dinoprost and Skin-Neoplasms

Whilst in the early stages, neoplastic development is predominantly triggered by environmental genotoxic and non-genotoxic carcinogens, tumour progression becomes more and more autonomous at later stages. In this context a dysregulation of arachidonic acid metabolism seems to play a disastrous role. Conversely, non-steroidal anti-inflammatory drugs (NSAIDs) rank among the most potent and most promising agents for cancer chemoprevention probably because of their ability to inhibit prostaglandin biosynthesis, in particular, at the level of the 'pro-inflammatory' enzyme cyclooxygenase-2 (COX-2). A pathological overexpression of COX-2 resulting in excessive prostaglandin production has been found already in early stages of carcinogenesis and seems to be a consistent feature of neoplastic development in a wide variety of tissues. COX-2 overexpression is thought to occur along signalling pathways of inflammation and tissue repair which become activated in the course of tumour promotion and, due to autocrine and auto-stimulatory mechanisms, finally lead to some autonomy of tumour development (self-promotion). Prostaglandins formed along a dysregulated COX pathway have been shown to mediate tumour promotion in animal experiments and may play a role, in addition, in other processes involved in tumour growth such as angiogenesis, metastasis and immunosuppression. Moreover, genotoxic byproducts such as organic free radicals, reactive oxygen species and malondialdehyde produced in the course of prostanoid biosynthesis may contribute to genetic instability (mutator phenotype) of neoplastic cells thereby promoting malignant progression. Such mixtures of physiologically highly active mediators and genotoxic byproducts are, in addition, formed along the various lipoxygenase-catalysed pathways of arachidonic acid metabolism some of which also become dysregulated during tumour development and, therefore, provide novel targets of future chemopreventive approaches.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Cell Transformation, Neoplastic; Colonic Neoplasms; Cyclooxygenase 2; Dinoprost; Down-Regulation; Eicosanoids; Humans; Isoenzymes; Membrane Proteins; Mice; Neoplasms, Experimental; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Signal Transduction; Skin Neoplasms

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

Topics: Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Dinoprost; Gene Expression Regulation, Neoplastic; Humans; Melanocytes; Melanoma; Neoplasm Invasiveness; Nevus, Pigmented; Receptors, Prostaglandin; RNA, Messenger; Skin Neoplasms

One of the most toxic environmental pollutants known to man is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). There is growing evidence that indicates TCDD is a potent tumor promoter in rat and mouse liver, as well as in mouse skin. The mouse skin carcinogenesis model has been used extensively to assess whether a chemical or physical agent carries a carcinogenic hazard to humans and to define the mechanism involved with the carcinogenic effects. We applied the mouse skin model to ICR male mice and the results showed that following the application of DMBA, repeated dorsal application of all doses of TCDD produced no papillomas. These findings imply that the ICR male mouse is an extremely insensitive strain as a TCDD-induced two-stage mouse skin carcinogenesis model. However, severe hepatic injuries and wasting syndrome were seen in mice treated topically with TCDD. Meanwhile, serum TNF-alpha levels increased during the experimental periods. Inflammatory cell infiltration, fatty liver, and nodule formation could be observed in damaged livers. Elevated hepatic EROD activity and urinary 8-epi-PGF2alpha were also observed in mice with short-term exposure of TCDD.

Topics: Administration, Topical; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A1; Dinoprost; Environmental Pollutants; Immunohistochemistry; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Polychlorinated Dibenzodioxins; Proliferating Cell Nuclear Antigen; Skin Neoplasms; Tumor Necrosis Factor-alpha

Reverse transcription polymerase chain reaction (RT-PCR) and Northern blot analysis was used to determine the level of expression of prostaglandin F(2alpha) (FP) receptor mRNA in various mouse tissues, including normal, hyperplastic and neoplastic mouse epidermis. Steady-state concentrations of FP receptor mRNA were low in normal and hyperplastic epidermis. The response of the epidermis to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was biphasic in that FP receptor mRNA was increased immediately after treatment, followed by a long-lasting down-regulation at later time points. FP receptor mRNA was down-regulated in the majority of papillomas obtained by the mouse skin carcinogenesis initiation-promotion protocol. In carcinomas, FP receptor mRNA expression was similar to that in normal epidermis. The steady-state concentration of FP mRNA was inversely correlated with PGF(2alpha) levels in normal and hyperplastic epidermis and in papillomas, indicating that FP mRNA expression is regulated by this eicosanoid.

Topics: Adolescent; Animals; Base Sequence; Carcinogens; Dinoprost; DNA Primers; Female; Humans; Hyperplasia; Mice; Polymerase Chain Reaction; Receptors, Prostaglandin; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

The intraocular pressure-lowering drug latanoprost, a phenyl-substituted analogue of prostaglandin F2 alpha (PGF2 alpha), increases iris pigmentation in a small number of patients. In theory, this could be due to increased melanogenesis or melanocyte proliferation. To distinguish these two possibilities, the present study examined the effects of latanoprost on tyrosinase activity (the rate-limiting step for melanin synthesis) and mitotic index of cultured melanoma lines. Murine cutaneous melanoma lines (S91 and B16), and human uveal (OCM1, OCM3, and OM431) and cutaneous (SK-MEL5 and M21) melanoma lines were cultured with PGE1, PGE2, PGF2 alpha, latanoprost, or the adenylate cyclase stimulating agent forskolin. After treatment, tyrosinase was assayed with respect to its dopa oxidase activity using a colorimetric assay. PGE1, PGE2, PGF2 alpha, and latanoprost greatly increased tyrosinase activity in murine melanoma lines and caused small increases in tyrosinase activity in human uveal and cutaneous melanoma lines. Similar results were obtained with the cAMP-elevating compound forskolin. Cyclic AMP content, as determined by an enzyme-linked immunoassay, was similarly increased by all treatments, with forskolin being the most potent stimulator. Since the species difference in tyrosinase activity was observed without an apparent difference in induction of cAMP, latanoprost would appear to induce tyrosinase activity through a non-cAMP-dependent pathway. Finally, latanoprost and PGF2 alpha did not enhance the mitotic index of human uveal or cutaneous melanoma lines, measured by [6-3H] thymidine uptake, although they increased the mitotic index of one murine cutaneous line. Given that latanoprost induced tyrosinase activity, but did not increase the mitotic index in any of the human melanoma lines studied, this suggests that the in vivo iris pigmentation side effect of latanoprost may not result from increased cell division, but from elevated tyrosinase activity.

Topics: Adenylyl Cyclases; Alprostadil; Animals; Colforsin; Cyclic AMP; Dinoprost; Dinoprostone; Enzyme Induction; Enzyme-Linked Immunosorbent Assay; Humans; Intraocular Pressure; Latanoprost; Melanoma; Mice; Mitotic Index; Monophenol Monooxygenase; Pigmentation; Prostaglandins F, Synthetic; Skin Neoplasms; Stimulation, Chemical; Time Factors; Tumor Cells, Cultured; Uveal Neoplasms

We studied the response of a human squamous cell carcinoma cell line, SCC-12F, to human complement attack and found that the cells were completely resistant to complement lysis. In the absence of lysis, there was significant C3 deposition and C5b-9 deposition on the cells. Removal of the lipid-linked complement regulatory proteins CD59 and decay-accelerating factor (DAF) by treatment of the cells with phosphatidylinositol-specific phospholipase C (PIPLC) resulted in increased C3b and C5b-9 deposition on the cells and a slight increase in cell death. Treatment of the cells with complement caused them to release membrane vesicles containing the terminal complement proteins. In addition, complement induced SCC-12F to produce significant amounts of prostaglandin F2alpha (PGF2alpha). We conclude that CD59 and DAF are important in the resistance of SCC-12F to complement and that these cells produce membrane vesicles and PGF2alpha in response to complement attack. These responses, in the absence of cell death, may be important in the pathogenesis of inflammatory skin disease in which complement is deposited.

Topics: Animals; Carcinoma, Squamous Cell; Complement Inactivator Proteins; Complement Membrane Attack Complex; Complement System Proteins; Cytotoxicity, Immunologic; Dinoprost; Facial Neoplasms; Humans; Immune Sera; Keratinocytes; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoinositide Phospholipase C; Rabbits; Skin Neoplasms; Tumor Cells, Cultured; Type C Phospholipases

When applied to NMRI mouse skin in vivo, phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) have been found to induce two early waves of prostaglandin E2 (PGE2) synthesis after 15 and 90 min and a delayed accumulation of prostaglandin F2 alpha (PGF2 alpha) after 2 h. With respect to PGF2 alpha formation different activities of both agents were observed, in that TPA but not RPA induced additional PGF2 alpha waves after 4 and 17 h. Functionally, PGE2 was previously shown to be an endogenous mediator of the TPA- or RPA-induced epidermal hyperproliferation and hyperplasia. A functional role of PGF2 alpha could be attributed to the post-initiation stages of tumor development in initiated mouse skin, i.e. the conversion stage (stage I of tumor promotion) elicited by two TPA applications and the promotion stage (stage II of promotion) brought about repetitive RPA treatments. PGF2 alpha, appearing as one distinct biosynthetic wave 3-4 h after TPA application seems to be critically involved in the conversion steps since (i) inhibition of its accumulation by indomethacin led to an inhibition of tumor formation, (ii) the inhibitory effect of indomethacin could be reversed by PGF2 alpha and (iii) RPA was not able to give rise to the accumulation of PGF2 alpha 4 h after application as obtained by TPA treatment. Moreover, RPA-induced promotion of DMBA- and TPA-treated mouse skin was inhibited by indomethacin. The inhibitory effect of indomethacin on papilloma formation was again reversed by PGF2 alpha treatment concomitant with RPA.

Topics: Animals; Cocarcinogenesis; Dinoprost; Dinoprostone; Epidermis; Indomethacin; Mice; Papilloma; Phorbol Esters; Skin Neoplasms; Tetradecanoylphorbol Acetate

There is evidence suggesting a role of eicosanoids in the growth of certain tumors. In this study, tissue samples were collected from basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin. Both BCCs and SCCs contained more prostaglandin E2 and F2 alpha (PGE2 and PGF2 alpha) than normal epidermis. In vitro incubation of tumor samples with arachidonic acid also resulted in PGE2 and PGF2 alpha formation. Basal cell carcinomas exhibiting a histologically aggressive growth pattern contained higher levels of prostaglandins than those with a nonaggressive growth pattern, both in vivo and after in vitro incubation. Lipoxygenase products (12- and 15-hydroxyeicosatetraenoic acid) were present in smaller amounts than cyclo-oxygenase products (PGE2 and PGF2 alpha) in vivo. Compared with normal epidermis, SCCs and, particularly, BCCs produced smaller amounts of 12-hydroxyeicosatetraenoic acid during in vitro incubation with arachidonic acid. The levels of lipoxygenase products were not related to the tumor growth pattern. These results indicate that excessive prostaglandin levels in BCCs may be associated with an aggressive growth pattern.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acids; Breast Neoplasms; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Dinoprost; Dinoprostone; Head and Neck Neoplasms; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Mice; Prostaglandins; Prostaglandins E; Prostaglandins F; Rabbits; Radioimmunoassay; Skin Neoplasms

Topics: Calcimycin; Cell Division; Cocarcinogenesis; Dinoprost; Dinoprostone; Epidermal Cells; Hyperplasia; Indomethacin; Prostaglandins E; Prostaglandins F; Skin; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

TPA promotion of skin tumors in mice can be modified by application of various prostaglandins or their precursors. The effects depend on the particular prostaglandin used: PGF2alpha enhances promotion, whereas PGE1 consistently inhibits promotion. Time of application of the prostaglandin with respect to TPA determines whether PGE2 enhances or inhibits. Dose-dependent inhibition was observed for arachidonic acid. The prostaglandins alone were unable to elicit tumors in initiated mice.

Topics: Animals; Arachidonic Acid; Carcinogens; Cell Transformation, Neoplastic; Cocarcinogenesis; Dinoprost; Dinoprostone; Female; Mice; Mice, Inbred SENCAR; Oxytocics; Papilloma; Prostaglandins; Skin Neoplasms; Tetradecanoylphorbol Acetate