benzofurans and Skin-Neoplasms

The controversy about dioxin effects on human health received a great deal of attention recently when the State of Missouri was declared to have a dioxin crisis. However, dioxin and several related chemicals are widespread throughout the world. Cutaneous signs play an important part in evaluating toxicity of dioxin and similar chemicals. Chloracne is the most sensitive indicator of significant dioxin exposure. Porphyria cutanea tarda and hyperpigmentation are other known cutaneous effects, and malignant fibrous histiocytomas of the skin may possibly be associated, although data are inconclusive on this point. The AMC Council on Scientific Affairs recommended that all physicians become familiar with chloracne and other toxic effects of dioxin. Dermatologists, especially, should be aware of the problem and may discover early cases of previously unsuspected exposure to this group of chemicals.

Topics: Abnormalities, Drug-Induced; Animals; Benzofurans; Dibenzofurans, Polychlorinated; Dioxins; Dose-Response Relationship, Drug; Environmental Exposure; Environmental Pollutants; Histiocytoma, Benign Fibrous; Humans; Hydrocarbons, Chlorinated; Lethal Dose 50; Naphthalenes; Pigmentation Disorders; Polybrominated Biphenyls; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polychloroterphenyl Compounds; Porphyrias; Skin Absorption; Skin Diseases; Skin Neoplasms

Topics: Animals; Benzofurans; Cantharidin; Carcinogens; DNA Replication; Drug Evaluation, Preclinical; Female; Male; Mice; Skin; Skin Neoplasms

Skin cancer is the commonly found type, which contributes to 40% of whole cancer incidences worldwide. Dieckol is an active compound occurs in the marine algae with many biological benefits. In this exploration, we intended to investigate the therapeutic potency of dieckol against the 7,12-dimethylbenz(a)anthracene (DMBA)-triggered skin carcinogenesis in mice. The skin cancer was stimulated to the animals via injecting the 25 μg of DMBA in 100 μL of acetone in shaved dorsal portion along with the 30 mg/kg of dieckol supplementation for 25 week. The antioxidant enzymes and phase-I and -II detoxifying enzymes in the test animals were inspected via standard protocols. Pro-inflammatory markers (IL-6, IL-1β, and TNF-α) level was examined via ELISA kits and the expression of inflammatory molecular markers like p-NF-ƙB, IƙBα and p-IƙBα were studied through western blotting. The expression status of pro- and anti-apoptotic proteins (p53, Bax, Bcl-2, caspase-3, caspase-9, COX-2, TGF-β1) was investigated via real-time polymerase chain reaction (RT-PCR). Our results revealed that the 30 mg/kg of dieckol supplementation noticeably regained the body and liver weight and also diminished the tumor incidence in the DMBA-incited animals. Dieckol treatment exhibited an enhanced antioxidants (SOD, CAT, GPx, and GSH) and reduced phase-I enzymes Cyt-p450 and Cyt-b5 in the DMBA-induced animals. Dieckol also diminished the pro-inflammatory modulators like IL-6, IL-1β and TNF-α. Western blotting result evidenced that the dieckol was inhibited the IƙB/NF-ƙB signaling pathway. RT-PCR study proved the enhanced expression of pro-apoptotic protein (p53, Bax, caspase-3 and -9) in the dieckol treated animals. Histological study also confirmed the therapeutic benefits of Dieckol. Altogether with these findings, it was clear that the dieckol has appreciably allayed the DMBA activated skin tumorigenesis in the mice and it could be a promising agent to treat the human skin cancer in future.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Antioxidants; Benzofurans; Biomarkers; Carcinogenesis; Mice; Skin Neoplasms

The molecular pathways by which flavagline derivatives exert their cytotoxicity against various cancer cell types are well documented, while the mechanisms that prevent their cytotoxic effects on normal cells still have to be clarified. Here we provide the underlying molecular events by which normal skin cells remain unaffected after exposure to the synthetic flavagline FL3. Indeed, the anticancer agent fails to trigger apoptosis of healthy cells and is unable to induce the depolarization of their mitochondrial membrane and the cytosolic release of cytochrome C, in contrast to what is observed for cancer cells. Most importantly, FL3 specifically induces in normal cells, but not in malignant cells, an activation of Bad, without significant mitochondrial and cytosolic redistribution of Bax or Bcl-2. Moreover, gene knockdown of Bad sensitizes the normal fibroblastic cells to FL3 and induces a caspase-3 dependent apoptosis. Bad activation, known to promote survival and block apoptosis, explains therefore the lack of cytotoxicity of FL3 on normal skin cells. Finally, these findings provide new insights into the molecular mechanisms of resistance of healthy cells against FL3 cytotoxicity and identify it as a promising anticancer drug.

Topics: Antineoplastic Agents; Apoptosis; bcl-Associated Death Protein; Benzofurans; Cell Line; Fibroblasts; Humans; Keratinocytes; Membrane Potential, Mitochondrial; Skin; Skin Neoplasms

Skin cancer is the most common type of cancer. The incidence rate of skin cancer has continuously increased over the past decades. In an effort to discover novel anticancer agents, we identified a novel tubulin inhibitor STK899704, which is structurally distinct from other microtubule-binding agents such as colchicine, vinca alkaloids and taxanes. STK899704 inhibited microtubule polymerization leading to mitotic arrest and suppressed the proliferation of various cancer cell lines as well as multidrug resistance cancer cell lines. In this study, our investigation is further extended into animal model to evaluate the effect of STK899704 on skin carcinogenesis in vivo. Surprisingly, almost 80% of the tumors treated with STK899704 were regressed with a one-fifth reduction in tumor volume. Furthermore, the efficacy of STK899704 was nearly 2 times higher than that of 5-fluorouracil, a widely used skin cancer therapeutic. Overall, our results suggest that STK899704 is a promising anticancer chemotherapeutic that may replace existing therapies, particularly for skin cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antimetabolites, Antineoplastic; Benzofurans; Carcinogenesis; Colchicine; Disease Models, Animal; Fluorouracil; Male; Mice; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tubulin; Tubulin Modulators

Polychlorinated biphenyls (PCB) are well known persistent and toxic environmental pollutants. Our aim was to identify effects of moderate-high exposure to dioxin-like (dl) and non-dioxin-like (ndl)-PCBs on the skin in order to provide more insight in the pathophysiological effects of these compounds. We performed a dermatological examination on 92 former workers from a transformer recycling company with known elevated serum PCB and/or dioxin (polychlorinated dibenzo-p-dioxin/polychlorinated dibenzo-p-furan (PCDD/F)) levels. In addition, we performed a skin cancer screening over a period of seven years (2010-2016) on resp. 268, 271, 210, 149, 92, 129 and 79 participants. We found a higher incidence of acne and malignancies of the skin (malignant melanoma, basal cell carcinoma and mycosis fungoides) in the workers compared to normal population. The probability of having hyperpigmentation on the skin was statistically significantly higher in workers with higher sumPCBs- (OR:1.09(1.12-2.17)), dioxin-like (dl)-PCBs- (OR:1.56(1.12-2.17)) and dioxin (PCDD/Fs) (OR:1.09(1.02-1.16)) levels. Age was a confounding factor in this model. Formation of hyperpigmentation could be an indicator for (moderate-high) exposure to toxic compounds like PCBs. The higher incidence of cutaneous malignancies found in the workers might be associated with PCB- and dioxin exposure, warranting further investigation on larger cohorts.

Topics: Adult; Aged; Benzofurans; Dibenzofurans, Polychlorinated; Dioxins; Environmental Pollutants; Female; Humans; Hyperpigmentation; Incidence; Male; Middle Aged; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Skin Neoplasms

Many components derived from dietary or medicinal plants showing antioxidant and anti-inflammatory potential have been found to possess chemopreventive properties. In our previous study, we achieved the total synthesis of ailanthoidol (AT), a neolignan from Zanthoxylum ailanthoides or Salvia miltiorrhiza Bunge, which are used in Chinese traditional herbal medicine. In the present study, preliminarily, AT exhibited a radical quenching property by DPPH assay. Following this, we assessed the effect of AT on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in female CD-1 mouse skin which was closely linked to tumor promotion. The topical application of AT (0.5-2.5 mM; 200 microl) reduced the formation of hydrogen peroxide and inhibited the myeloperoxidase (MPO) activity in the mouse skin when compared with that of the TPA-treated alone group. In addition, AT presented a suppression effect on the TPA-induced hyperplasia and leukocyte infiltration in the epidermis and edema of mouse ears. Furthermore, it showed that AT inhibited the TPA-induced expression of COX-2 protein and ornithine decarboxylase (ODC) activity in epidermis. Finally, AT was evaluated for its ability to inhibit the TPA-induced promotion in skin tumors of female CD-1 mice. Topical application of AT 5 min prior to TPA (5 nmol) three times weekly for 12 weeks to mice which were initiated with benzo[a]pyrene (B[a]P) inhibited the incidence of skin tumors in mice and the average number of tumors per mice as compared to TPA-treated alone. These results indicate that AT possesses potential as a chemopreventive agent against tumor promotion.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Benzo(a)pyrene; Benzofurans; Carcinogens; Female; Mice; Mice, Inbred ICR; Neoplasms; Peroxidase; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

Chronic exposure of the skin to ultraviolet B (UVB) radiation induces oxidative stress, which plays a crucial role in the induction of skin cancer. In this study, the effect of dietary feeding and topical application of brown algae polyphenols on UVB radiation-induced skin carcinogenesis in SKH-1 mice was investigated. SKH-1 hairless mice were randomly divided into 9 groups, including control, UVB control and treatment groups. They were treated orally (0.1% and 0.5% with AIN-76 diet, w/w) and topically (3 and 6 mg/0.2 ml of vehicle) with brown algae polyphenols and irradiated with UVB for 26 weeks. Dietary feeding (0.1% and 0.5%) of brown algae polyphenols significantly reduced tumor multiplicity (45% and 56%) and tumor volume (54% and 65%), and topical administration (3 and 6 mg) significantly decreased tumor multiplicity (60% and 46%) and tumor volume (66% and 57%), respectively, per tumor-bearing mouse. Dietary feeding and topical administration of the polyphenols also inhibited tumor incidence by 6% and 21%, respectively, but the results were not significant. Dietary and topical administration of the polyphenols markedly inhibited cyclooxygenase-2 activity and cell proliferation. These observations show that brown algae polyphenols have an antiphotocarcinogenic effect which may be associated with the prevention of UVB-induced oxidative stress, inflammation, and cell proliferation in the skin.

Topics: Administration, Cutaneous; Administration, Oral; Animals; Benzofurans; Blotting, Western; Cell Proliferation; Cyclooxygenase 2; Dinoprostone; Dioxins; Epidermis; Female; Flavonoids; Gene Expression; Immunohistochemistry; Mice; Molecular Structure; Neoplasms, Radiation-Induced; Phaeophyceae; Phenols; Polyphenols; Proliferating Cell Nuclear Antigen; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; Skin; Skin Neoplasms; Ultraviolet Rays

Chlorinated aromatic contaminants are active in carcinogenic processes within the skin and may have the potential to modulate ultraviolet radiation (UV)-induced skin carcinogenesis. Exposure to a complex environmental PCB/PCDD/PCDF mixture (polychlorinated biphenyls/polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans) during the irradiation phase of photocarcinogenesis was associated with significant (P < or = 0.001) reductions in papilloma incidence and squamous cell carcinoma multiplicity at irradiated skin sites. This protective effect was associated with significantly (P < 0.0001) reduced chronic epidermal thickening in UV and contaminant-exposed mice compared with mice exposed to UV only. Contaminant exposure was also associated with increased UV absorbance of skin methanol extracts implying a sunscreen-like effect.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dibenzofurans, Polychlorinated; Environmental Pollutants; Female; Methanol; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Papilloma; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Skin; Skin Neoplasms; Soil Pollutants; Ultraviolet Rays

Salvia miltiorrhiza is a traditional Chinese medicine which has been well documented for its anti-cancer effects. Based on the structure of danshinone, one of the active compounds derived from Salvia miltiorrhiza, we synthesized a simplified phenolic analog, S-3-1, and tried to explore its possible actions in preventing the development of cancer. With the Ames test, S-3-1 was found to efficiently suppress the mutagenicity of benzo[alpha]pyrene. This result is consistent with the inhibitory effect of S-3-1 on the activation of benzo[alpha]pyrene by hepatic microsomal enzymes. Besides the anti-initiation effects, S-3-1 could significantly inhibit the croton oil-induced increase of mouse skin epithermal ornithine decarboxylase activity. Moreover, S-3-1 quenched both superoxide and hydroxyl free radicals whereas it inhibited lipid peroxidation in the in vitro model. These results suggest that S-3-1 might act as anti-initiation and anti-promotion agents through reversing the biochemical alterations induced by carcinogen during carcinogenesis. Therefore, we further investigated the effects of S-3-1 on carcinogenesis. In vitro, S-3-1 inhibited the benzo[alpha]pyrene-induced transformation of V79 Chinese hamster lung fibroblasts. At 10-40 mg/kg, S-3-1 was found to inhibit the development of DMBA/croton oil-induced skin papilloma in mice through decreasing the incidence of papilloma, prolonging the latent period of tumor occurrence and reducing tumor number per mouse in a dose-dependent manner. We concluded from this study that S-3-1 might be developed as a new chemopreventive drug.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Benzofurans; Bepridil; Biphenyl Compounds; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Croton Oil; Cysteine; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Epithelial Cells; Fibroblasts; Free Radical Scavengers; Hypoxanthine; In Vitro Techniques; Iron; Lipid Peroxidation; Lung; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred ICR; Microsomes, Liver; Molecular Structure; Mutagens; Ornithine; Ornithine Decarboxylase; Papilloma; Pentetic Acid; Phenanthrenes; Picrates; Plants, Medicinal; Rats; Salmonella; Skin; Skin Neoplasms; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Xanthine Oxidase

(1) To compare scintigraphy using the new dopamine D2 receptor binding radioligand iodobenzofuran (IBF) versus whole-body positron emission tomography (PET) in demonstrating metastasizing melanoma, and (2) to determine, for the first time using a panel of histochemical techniques, whether the ability of D2 receptor binding radioligands to detect melanoma metastases is due to tumor-expressed D2 receptors.. Seven patients with metastatic melanoma were examined using 123I-IBF scintigraphy. Findings were compared to the results of PET and metastasis histochemistry: D2 receptor mRNA assay (metastases: n = 5; melanoma cell lines: n = 4) using the reverse transcriptase polymerase chain reaction (RT-PCR) versus D2 receptor-transfected Chinese hamster ovary cell controls: in vitro 125I-IBF binding (n = 19), and immunohistochemical staining for dopamine D2 receptor protein (n = 19).. IBF scintigraphy detected 2/10 melanoma metastases detected by PET (sensitivity 20%). No dopamine D2 receptor mRNA was found in melanoma cells using RT-PCR. The binding of 125I-IBF correlated with the amount of melanin present in the metastases; two amelanotic melanomas both failed to bind 125I-IBF. Immunohistochemical staining was negative in all metastases.. Melanoma cells do not appear to express dopamine D2 receptors. Although IBF had high dopamine D2 receptor affinity, its ability to detect melanoma metastases is more likely explained by low affinity binding to melanin than by the presence of dopamine receptors.

Topics: Adult; Aged; Animals; Benzofurans; Cell Line, Transformed; Cricetinae; Cricetulus; Female; Gene Expression Regulation, Neoplastic; Histocytochemistry; Humans; Immunohistochemistry; Iodine Radioisotopes; Male; Melanins; Melanoma; Middle Aged; Polymerase Chain Reaction; Radiopharmaceuticals; Receptors, Dopamine; RNA, Messenger; Skin Neoplasms; Tomography, Emission-Computed; Transcription, Genetic; Tumor Cells, Cultured

An effect of 2,3,4,7,8-pentachlorodibenzofuran (PCDF) as a promoter on a course of experimental skin carcinogenesis in mice by chemicals 20-methylcholanthrene (MC) has been proved by our previous studies. Details of ultrastructural epidermal alterations induced by MC and PCDF were observed and an attempt to differentiate benign tumor from malignant one in which a combined application of MC and PCDF on mice skin resulted was done electron microscopically. Four significant findings as follows were detected. First of all even the epidermal cells without tumor had some atypicality. Secondly both of benign tumor and normal-appeared skin without tumor had giant and round-shaped keratohyalin granules (KHGs) which show a tendency of less keratinization. Thirdly cytoplasmic projections of epidermal cells increased in number and sparse tonofilaments scattered in the cytoplasm of benign tumor. This is also an appearance of mucous metaplasia of keratinocytes as well as the form of KHGs mentioned above. Finally benign tumor had thick horny cells including numerous lipid droplets, and that is a sign of acceleration of epidermal turn over. Since epidermal cells have little chance to be exposed to carcinogens when they quickly keratinize, they rarely form a cancer. When epidermal cells have such tendency as less keratinization or more keratinization, they are supposed to be less sensitive to any stimuli of carcinogens, and consequently they incline to be benign tumor instead of malignant one.

Topics: Animals; Benzofurans; Methylcholanthrene; Mice; Skin; Skin Neoplasms

2,3,7,8-Tetrachlorodibenzo-p-dixoin 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are highly toxic members of a class of environmental contaminants, the polychlorinated aromatic hydrocarbons (PCAH), which exhibit a similar and highly characteristic spectrum of toxic effects. For purposes of risk assessment, it is important to be able to make accurate estimates of the relative potency of these and related compounds. Previous investigations have indicated that, in acute exposure or in vitro studies, PCDF is approximately 0.1 times as toxic and HCDF is approximately 0.01 times as toxic as TCDD. In this study, we compared the relative toxicity and tumor-promoting abilities of TCDD, PCDF, and HCDF in hairless mouse skin. Female hairless mice (HRS/J hr/hr) were treated dermally with the initiator MNNG, then dosed twice weekly for 20 weeks with acetone, TCDD (2.5-10 ng/mouse/dose), PCDF (25-100 ng/mouse/dose), or HCDF (250-1000 ng/mouse/dose) as promoter. TCDD, PCDF, and HCDF were all potent promoters for the induction of squamous cell papillomas. There was, however, no difference in the incidence or multiplicity of papilloma formation between groups. The same doses of the three PCAH, in the absence of initiator, induced no skin papillomas. TCDD produced a significant increase in liver:body weight ratio (p less than 0.001) at all doses and a decrease in thymus:body weight ratio at a dose of 10 ng (p less than 0.001). Mice treated with PCDF and HCDF had marked thymic and splenic involution, liver hypertrophy, mucous cell hyperplasia in the fundic portion of the glandular stomach, and loss of body weight. PCDF and HCDF produced a greater incidence and severity of dermatotoxic effects than TCDD. Based on data for dermal toxicity and changes in body weight and organ weights, PCDF is estimated to be 0.2 to 0.4 times, and HCDF 0.08 to 0.16 times, as toxic as TCDD following repeated dermal exposure. Therefore, toxic equivalence factors generated using data from acute and/or in vitro studies may underestimate the risk from repeated low-dose exposures to these compounds.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dioxins; Female; Hypertrophy; Liver; Mice; Mice, Hairless; Papilloma; Polychlorinated Dibenzodioxins; Skin; Skin Diseases; Skin Neoplasms

In order to examine the carcinogenicity of 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran, these two chemicals were subcutaneously administered to Wistar strain male rats at the dose of 80 micrograms, 40 micrograms or 4 micrograms per rat. At sacrifice in two years after the start of the experiment, tumors were observed in the subcutaneous tissue and the liver. Although the number of the rats used is small, the tumor occurrence showed some tendency to relate with the dose of the chemicals given.

Topics: Animals; Benzofurans; Fibroma; Fibrosarcoma; Lipoma; Liver Neoplasms, Experimental; Male; Rats; Rats, Inbred Strains; Skin Neoplasms

To ascertain whether 2,3,4,7,8-pentachlorodibenzofuran (PCDF) has the possibility of cocarcinogen, three different concentrations of 0.5, 1 and 5 ppm PCDF was evaluated in the course of experimental carcinogenesis in mice. Concerning the difference of total number of tumors occurred among the groups of mice with various treatments, the mice treated with 0.5 ppm PCDF and 20-methylcholanthrene (MC) have produced twice as many tumors as those of the other groups. Then the adequate concentration of PCDF to be a promoter was supposed to be 0.5 ppm. Two kinds of tumors were seen in mice which were treated by MC with or without PCDF, and there was no difference of tumors between the groups by appearance and pathologically. One is a benign papilloma, and the other is a squamous cell carcinoma which tends to keratinize and looks like a keratoacanthoma. The latter had a tendency to arise much more four weeks after the treatments had been done, even though the number of the former increased gradually. There was no evidence that PCDF of these concentrations could permeate through the skin and could be toxic. Furthermore PCDF seemed to neither stay nor act directly on the follicular epithelium, since there was no acne formation on the back skin of mice. One of the possible factors to cause malignant changes of epidermal cells was supposed to be a prolonged inflammation of the skin.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Methylcholanthrene; Mice; Skin Neoplasms

Topics: Animals; Benzofurans; Cocarcinogenesis; Methylcholanthrene; Mice; Polymers; Skin; Skin Neoplasms

Topics: Aged; Amiodarone; Benzofurans; Chemical Phenomena; Chemistry; Female; Humans; Papilloma; Skin Neoplasms

Topics: Adult; Aged; Antineoplastic Agents; Benzoates; Benzofurans; Cacao; Caffeine; Carcinoma, Squamous Cell; Castor Oil; Colchicine; Female; Humans; Male; Middle Aged; Neoplasms, Radiation-Induced; Ointments; Plant Extracts; Skin; Skin Neoplasms; Uracil

Topics: Animals; Benzofurans; Croton Oil; DNA, Neoplasm; Female; Leucine; Macromolecular Substances; Mice; Neoplasm Proteins; Neoplasms, Experimental; Nucleosides; Papilloma; RNA, Neoplasm; Skin; Skin Neoplasms; Thymidine; Tritium; Wound Healing