotective agents for the prevention of skin cancer.

Topics: Antioxidants; Cinnamates; Humans; Propiophenones; Resveratrol; Skin Neoplasms; Stilbenes; Sun Protection Factor; Sunscreening Agents; Ultraviolet Rays

DNA methylation plays important roles in various kinds of carcinogenesis. Vitamin C could induce Tet-dependent DNA demethylation in embryonic stem cells. Therefore, the antagonizing activity of vitamin C on ultraviolet (UV)-induced apoptosis was investigated in this study.. Apoptosis of human epidermoid carcinoma A431 cells and p16-knockout (KO) or p21-KO fibroblasts was assessed by a fluorescence-activated cell sorter. Real-time PCR and western blot were used to determine the relative expression levels of p12, p21, and Tet1/2/3 genes. The global DNA methylation levels were determined using MethylFlash Methylated DNA Quantification Kit in A431 cells with or without vitamin C treatment. To examine the DNA demethylation activity of vitamin C, DNA immunoprecipitation (DIP)-qPCR was performed to determine the relative levels of 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) in p16 and p21 promoter regions containing cytosine-phosphorothiolated guanine (CpG) islands.. The increasing apoptosis of A431 cells under prolonged UV irradiation was remarkably decreased by the combination of vitamin C treatment, suggesting that vitamin C protects against UV-induced apoptosis. Concurrently, vitamin C induced a significant reduction of global DNA methylation in a time- and dose-dependent manner in A431 cells. Vitamin C also reactivated the expression of p16 and p21 at mRNA and protein levels. Mechanistically, about 27% 5hmC-positive cells were observed in vitamin C-treated A431 cells, and the 5hmC enrichment at p16 and p21 promoter regions was also largely increased by vitamin C. Moreover, the expression of p16 and p21 was decreased in Tet1/2 double-knockdown cells, in which the inhibitory effect of vitamin C on UV-induced apoptosis was dismissed. Furthermore, the inhibition of UV-induced apoptosis on vitamin C treatment nearly disappeared in p16- or p21-knockout primary cultured fibroblasts.. These results demonstrate that vitamin C effectively antagonizes UV-induced apoptosis through regulation of Tet activity, DNA demethylation, and subsequent tumor suppressor gene activation in skin cancer cells.

Topics: Animals; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; DNA Methylation; Gene Knockout Techniques; Genes, Tumor Suppressor; Humans; Mice, Knockout; Neoplasm Proteins; Skin Neoplasms; Transfection; Ultraviolet Rays

Benzanthrone (BA) exposed occupational workers have been found to exhibit toxicological manifestations in the skin, thus it is quite likely that long term exposure may lead to skin tumorigenicity. Thus, attempts were made to elucidate the tumor initiating and promoting potentials of pure (PBA) and commercial benzanthrone (CBA). Additionally, the preventive role of ascorbic acid (AsA) was also assessed. PBA showed tumor initiating activity while CBA demonstrated tumor initiating as well as promoting activities in two-stage mouse skin tumor protocol. Further, prior treatment of AsA to PBA and CBA followed by twice weekly application of 12-o-tetradecanoyl phorbal myristate acetate (TPA) resulted into delayed onset of tumor formation and similarly single application of 7,12-dimethylbenz [α] anthracene (DMBA) followed by twice weekly application of AsA and CBA showed an increase in the latency period. Thus, AsA showed a protective effect against CBA promoted skin tumor. Furthermore, the topical application of CBA significantly increased the levels of xenobiotic enzymes. The animals topically treated with AsA along with topical application of CBA, restored all the impairment observed in enzyme activities. Thus, this study suggested that AsA can be useful in preventing PBA and CBA induced skin tumorigenicity.

Topics: Administration, Cutaneous; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Benz(a)Anthracenes; Carcinogens; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Down-Regulation; Enzyme Induction; Female; Glutathione Transferase; Mice; Neoplasm Proteins; Quinone Reductases; Skin; Skin Neoplasms; Time Factors

Cutaneous melanoma incidence has been increasing during the last few years, and diet has been suggested as one of the lifestyle factors responsible for this increase. Since antioxidant nutrients such as ascorbic acid might prevent skin carcinogenesis, we investigated the risk of cutaneous melanoma related to vitamin C intake in a population-based case-control study in Northern Italy based on 380 melanoma patients and 719 matched controls, to whom we administered a semiquantitative food-frequency questionnaire. After adjusting for potential confounders, odds ratio of melanoma were 0.86 (95 % confidence interval 0.65 - 1.15) and 0.59 (95 % confidence interval 0.37 - 0.94) in the intermediate and highest categories of vitamin C dietary intake respectively, compared with the bottom one. The association between vitamin C and decreased risk persisted after adjustment for some potential confounders. In age- and gender-stratified analyses, this association was seen in young females (< 60 years old), and was found to be enhanced in subjects with phototypes II and III. These results suggest a possible protective activity of vitamin C intake against cutaneous melanoma in specific subgroups of this population of Northern Italy.

Topics: Age Distribution; Antioxidants; Ascorbic Acid; Case-Control Studies; Diet; Feeding Behavior; Female; Humans; Italy; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Odds Ratio; Risk Factors; Sex Distribution; Skin Neoplasms; Surveys and Questionnaires

Studies suggest that diet may influence in skin ageing and skin appearance. However, the effect of diet in the elastotic changes of dermis, which is the main histological sign of ageing, has not been studied previously. The objective was to investigate if the dietary habits influence the dermal elastosis observed in BCCs.. The 136 patients with facial BCCs, who underwent surgery, were interviewed to assess the consumption of fruit, vegetables, fat, red meat, coffee and tea. We reviewed 136 specimens of BCC to identify the presence of solar elastosis. We also analysed clinical variables such as gender, age, phototype and smoking.. Severe solar elastosis was found in 22 patients (16%), middle reticular dermis in 37 (27 %) and 77 patients (57%) had abscence or light elastosis. Fat consumption was reported by most of participants from our sample, while fruit and tea consumption was less common. Intakes of fat, vegetables and coffee were not associated with the grade of elastosis whereas Vitamin E and C-rich fruits and tea were correlated with less risk of elastosis. Smokers showed higher grades of elastosis than non-smokers.. Our study provides evidence that the presence of dermal elastosis and cutaneous ageing may be influenced by the type of food intake: Vitamin E and C-rich fruit and tea are positively associated with less elastosis.

Topics: Aged; Ascorbic Acid; Biopsy, Needle; Carcinoma, Basal Cell; Chi-Square Distribution; Cohort Studies; Dietary Supplements; Eating; Elasticity; Feeding Behavior; Female; Humans; Immunohistochemistry; Male; Middle Aged; Risk Assessment; Skin Aging; Skin Neoplasms; Smoking; Surveys and Questionnaires; Ultraviolet Rays; Vitamin E

The present study evaluates the modulatory potential of Phyllanthus niruri on chemically induced skin carcinogenesis, and its influence on oxidative stress and the antioxidant defense system. Oral administration of P. niruri extract (PNE), during peri- (Gr. III), post- (Gr. IV), or peri- and post- (Gr. V) initiational stages of 7,12-dimethylbenz(a) anthracene (DMBA)-croton oil–induced papillomagenesis considerably reduced tumor burden to 4.20, 4.00, and 3.33(positive control value 6.20); cumulative number of papillomas to 21, 16, and 10, respectively, (positive control value 62); and incidence of mice bearing papillomas to 50, 40, and 30%, respectively (positive control value 100%), but significantly increased the average latent period to 10.14, 10.62, and 11.60, and inhibition of tumor multiplicity to 66, 74,and 83%, respectively. Enzyme analysis of skin and liver showed a significant (p ≤ 0.05, ≤ 0.01, ≤ 0.001) elevation in antioxidant parameters such as superoxide dismutase, catalase, glutathione, and vitamin C in PNE-treated groups (Gr. III–V) when compared with the carcinogen-treated control (Gr. II). The elevated level of lipid peroxidation in the carcinogen-treated positive control group was significantly (p ≤ 0.05, ≤ 0.01, ≤ 0.001) inhibited by PNE administration. These results indicate that P. niruri extract has potentiality to reduce skin papillomas by enhancing antioxidant defense system.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Ascorbic Acid; Glutathione; Lipid Peroxidation; Male; Mice; Oxidative Stress; Papilloma; Phyllanthus; Phytotherapy; Plant Extracts; Skin Neoplasms

Quercetin (Qu) is currently being investigated as a chemopreventive agent for several cancers, including nonmelanoma skin cancer induced by UV light. We previously reported that Qu degradation has important consequences on signaling and cell biology. In the current study, we report that Qu induces c-Fos mRNA and protein expression through activation of p38 and cAMP-responsive element binding protein (CREB), and Qu potentiates UVB-induced c-Fos expression. Inclusion of ascorbic acid (AA) in cell culture medium stabilizes Qu and completely prevents both Qu- and UVB-induced p38 and CREB activation, leading to a blockade of c-fos gene expression through reduced CREB/cAMP-responsive element binding. AA stabilizes c-Fos mRNA, increasing steady-state levels even when c-fos gene expression is suppressed, but this has no effect on c-Fos protein levels in either mock- or UVB-irradiated cells. We report that Qu blocks mammalian target of rapamycin signaling and inhibits c-Fos protein expression directly through this mechanism because cotreatment with Qu and AA resulted in the complete suppression of UVB-induced c-Fos protein expression even in the presence of significantly increased mRNA levels. We further confirmed that this was not due to increased protein turnover because inhibition of proteasome activity with MG-132 did not raise c-Fos protein levels in Qu+AA-treated cells. Together, these data indicate that although Qu has been reported to have some beneficial properties as a chemopreventive agent, it is also capable of inducing c-fos expression, a cellular event important for the promotion phase of tumor development, if it is not stabilized.

Topics: Anticarcinogenic Agents; Ascorbic Acid; Cell Line; Cyclic AMP Response Element-Binding Protein; Drug Stability; Humans; Intracellular Signaling Peptides and Proteins; Keratinocytes; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-fos; Quercetin; Skin Neoplasms; TOR Serine-Threonine Kinases; Ultraviolet Rays

Previously, we reported that acetaminophen (APAP) showed selective toxicity towards melanoma cell lines. In the current study, we investigated further the role of tyrosinase in APAP toxicity in SK-MEL-28 melanoma cells in the presence of a short hairpin RNA (shRNA) plasmid, silencing tyrosinase gene. Results from tyrosinase shRNA experiments showed that APAP led to negligible toxicity in shRNA plasmid-treated cells. It was also found that APAP selectively caused escalation in reactive oxygen species (ROS) formation and intracellular GSH (ICG) depletion in melanocytic human SK-MEL-28 and murine B16-F0 melanoma cells that express functional tyrosinase whereas it lacked significant effects on ROS formation and ICG in amelanotic C32 melanoma cells that do not express functional tyrosinase. These findings suggest that tyrosinase plays a major role in APAP selective induced toxicity in melanocytic melanoma cell lines. Furthermore, the in vivo efficacy and toxicity of APAP in the skin melanoma tumor model in mice was investigated. Mice receiving APAP at 60, 80, 100 and 300 mg/kg/day, day 7 through 13 post melanoma cell inoculation demonstrated tumor size growth inhibition by 7+/-14, 30+/-17, 45+/-11 and 57+/-3%, respectively. Mice receiving APAP day 1 through 13 post melanoma cell inoculation showed tumor size growth inhibition by 11+/-7, 33+/-9, 36+/-20 and 44+/-28%, respectively.

Topics: Acetaminophen; Animals; Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glutathione; Humans; Inhibitory Concentration 50; Kidney; Lipid Peroxidation; Liver; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Monophenol Monooxygenase; NAD; Oxidation-Reduction; Phenacetin; Reactive Oxygen Species; RNA Interference; Skin Neoplasms; Sulfhydryl Compounds; Time Factors

The annual incidence of all forms of skin cancer, the most common of all human cancers, is increasing yearly. A unique nutrient mixture (NM) was shown to exhibit anticancer activity in vivo and in vitro. We examined the effect of NM on the development of skin cancer induced by 7,12-dimethylbezanthracene (DMBA) in female SENCAR mice by a complete carcinogenesis protocol. Mice (n=55) were divided into four groups and carefully shaved on dorsum. After 2 days, the mice in Groups 1 (n=10), 3 (n=20), and 4 (n=20) were treated topically with 100 nM DMBA in 0.2 ml of acetone twice a week for 4 weeks; Group 2 (n=5), the control group, was treated with acetone 0.2 ml. Groups 1 and 2 were fed the regular diet. Group 3A (n=10) was fed a diet containing 0.5% NM from the day of DMBA treatment and 3B (n=10) the regular diet and received NM (75 mg in 0.4 ml of 1:1 acetone/water) topically to the shaved area 15 min before DMBA application twice a week for 4 weeks. Group 4 mice were fed a diet containing 0.5% NM for 2 weeks prior to the application of DMBA and then divided into two groups: 4A (n=10) was fed the 0.5% NM diet as in 3A, and 4B (n=10) the regular diet as described for 3B. Body weight and diet consumption of the mice were monitored and the skin tumors (papillomas) were counted and recorded. Ten weeks thereafter the mice were euthanized, skinned, and tumors were processed for histology. NM significantly (P<0.0001) inhibited DMBA-induced skin tumor multiplicity by 59, 62, 69, and 86% in NM-treated Groups 3A, 3B, 4A, and 4B, respectively. These results suggest that NM has strong potential as a useful therapeutic regimen for skin cancer by significantly inhibiting the incidence and tumor multiplicity of DMBA-induced skin tumors.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetylcysteine; Amino Acids; Animals; Arginine; Ascorbic Acid; Camellia sinensis; Carcinogens; Copper; Diet; Female; Keratoacanthoma; Lysine; Manganese; Mice; Mice, Inbred SENCAR; Papilloma; Plant Extracts; Proline; Selenium; Skin; Skin Neoplasms

We assessed whether the functional V16A polymorphism in the MnSOD gene is associated with skin cancer risk.. We conducted a nested case-control study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 matched controls) within the Nurses' Health Study. Genotyping was performed by the 5' nuclease assay (TaqMan). We used logistic regression to model the association between the genotype and skin cancer risk.. Overall, there was no significant association between this polymorphism and the risk of each type of skin cancer. No significant interaction was observed between this polymorphism and sunburn history and constitutional susceptibility on skin cancer risk. For interactions between intakes of alpha-carotene and beta-carotene and the MnSOD polymorphism on SCC, the inverse association of intake of either carotene with SCC risk was limited to the Val carriers, whereas no association was observed among women with the AA genotype. We observed an interaction between total vitamin C intake and the MnSOD polymorphism on melanoma risk. No interaction was observed for the intakes of other carotenoids, vitamin E, and vitamin A. Further research is needed to confirm these possible associations.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Case-Control Studies; Female; Genotype; Humans; Logistic Models; Middle Aged; Oxidative Stress; Polymorphism, Genetic; Risk Assessment; Risk Factors; Skin Neoplasms; Superoxide Dismutase

Cancer is associated with increased cell growth, and expression of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-beta). The dose-dependent effects of ascorbate (Vitamin C) on cancer cell growth, and expression of MMPs and TGF-beta were examined. Renal-adenocarcinoma, melanoma and mammary cancer cells were dosed with 0-100mM ascorbate and examined for cell survival or proliferation, and expression of MMP-1, MMP-2 and TGF-beta at protein and/or mRNA levels. The lower concentrations of ascorbate significantly inhibited cancer cell viability while stimulating MMPs and TGF-beta expression, indicating elimination of cancer cells with damage to the extracellular matrix (ECM). Conversely, ascorbate at higher concentrations dramatically stimulated cell proliferation and inhibited MMPs and TGF-beta expression, implicating growth and ECM advantage.

Topics: Adenocarcinoma; Antioxidants; Ascorbic Acid; Breast Neoplasms; Cell Survival; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Humans; Kidney Neoplasms; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Melanoma; RNA, Messenger; Skin Neoplasms; Transforming Growth Factor beta1; Tumor Cells, Cultured

To investigate the associations between intake of antioxidant nutrients and risk of basal cell (BCC) and squamous cell carcinomas (SCC) of the skin, we carried out a prospective study among 1001 randomly selected adults living in an Australian community. Intake of antioxidants was estimated in 1996. Incident, histologically-confirmed BCC and SCC were recorded between 1996 and 2004. High dietary intake of lutein and zeaxanthin was associated with a reduced incidence of SCC in persons who had a history of skin cancer at baseline (highest versus lowest tertile, multivariable adjusted relative risk (RR)=0.47, 95% confidence interval (CI): 0.25-0.89; P for trend=0.02). In persons without a history of skin cancer at baseline, development of BCC was positively associated with intake of vitamins C and E from foods plus supplements (RR=3.1, 95% CI: 1.1-8.6; P for trend=0.03 and RR=2.6, 95% CI: 1.1-6.3; P for trend=0.02, respectively). In those with a skin cancer history at baseline, dietary intake in the second tertile for beta-carotene (multivariable adjusted RR=2.2, 95% CI: 1.2-4.1) and for vitamin E (multivariable adjusted RR=2.1, 95% CI: 1.1-3.9) was associated with increased BCC risk, with no trend, and similar results were seen in those with a specific history of BCC. These data suggest quite different associations between antioxidant intake and SCC compared with BCC, consistent with other evidence of their different causal pathways.

Topics: Aged; Antioxidants; Ascorbic Acid; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Epidemiologic Methods; Female; Humans; Male; Middle Aged; Queensland; Selenium; Skin Neoplasms; Vitamin E

Vitamin C has been reported to be useful in the treatment and prevention of cancer. Inconsistent effects from growth stimulation to induction of apoptosis of malignant tumor cells, however, have been reported. Melanoma is an increasingly common and potentially lethal malignancy. It was reported that melanoma cells were more susceptible to ascorbate toxicity than any other tumor cells. The mechanisms accounting for ascorbate-induced apoptosis in human melanoma cells, however, have remained unclear. This study was undertaken to investigate the effect of sodium ascorbate on cytotoxicity and apoptosis in human malignant melanoma A375.S2 cells. A375.S2 cells were incubated with a certain range of concentrations of sodium ascorbate for various time periods. In order to examine the effects of sodium ascorbate on cell proliferation, cell cycle, apoptosis and necrosis, we performed 4,6-diamidino-2-phenylindole dihydrochloride assays and flow cytometry analysis. Polymerase chain reaction was used to examine the mRNA levels of p53, p21, p27, cyclin A, cyclin E, CDK2 and CDK4, which are associated with cell cycle S-phase arrest and apoptosis. Flow cytometric analysis showed that sodium ascorbate significantly induced cell cycle arrest and apoptosis in the A375.S2 cell line in a dose-dependent manner. The increased expressions of p53 and p21, and the decreased expressions of cyclin A, cyclin E, CDK2 and CDK4, indicated the cell cycle arrest at G1/S phase after the cells had been treated with sodium ascorbate. Induction of apoptosis involved an increase in the levels of p53, p21 and cellular Ca, and a decrease in mitochondrial membrane potential and activation of caspase 3 before culminating in apoptosis in sodium ascorbate-treated A375.S2 cells.

Topics: Apoptosis; Ascorbic Acid; Calcium; Caspase 3; Cell Proliferation; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Flow Cytometry; G1 Phase; Humans; Intracellular Signaling Peptides and Proteins; Melanoma; Membrane Potential, Mitochondrial; Oncogene Proteins; Reactive Oxygen Species; S Phase; Skin Neoplasms; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Helicobacter pylori (H. pylori) infection, the main cause of chronic gastritis, increases gastric cancer risk. The infection causes inflammatory cells to produce reactive oxygen metabolites that may damage DNA and promote carcinogenesis. However, its precise role in gastric carcinogenesis is as yet unknown. Recently we reported that H. pylori water extract (HPE) has an initiating activity on two-stage mouse skin carcinogenesis. In this study, we investigated the effects of anti-oxidants, ascorbic acid and a combination of superoxide dismutase (CuZnSOD)and catalase, on two-stage mouse skin carcinogenesis. Ascorbic acid and CuZnSOD/catalase were given to mice during the period of HPE-initiation. Both the ascorbic acid and CuZnSOD/catalase treatment attenuated the incidence of tumor formation. The present results suggest that HPE induces tumor formation via reactive oxygen species (ROS) production.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Fractionation; Female; Helicobacter pylori; Mice; Mice, Inbred SENCAR; Mutation; Reactive Oxygen Species; Skin Neoplasms; Superoxide Dismutase

The light emitted by halogen quartz bulbs contains a broad spectrum of UV wavelengths, is strongly genotoxic and is a potent inducer of skin tumors in hairless mice. By using a UVC filter, this light mimics solar radiation and induces a variety of genomic and transcriptional alterations in mouse skin. UV-related carcinogenesis involves depletion of antioxidants and glutathione in skin cells. On this basis, we evaluated modulation of carcinogenicity of UVC-filtered halogen lamps in SKH-1 hairless mice by the antioxidants N-acetyl-l-cysteine (NAC) and ascorbic acid (AsA). Both agents were given in the drinking water, either individually or in combination. The earliest skin lesions were detected after 300 days' exposure to light and became confluent in a number of mice after 480 days. NAC administration prolonged the latency time by 90 days. Moreover, NAC considerably and significantly decreased both incidence and multiplicity of light-induced skin tumors, prevented the occurrence of malignant lesions (squamocellular carcinomas) and reduced the tumor size. In contrast, AsA, which may behave as a prooxidant rather than an antioxidant, increased the multiplicity of total skin tumors, carcinomas in situ and squamocellular carcinomas. Co-administration of NAC with AsA significantly attenuated the negative effect of AsA, presumably due to the ability of this thiol to maintain a reduced environment. Therefore, in agreement with our previous in vitro findings, oral NAC is able to attenuate the detrimental effects of AsA.

Topics: Acetylcysteine; Animals; Ascorbic Acid; Female; Mice; Mice, Hairless; Skin Neoplasms; Ultraviolet Rays

Sodium ascorbate (vitamin C) has a reputation for inconsistent effects upon malignant tumor cells, which vary from growth stimulation to apoptosis induction. Melanoma cells were found to be more susceptible to vitamin C toxicity than any other tumor cells. The present study has shown that sodium ascorbate decreases cellular iron uptake by melanoma cells in a dose- and time-dependent fashion, indicating that intracellular iron levels may be a critical factor in sodium ascorbate-induced apoptosis. Indeed, sodium ascorbate-induced apoptosis is enhanced by the iron chelator, desferrioxamine (DFO) while it is inhibited by the iron donor, ferric ammonium citrate (FAC). Moreover, the inhibitory effects of sodium ascorbate on intracellular iron levels are blocked by addition of transferrin, suggesting that transferrin receptor (TfR) dependent pathway of iron uptake may be regulated by sodium ascorbate. Cells exposed to sodium ascorbate demonstrated down-regulation of TfR expression and this precedes sodium ascorbate-induced apoptosis. Taken together, sodium ascorbate-mediated apoptosis appears to be initiated by a reduction of TfR expression, resulting in a down-regulation of iron uptake followed by an induction of apoptosis. This study demonstrates the specific mechanism of sodium ascorbate-induced apoptosis and these findings support future clinical trial of sodium ascorbate in the prevention of human melanoma relapse.

Topics: Animals; Antioxidants; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Iron; Melanoma; Mice; Receptors, Transferrin; RNA Processing, Post-Transcriptional; Skin Neoplasms

Adequate cellular transport of ascorbic acid (AA) and its oxidation product dehydroascorbate (DHA) is assured through specific carriers. It was shown that vitamin C is taken up as DHA by most cell types, including cancer cells, via the facilitative GLUT transporters. Thus, AA oxidation to DHA can be considered a mechanism favoring vitamin C uptake and intracellular accumulation. We have investigated whether such an AA-oxidizing action might be provided by plasma membrane gamma-glutamyltransferase (GGT), previously shown to function as an autocrine source of prooxidants. The process was studied using two distinct human metastatic melanoma clones. It was observed that the Me665/2/60 clone, expressing high levels of membrane GGT activity, was capable of effecting the oxidation of extracellular AA, accompanied by a marked increase of intracellular AA levels. The phenomenon was not observed with Me665/2/21 cells, possessing only traces of membrane GGT. On the other hand, AA oxidation and stimulation of cellular uptake were indeed observed after transfection of 2/21 cells with cDNA coding for GGT. The mechanism of GGT-mediated AA oxidation was investigated in acellular systems, including GGT and its substrate glutathione. The process was observed in the presence of redox-active chelated iron(II) and of transferrin or ferritin, i.e., two physiological iron sources. Thus, membrane GGT activity-often expressed at high levels in human malignancies-can oxidize extracellular AA and promote its uptake efficiently.

Topics: Ascorbic Acid; Biological Transport; Cell Line, Tumor; Cell Membrane; gamma-Glutamyltransferase; Glutathione; Humans; Iron Chelating Agents; Melanoma; Oxidation-Reduction; Skin Neoplasms; Transfection; Transferrin

Our objective was to examine prospectively the intake of vitamins A (including retinol and total vitamin A), C and E; folate; total carotene; and several individual carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin and lutein/zeaxanthin) in relation to incidence of SCC of the skin in 2 large cohorts of men and women. We used a prospective cohort study design with up to 14 years of follow-up in women and 10 years in men. Diet was measured with FFQs every 2-4 years; cases of SCC of the skin were ascertained on biennial questionnaires and confirmed by medical records. Participants were female nurses and male health professionals, from the Nurses' Healthy Study and the Health Professionals Follow-up Study in the United States, without a history of any cancer in 1982 (n = 85,944 women) and 1986 (n = 43,867 men). Follow-up response was achieved for over 90% of potential person-years. Relative risks and 95% confidence intervals for development of SCC of the skin are reported. We recorded 369 cases of SCC in women and 305 cases in men. After multivariate adjustment for various known behavioral, sun-exposure and sun-sensitivity risk factors for SCC, there were no significant inverse associations between these dietary factors and SCC incidence. No evidence was found that vitamins A, C and E; folate; or carotenoids play an important protective role against incident SCC.

Topics: Adult; Aged; Ascorbic Acid; Carcinoma, Squamous Cell; Carotenoids; Cohort Studies; Female; Humans; Incidence; Male; Middle Aged; Prospective Studies; Risk Factors; Sensitivity and Specificity; Skin Neoplasms; United States; Vitamin A; Vitamin E

We have shown previously that Vitamin E acts as a tumor promoter in 7,12-dimethylbenz(a)anthracene (DMBA) initiated mouse skin. We now show that high concentrations (80 micromol) of Vitamin E are required for promotion, and that 10-fold lower concentrations do not promote tumor formation. The same high concentration of the water-soluble anti-oxidant Vitamin C did not act as a tumor promoter, but did amplify the promoting effect of high, but not low, concentrations of Vitamin E. Oxidizing free radicals generated by beta-radiation exposure of the skin at the time of Vitamin E treatment also enhanced promotion by high (but not low) concentrations of Vitamin E. The results are consistent with a process whereby tumor promotion by the lipid-soluble Vitamin E occurs as a result of alpha-tocopherol acting as a free radical scavenger, with the formation and subsequent transfer of the alpha-tocopherol free radical center to the surrounding lipids, resulting in lipid oxidations.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Antioxidants; Ascorbic Acid; Beta Particles; Carcinogens; Cocarcinogenesis; Female; Free Radical Scavengers; Mice; Mice, Inbred SENCAR; Oxidation-Reduction; Radiation, Ionizing; Skin; Skin Neoplasms; Vitamin E

Acute effects of UV irradiation include UV-induced erythema. Sunlight plays an important role in the development of skin cancer. Several predictive factors of UV-induced erythema could also be predictive for skin cancer.. Our objective was to quantitatively assess phenotypical and nutritional determinants of sensitivity to UV irradiation, as assessed by the minimal erythema dose (MED).. We conducted a cross-sectional study among 335 volunteers. Sensitivity to UV irradiation was established through assessment of the MED. Phenotypical determinants, including skin melanin content, hair color and iris color were determined by skin reflectance spectrometry, a subjective questionnaire and an objective classification system, respectively. Furthermore, dietary exposure was measured by carotenoids, vitamin C, retinol and alpha-tocopherol in serum.. Male subjects were found to be more sensitive to UV irradiation; that is, the MED was significantly lower compared to female subjects. Skin melanin content, which was positively associated with iris color in both sexes and with hair color in men, was the main phenotypical determinant of sensitivity to UV irradiation. No associations were found between serum carotenoids and MED in the total study group. Vitamin C was inversely associated with MED. However, associations between carotenoids concentrations and MED showed a positive trend in subjects with melanin values above and a negative trend in subjects below the median after adjustment for gender and total cholesterol.. Skin melanin content and gender are important determinants of sensitivity to UV irradiation. No relation was found between serum carotenoids and MED in the total study group. The inverse association between vitamin C and MED was against our hypothesis. For the modifying effect of melanin on the association between carotenoids and MED, we do not have a clear biological explanation.

Topics: Adolescent; Adult; Aged; Ascorbic Acid; Carotenoids; Cross-Sectional Studies; Dose-Response Relationship, Radiation; Erythema; Eye Color; Female; Hair Color; Humans; Male; Melanins; Middle Aged; Sex Factors; Skin; Skin Neoplasms; Skin Pigmentation; Ultraviolet Rays

We recently reported that interleukin-18 (IL-18) is highly expressed in malignant skin tumours such as melanomas, and may play a key role in the malignancy of such tumours. This study was designed to investigate the mechanisms of IL-18 regulation by vitamin C in B16F10 murine melanoma cells. Cells were treated with vitamin C, and the expression of IL-18 was measured by reverse transcription-polymerase chain reaction and intracellular flow cytometry analysis. Decreased IL-18 production and a significant reduction in IL-18 mRNA transcript were detected in cells treated with vitamin C. The effect of vitamin C treatment was blocked by the antioxidant N-acetyl-L-cysteine, suggesting that vitamin C affects IL-18 expression by up-regulating intracellular reactive oxygen intermediate (ROI) levels. To investigate whether the mitogen-activated protein kinase (MAPK) signalling pathway is involved in the downregulation of IL-18 production, cells were pretreated with SB203580, an inhibitor of p38 MAPK, prior to the addition of vitamin C. This pretreatment blocked the decrease in IL-18 production. However, vitamin C treatment enhanced the expression of phosphorylated p38 MAPK. Taken together, we conclude that vitamin C increases intracellular ROI levels, and regulates IL-18 production through the MAPK signalling pathway.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Blotting, Western; Cell Line, Tumor; Densitometry; Down-Regulation; Enzyme Inhibitors; Flow Cytometry; Imidazoles; Immunoprecipitation; Interleukin-18; MAP Kinase Signaling System; Melanoma; Mice; p38 Mitogen-Activated Protein Kinases; Pyridines; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Skin Neoplasms; Time Factors

We examined prospectively intakes of vitamins A. C, and E, folate, and specific carotenoids in relation to the risk of basal cell carcinoma of the skin (BCC) in women.. Dietary intake was assessed by food-frequency questionnaires every two-four years and the first diagnosis of BCC was ascertained by self-report every two years. We used logistic regression to model the association between dietary intake and the risk of BCC adjusting for various health, sun exposure, and sun sensitivity factors.. During 12 years of follow-up we recorded 5392 cases. We did not find any significant inverse associations between these dietary factors and BCC. On the contrary. weak positive trends were seen with vitamins A, C, and E, and folate. The multivariate relative risks (RRs) comparing the top to bottom quintile were 1.20 (95% CI = 1.10-1.31) for folate, 1.16 (95% CI = 1.06-1.26) for vitamin A. 1.13 (95% CI = 1.03-1.23) for vitamin C, and 1.15 (95% CI = 1.06-1.26) for vitamin E. Exploration of latency periods did not suggest different associations with a particular duration.. We did not find evidence that vitamins A, C, and E. and folate. or specific carotenoids play an important protective role against the incidence of BCC.

Topics: Adult; Age Distribution; Ascorbic Acid; Carcinoma, Basal Cell; Carotenoids; Cohort Studies; Confidence Intervals; Diet; Dietary Supplements; Female; Humans; Incidence; Logistic Models; Middle Aged; Probability; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Skin Neoplasms; United States; Vitamin A; Vitamin E; Vitamins

The inhibitory effects of N-(4-hydroxyphenyl)retinamide (4HPR) on the process of carcinogenesis are not fully understood and may result from its ability to induce apoptosis in transformed cells. This study investigated the apoptotic properties of 4HPR in four human cutaneous squamous cell carcinoma cell lines. Apoptosis induction, detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling method, occurred in a dose- and time-dependent fashion after treatment with 4HPR. 4HPR promoted reactive oxygen species (ROS) determined by oxidation of 2',7'-dichlorofluorescin. 4HPR-induced ROS, and apoptosis could be inhibited by L-ascorbic acid. Rhodamine 123 retention revealed that 4HPR treatment promoted a gradual dissipation of mitochondrial inner transmembrane potential, and this could be inhibited by L-ascorbic acid, implying that mitochondrial permeability transition was involved in apoptosis induction. Cyclosporin A and bongkrekic acid inhibited dissipation of mitochondrial inner transmembrane potential, ROS production, and DNA fragmentation after exposure to 4HPR, demonstrating that mitochondrial permeability transition was a central coordinating feature of 4HPR-induced apoptosis.

Topics: Anticarcinogenic Agents; Apoptosis; Ascorbic Acid; Carcinoma, Squamous Cell; Cell Division; Cyclosporine; DNA Fragmentation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Fenretinide; Fluoresceins; Fluorescent Dyes; Humans; Intracellular Membranes; Membrane Potentials; Mitochondria; Oxidation-Reduction; Permeability; Reactive Oxygen Species; Rhodamine 123; Skin Neoplasms; Tumor Cells, Cultured

Procyanidins present in grape seeds are known to exert anti-inflammatory, anti-arthritic and anti-allergic activities, prevent skin aging, scavenge oxygen free radicals and inhibit UV radiation-induced peroxidation activity. Since most of these events are associated with the tumor promotion stage of carcinogenesis, these studies suggest that grape seed polyphenols and the procyanidins present therein could be anticarcinogenic and/or anti-tumor-promoting agents. Therefore, we assessed the anti-tumor-promoting effect of a polyphenolic fraction isolated from grape seeds (GSP) employing the 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted SENCAR mouse skin two-stage carcinogenesis protocol as a model system. Following tumor initiation with DMBA, topical application of GSP at doses of 0.5 and 1.5 mg/mouse/application to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The observed anti-tumor-promoting effects of GSP were dose dependent and were evident in terms of a reduction in tumor incidence (35 and 60% inhibition), tumor multiplicity (61 and 83% inhibition) and tumor volume (67 and 87% inhibition) at both 0.5 and 1.5 mg GSP, respectively. Based on these results, we directed our efforts to separate and identify the individual polyphenols present in GSP and assess their antioxidant activity in terms of inhibition of epidermal lipid peroxidation. Employing HPLC followed by comparison with authentic standards for retention times in HPLC profiles, physiochemical properties and spectral analysis, nine individual polyphenols were identified as catechin, epicatechin, procyanidins B1-B5 and C1 and procyanidin B5-3'-gallate. Five of these individual polyphenols with evident structural differences, namely catechin, procyanidin B2, procyanidin B5, procyanidin C1 and procyanidin B5-3'-gallate, were assessed for antioxidant activity. All of them significantly inhibited epidermal lipid peroxidation, albeit to different levels. A structure-activity relationship study showed that with an increase in the degree of polymerization in polyphenol structure, the inhibitory potential towards lipid peroxidation increased. In addition, the position of linkage between inter-flavan units also influences lipid peroxidation activity; procyanidin isomers with a 4-6 linkage showed stronger inhibitory activity than isomers with a 4-8 linkage. A sharp increase in the inhibition of epid

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetone; Administration, Cutaneous; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Biflavonoids; Catechin; Cocarcinogenesis; Epidermis; Female; Flavonoids; Lipid Peroxidation; Mice; Mice, Inbred SENCAR; Microsomes; Molecular Structure; Phenols; Plant Extracts; Polymers; Proanthocyanidins; Rosales; Seeds; Skin Neoplasms; Tetradecanoylphorbol Acetate; Vitamin E

Reactive oxygen species and lipid peroxides have been implicated in the pathogenesis of a variety of diseases, particularly cancer. There may be an inverse correlation between lipid peroxidation and antioxidant defense mechanisms. The aim of this study was to investigate whether certain plasma antioxidants (ascorbic acid, alpha-tocopherol, total thiol groups, ceruloplasmin, urate, albumin and erythrocyte glutathione) are altered in actinic keratosis (AK) and basal cell carcinoma (BCC).. Plasma samples and red blood cells (RBC) of 13 patients with AK, 12 with BCC and 16 healthy controls were investigated.. Data analysis indicates significant decrease of ascorbic acid (P < 0.001), alpha-tocopherol (P < 0.05 and P < 0.001), total thiol groups (P < 0.001), ceruloplasmin (P < 0.001 and P < 0.05), and RBC glutathione (P < 0.05) values in both AK and BCC groups compared to controls. Comparison of AK and BCC groups evidenced a significant decrease of alpha-tocopherol and RBC glutathione (P < 0.05) in BCC patient.. Plasma antioxidants are decreased in the AK and BCC, probably due to the long exposure to UV irradiation which is one of the most important factors in the etiology of AK and BCC and alpha-tocopherol and RBC glutathione (P < 0.05) are most altered in BCC.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Carcinoma, Basal Cell; Ceruloplasmin; Erythrocytes; Female; Glutathione; Humans; Keratosis; Male; Middle Aged; Reference Values; Serum Albumin; Skin Neoplasms; Sulfhydryl Compounds; Uric Acid; Vitamin E

An inhibitory effect of ascorbic acid (AsA) on melanogenesis has been described. However, AsA is quickly oxidized and decomposed in aqueous solution and thus is not generally useful as a depigmenting agent.. Our purpose was to examine the effect on pigmentation of magnesium-L-ascorbyl-2-phosphate (VC-PMG), a stable derivative of AsA.. Percutaneous absorption of VC-PMG was examined in dermatomed human skin, and its effect on melanin production by mammalian tyrosinase and human melanoma cells in culture was also measured. A 10% VC-PMG cream was applied to the patients.. VC-PMG suppressed melanin formation by tyrosinase and melanoma cells. In situ experiments demonstrated that VC-PMG cream was absorbed into the epidermis and that 1.6% remained 48 hours after application. The lightening effect was significant in 19 of 34 patients with chloasma or senile freckles and in 3 of 25 patients with normal skin.. VC-PMG is effective in reducing skin hyperpigmentation in some patients.

Topics: Ascorbic Acid; Female; Humans; In Vitro Techniques; Melanins; Melanoma, Experimental; Melanosis; Monophenol Monooxygenase; Skin Absorption; Skin Neoplasms; Tumor Cells, Cultured

Environmental exposure to ultraviolet light B (UVB, wave lengths 290-320 nm) of the solar spectrum causes major damage, including an inflammatory response, in skin. In the present study, we estimated the ability of a stable derivative of ascorbic acid, ascorbic acid 2-O-alpha-glucoside (AA-2G), to reduce UVB damage, using the human keratinocyte cell line, SCC, established from squamous cell carcinoma. By pre- (9 h) and post-cultivation with AA-2G, a significant preventive effect on the decrease in the absolute number of surviving cells by exposure to UVB (typical dose, 20 mJ/cm2) was measurable by a neutral red-uptake assay. The release of lactate dehydrogenase from the cell membrane damaged by UVB was inhibited by AA-2G. In agarose gel electrophoresis, relatively high molecular weight DNA fragments were detected in irradiated cells after 6 h post-irradiation, suggesting that the mechanism of cell death was necrosis. Quantitative analysis of DNA content by flow cytometry indicated that AA-2G suppressed both an increase in debris with degraded nuclei and a decrease in cells in G1 and S phases, but not in the G2/M phase, by UVB exposure. These data suggest that AA-2G shows a photoprotective effect against UVB-induced damage in human epithelial cells.

Topics: Ascorbic Acid; Carcinoma, Squamous Cell; Cell Death; DNA; Flow Cytometry; Humans; Keratinocytes; L-Lactate Dehydrogenase; Radiation-Protective Agents; Skin Neoplasms; Tumor Cells, Cultured; Ultraviolet Rays

A number of lifestyle factors are important in the etiology of basal cell carcinoma. Previous studies have investigated smoking, alcohol, diet, and sun exposure as possible contributing factors. No previous studies have investigated case-controlled lifestyle influences in basal cell carcinomas referred for Mohs micrographic surgery.. Cases were obtained from Mohs-referred basal cell carcinoma patients. Matched controls were selected from a busy dermatology clinic. The only criteria for selection of controls was never having had cancer previously. Cases and controls were surveyed regarding lifestyle characteristics.. Forty-six age, sex, and skintype-matched controls were compared. Sun exposure, alcohol, and smoking were not significant factors. Dietary fat, fiber, and the vitamins A, C, and beta carotene, as well as selenium showed important, but not significant differences. Caffeine consumption was higher in the cancer group.. Our findings agree with previously published studies in regard to antioxidant consumption as a protective factor for basal cell carcinoma. Caffeine consumption was higher in the cancer patients.

Topics: Aged; Alcohol Drinking; Ascorbic Acid; beta Carotene; Caffeine; Carcinoma, Basal Cell; Carotenoids; Case-Control Studies; Female; Humans; Life Style; Male; Middle Aged; Mohs Surgery; Risk Factors; Selenium; Skin Neoplasms; Smoking; Vitamin E

In experiments involving the induction of squamous cell carcinoma in 1846 hairless mice that were maintained on a wide variety of diets, it was found that those diets with the least optimum balance of nutrients had the greatest inhibitory effect on growth of cancer. Rate of onset and severity of tumors was caused to vary over a 20-fold range by means of dietary balance alone. These experiments suggest that dietary variation in general and intentional malnutrition in particular should be given special attention in the control of existing cancer in humans.

Topics: Animal Feed; Animals; Ascorbic Acid; Carcinoma, Squamous Cell; Diet; Dietary Proteins; Female; Fruit; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Nutrition Disorders; Skin Neoplasms; Ultraviolet Rays; Vegetables; Vitamin E

The generation of free radicals from tumour-promoting organic peroxides applied to intact murine skin samples has been studied by EPR spectroscopy using two techniques: first direct observation of ascorbyl radicals produced from reactions of peroxide-related radicals with ascorbate, an important endogenous antioxidant, and secondly, observation of radical adducts produced by spin-trapping. Free radical generation from tumour-promoting organic peroxides can be seen to occur in intact skin tissue through a one-electron reductive pathway, and takes place at sites including the viable cells of the epidermis and/or dermis. This radical generation is dependent upon the penetration of the skin by the peroxides, with the stratum corneum representing a major diffusional barrier to their penetration of skin. The technique of using ascorbyl radical measurement by EPR spectroscopy as a means of studying and quantifying radical production in intact tissues, developed in this work, may prove of much use in the study of many free radicals and their reactions in a wide range of biological systems, particularly skin. When combined with appropriate spin-trapping techniques, which enable identification of radical species and elucidation of their mechanisms of production, this enables the direct, real-time observation of radical reactions and mechanisms not previously possible in intact tissue samples.

Topics: Animals; Ascorbic Acid; Cyclic N-Oxides; Dehydroascorbic Acid; Electron Spin Resonance Spectroscopy; Free Radicals; In Vitro Techniques; Male; Mice; Peroxides; Skin; Skin Neoplasms; Spin Labels

Vitamin E (alpha-tocopherol) is the major lipid-soluble chain-breaking antioxidant of membranes. Its UV-absorbance spectrum (lambda max 295 nm) extends well into the solar spectrum. We hypothesize that in skin alpha-tocopherol may absorb solar UV light and generate tocopheroxyl radicals. Reduction of tocopheroxyl radicals by other antioxidants (e.g. ascorbate, thiols) will regenerate (recycle) vitamin E at the expense of their own depletion. Hence, vitamin E in skin may act in two conflicting manners upon solar illumination: in addition to its antioxidant function as a peroxyl radical scavenger, it may act as an endogenous photosensitizer, enhancing light-induced oxidative damage. To test this hypothesis, we have illuminated various systems (methanol-buffer dispersions, liposomes and skin homogenates) containing alpha-tocopherol or its homologue with a shorter 6-carbon side chain, chromanol-alpha-C6 with UV light closely matching solar UV light, in the presence or absence of endogenous or exogenous reductants. We found that: (i) alpha-tocopheroxyl (chromanoxyl) radicals are directly generated by solar UV light in model systems (methanol-water dispersions, liposomes) and in skin homogenates; (ii) reducing antioxidants (ascorbate, ascorbate+dihydrolipoic acid) can donate electrons to alpha-tocopheroxyl (chromanoxyl) radicals providing for vitamin E (chromanol-alpha-C6) recycling; (iii) recycling of UV-induced alpha-tocopheroxyl radicals depletes endogenous antioxidant pools (accelerates ascorbate oxidation); (iv) beta-carotene, a non-reducing antioxidant, is not active in alpha-tocopherol recycling, and its UV-dependent depletion is unaffected by vitamin E.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Carotenoids; Electron Spin Resonance Spectroscopy; Free Radicals; Liposomes; Methanol; Mice; Mice, Hairless; Models, Biological; Neoplasms, Radiation-Induced; Oxygen; Phosphatidylcholines; Radiation Tolerance; Skin; Skin Neoplasms; Suspensions; Thioctic Acid; Ultraviolet Rays; Vitamin E; Water

Two large-scale studies of the effect of different amounts of L-ascorbic acid in the food on tumor-free survival have been conducted. One involved the incidence of spontaneous mammary tumors in RIII mice, with seven ascorbic acid and three control groups, 50 mice per group. With increasing ascorbic acid in the diet, there was a highly significant delay before appearance of the first tumor. Median age at first tumor was 82.5 wk in ad libitum controls, 124.9 wk in the highest-dose ascorbate group. The proportion of mice with tumors was also reduced. The other study involved dermal neoplasms in mice irradiated with ultraviolet light. A pronounced effect of vitamin C in decreasing the incidence and delaying the onset of malignant lesions was observed with high statistical significance. By 20 wk approximately five times as many mice had developed serious lesions in the zero-ascorbate as in the high-ascorbate group.

Topics: Animals; Ascorbic Acid; Incidence; Mammary Neoplasms, Animal; Mice; Mice, Hairless; Mice, Mutant Strains; Neoplasms, Radiation-Induced; Skin Neoplasms; Ultraviolet Rays

The effect of topical application of ascorbic acid (AA) and ascorbyl palmitate (AP) on 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced tumor promotion in mouse skin was investigated. A single application of TPA decreased epidermal AA by 45%. Repetitive application of 6 and 28 mumol AA with 2 nmol TPA inhibited tumor multiplicity by 39% and 76%. Repetitive application of 0.16, 0.8, and 4.0 mumol AA with 5 nmol TPA inhibited tumor multiplicity by 16%, 46%, and 91%. Because AA may be poorly absorbed cutaneously, we evaluated the effect of dietary AA. Supplementation of drinking water with AA increased epidermal ascorbic acid levels by 50%. Dietary intake of AA did not inhibit TPA-induced tumor promotion. Preliminary data suggest that the mice not receiving AA developed increased epidermal AA levels in response to the tumor promoting regimen. Recently we have found that dietary AP inhibited TPA-induced biochemical parameters associated with tumor promotion.

Topics: Animals; Ascorbic Acid; Diet; DNA; Epidermis; Female; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Osmolar Concentration; Skin Neoplasms; Tetradecanoylphorbol Acetate

Albino hairless mice (Skh:HR-1) exposed chronically to suberythemal doses of ultraviolet radiation develop visible skin changes, histological alterations, and tumors. Topical treatment of mice with solutions of superoxide-scavenging antioxidants (such as alpha-tocopherol, ascorbic acid, propyl gallate and Trolox) prior to each UVB radiation exposure reduced significantly the severity of these events. Tocopherol esters and ascorbyl palmitate were not as effective as the parent compounds in providing protection. The data suggest a role for superoxide in UVB radiation-induced skin photoaging and the protective potential of superoxide scavengers. In contrast, the severity of UVA radiation-induced mouse skin damage was not reduced by topical application of the antioxidants tested here.

Topics: Animals; Antioxidants; Ascorbic Acid; Chronic Disease; Female; Mice; Mice, Hairless; Photosensitivity Disorders; Skin Aging; Skin Neoplasms; Superoxides; Ultraviolet Rays

The effects of topically applied 12-O-tetradecanoylphorbol-13-acetate (TPA) on the level of ascorbic acid in the epidermis and the effects of topically applied ascorbic acid, ascorbyl palmitate (a synthetic lipophilic derivative of ascorbic acid), palmitic acid and sorbitan monopalmitate on TPA-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 5 or 16 nmol of TPA resulted in a 45-50% decrease in the amount of ascorbic acid per mg protein in mouse epidermis at 5 h after TPA application. Large topical doses of ascorbic acid inhibited TPA-induced tumor promotion in mouse epidermis, but smaller doses were inactive. The topical application of relatively small doses of ascorbyl palmitate had a marked inhibitory effect on TPA-induced ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse epidermis. Ascorbic acid, palmitic acid, and sorbitan monopalmitate were less effective than ascorbyl palmitate as inhibitors of tumor promotion. The topical application of 4 mumol of ascorbyl palmitate inhibited by 60-76% the induction of epidermal ornithine decarboxylase activity and DNA synthesis that occurred after a single topical application of 2 nmol of TPA whereas similar doses of ascorbic acid had no inhibitory effect. The topical application of 4 mumol of ascorbyl palmitate together with 5 nmol of TPA twice weekly for 20 weeks to previously initiated mice inhibited by 91% the number of tumors per mouse.

Topics: Administration, Topical; Animals; Ascorbic Acid; Diglycerides; DNA Replication; Drug Interactions; Enzyme Induction; Female; Mice; Ornithine Decarboxylase; Palmitic Acid; Palmitic Acids; Skin Neoplasms; Tetradecanoylphorbol Acetate

We have carried out a study of large malignant skin tumours (squamous-cell carcinomas) and other lesions in "hairless" mice (in groups of 45 or 60 mice) intermittently exposed to ultraviolet light over a period of 15 weeks, beginning when the mice were about 8 weeks old. Various groups were given a standard diet (Wayne Lab-Blox) or the same food with added vitamin C or vitamin E throughout the study. Lesions, classified by histopathologic study as atypical squamous-cell proliferations varying from early actinic keratoses to invasive poorly differentiated squamous-cell carcinomas, had begun to develop by the end of the period of irradiation. They were counted twice a month for five months. The observed fraction of mice that developed lesions during successive time periods was analyzed by the statistical method recommended by a committee of the International Agency for Research on Cancer. A pronounced effect of vitamin C in decreasing the incidence of the malignant lesions was observed with very high statistical significance. No significant effect of vitamin E was observed. We conclude that vitamin C should be given special attention with respect to the relation between diet and cancer.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinoma, Squamous Cell; Diet; Female; Mice; Mice, Hairless; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Skin Neoplasms; Ultraviolet Rays; Vitamin E

Skin papillomas were observed in the majority of toads when painted with 1 mg of 7,12-dimethyl-benz (alpha) anthracene (DMBA) dialy for 8 weeks. Animals injected with 10 mg/kg/day of ascorbic acid into the dorsal lymph sac showed tumor inhibition when painted with the same dose level of DMBA for 8 weeks. Tumor regression occurred in those animals receiving 10 mg/kg/day of ascorbic acid for 8 weeks.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Ascorbic Acid; Bufonidae; Female; Male; Neoplasms, Experimental; Papilloma; Skin Neoplasms

We have carried out a study of large malignant skin tumors (squamous cell carcinomas) and other lesions in hairless mice (groups of 38-45) intermittently exposed to ultraviolet light over a period of 15 weeks, beginning when the mice were about 10 weeks old. The several groups were given a standard diet with 0%, 0.3%, 5%, and 10% added L-ascorbic acid (vitamin C) throughout the study. No lesions developed in unirradiated control groups. The lesions were counted every 14 days for 4 months, beginning 4 weeks before the end of the period of irradiation. The observed incidence of lesions of several sizes during successive time periods was analyzed by the statistical method recommended by a committee of the International Agency for Research on Cancer. A pronounced effect of vitamin C in decreasing the incidence and delaying the onset of the malignant lesions was observed with high statistical significance.

Topics: Animals; Ascorbic Acid; Diet; Dose-Response Relationship, Drug; Mice; Mice, Mutant Strains; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Skin Neoplasms

The dominant role of the physical and chemical environment in the development of cancer is challenged. Analyses of the etiology of skin, bladder, respiratory and gastric cancers are presented which demonstrate the considerable extent to which one's health status may modify the initiation and promotion of environmentally associated cancers. It is concluded that although environmental factors may initiate and/or promote 85 to 90 percent of all cancers this is misleading since it neglects the critical role of the individual's health status as a factor modifying carcinogenesis.

Topics: Ascorbic Acid; Benzopyrenes; Carcinogens, Environmental; Carcinoma, Bronchogenic; Diet; Humans; Hydrocarbons; Neoplasms; Neoplasms, Radiation-Induced; Racial Groups; Riboflavin; Skin Neoplasms; Smoking; Stomach Neoplasms; Ultraviolet Rays; Urinary Bladder Neoplasms; Vitamin A

Topics: Ascorbic Acid; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Skin Neoplasms

Butylated hydroxytoluene, butylated hydroxyanisole, and vitamins C and E are effective inhibitors of 7,12-dimethylbenz(a)anthracene tumor initiation in a two-stage system of tumorigenesis. These antioxidants did not significantly induce epidermal aryl hydrocarbon [benzo(a)pyrene]hydroxylase, nor did they have any effect when added directly to the in vitro aryl hydrocarbon [benzo(a)pyrene]hydroxylase assay. However, butylated hydroxytolene and butylated hydroxyanisole, when topically to mice, inhibited the in vitro, epidermally mediated, covalent binding of radioactive benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene to DNA. When butylated hydroxytolene and butylated hydroxyanisole were added in vitro, they did not inhibit the epidermally mediated covalent binding of the hydrocarbons to DNA. The inhibition of polycyclic hydrocarbon tumorigenesis by antioxidants may be related to the ability of antioxidants to prevent the in vivo activation of hydrocarbons to carcinogenic epoxides and/or other electrophilic intermediates or may be related to their ability to increase detoxification of the reactive intermediate that requires intact cells to be operational. In any event, the results suggest that the antioxidants have an indirect effect on the epidermal metabolizing system which leads to a decrease in covalent binding to DNA.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Ascorbic Acid; Benz(a)Anthracenes; Benzopyrenes; Butylated Hydroxyanisole; Butylated Hydroxytoluene; DNA; Enzyme Induction; Female; Flavonoids; In Vitro Techniques; Mice; Neoplasms, Experimental; Skin; Skin Neoplasms; Vitamin E

Topics: Adenocarcinoma; Adult; Aged; Ascorbic Acid; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Middle Aged; Skin Neoplasms

Topics: Adult; Ascorbic Acid; Breast Neoplasms; Child; Female; Humans; Leukocytes; Lung Neoplasms; Mouth Neoplasms; Neoplasms; Rectal Neoplasms; Skin Neoplasms; Urinary Bladder Neoplasms; Uterine Cervical Neoplasms

Topics: Adolescent; Aged; Ascorbic Acid; Carcinoma; Child; Child, Preschool; Humans; Leukemia, Lymphoid; Leukocytes; Lung Neoplasms; Male; Middle Aged; Neoplasms; Skin; Skin Neoplasms

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Diet; Female; Glutathione; Mice; Neoplasms, Radiation-Induced; Radiation-Protective Agents; Skin Neoplasms; Toluene; Ultraviolet Rays; Vitamin E

Topics: Acetone; Acid Phosphatase; Animals; Antioxidants; Ascorbic Acid; Benz(a)Anthracenes; Croton Oil; Female; Lysosomes; Mice; Neoplasms, Experimental; Peroxides; Resins, Plant; Selenium; Skin; Skin Neoplasms; Sulfatases; Vitamin E

Topics: Animals; Ascorbic Acid; Cell Differentiation; Collagen; Female; Granulation Tissue; Kidney; Male; Seasons; Skin; Skin Neoplasms; Urodela; Wound Healing; Wounds and Injuries