cyclic-gmp and Skin-Neoplasms

Anthralin was first synthesized in 1916. Earlier, a natural product, chrysarobin, originally derived from the South American araroba tree, had been used to treat psoriasis. Anthralin was first used in Germany, and later in the Ingram regimen in Britain, but it has never been popular with American dermatologists. This is probably due to the side effects of staining and irritation of the skin. Attempts to reduce these using low concentration, short contact therapy, and concomitant steroid therapy, have been only partially successful. It may be that better instruction of patients and physicians will lead to wider use of this effective topical agent for the treatment of psoriasis. The mode of action of anthralin is thought to be either through its effect on deoxyribonucleic acid (DNA), probably mitochondrial DNA, which reduces cell turnover, or through its effects on various enzyme systems, including those of polyamine synthesis and respiration. The aims of this review are to discuss historical aspects of anthralin and to update its chemistry, pharmacology, and clinical usage.

Topics: Anthracenes; Anthralin; Cell Division; Chemistry; Cyclic AMP; Cyclic GMP; DNA Replication; Drug Administration Schedule; England; Erythema; Glucosephosphate Dehydrogenase; History, 19th Century; History, 20th Century; Humans; Mitochondria; Oxidation-Reduction; Polyamines; Psoriasis; Skin Absorption; Skin Neoplasms; Structure-Activity Relationship

Drug resistance mechanisms still characterize metastatic melanoma, despite the new treatments that have been recently developed. Targeting of the cGMP/protein kinase G pathway is emerging as a therapeutic approach in cancer research. In this study, we evaluated the anticancer effects of two polymeric-linked dimeric cGMP analogs able to bind and activate protein kinase G, called protein kinase G activators (PAs) 4 and 5. PA5 was identified as the most effective compound on melanoma cell lines as well as on patient-derived metastatic melanoma cells cultured as three-dimensional spheroids and in a zebrafish melanoma model. PA5 was able to significantly reduce cell viability, size, and invasion of melanoma spheroids. Importantly, PA5 showed a tumor-specific outcome because no toxic effect was observed in healthy melanocytes exposed to the cGMP analog. We defined that by triggering protein kinase G, PA5 interfered with the EGF pathway as shown by lower EGFR phosphorylation and reduction of activated, phosphorylated forms of protein kinase B and extracellular signal‒regulated kinase 1/2 in melanoma cells. Finally, PA5 significantly reduced the metastatic process in zebrafish. These studies open future perspectives for the cGMP analog PA5 as a potential therapeutic strategy for melanoma.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Humans; Melanocytes; Melanoma; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Skin Neoplasms; Zebrafish

Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.

Topics: Animals; Antibodies, Monoclonal; Cancer Vaccines; CD40 Antigens; CD8-Positive T-Lymphocytes; Cyclic GMP; Epitopes, T-Lymphocyte; Humans; Immunotherapy; Interferon Type I; Lymphocyte Activation; Melanoma, Experimental; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly I-C; Receptors, Interferon; Skin Neoplasms; Vaccines, Subunit

VILIP-1 (visinin-like protein 1) is downregulated in various human squamous cell carcinoma (SCC). In a mouse skin SCC model VILIP-1 expression is reduced in aggressive tumor cells, accompanied by reduced cAMP levels. Overexpression of VILIP-1 in aggressive SCC cells led to enhanced cAMP production, in turn causing a reduction in invasive properties. Moreover, in primary neurons and neuronal tumor lines VILIP-1 enhanced cGMP signaling. Here, we set out to determine whether and how cAMP and cGMP signaling contribute to the VILIP-1 effect on enhanced SCC model cell migration, and thus most likely invasiveness in vivo. We found stronger increase in cGMP levels in aggressive, VILIP-1-negative SCC cells following stimulation of guanylyl cyclases NPR-A and -B with the natriuretic peptides ANP and CNP, respectively. Incubation with ANP or 8Br-cGMP to increase cGMP levels further enhanced the migration capacity of aggressive cells, whereas cell adhesion was unaffected. Increased cGMP was caused by elevated expression levels of NPR-A and -B. However, the expression level of VILIP-1 did not affect cGMP signaling and guanylyl cyclase expression in SCC. In contrast, VILIP-1 led to reduced migration of aggressive SCC cells depending on cAMP levels as shown by use of adenylyl cyclase (AC) inhibitor 2',3'-dideoxyadenosine. Involvement of cAMP-effectors PKA and EPAC play a role downstream of AC activation. VILIP-1-positive and -negative cells did not differ in mRNA expression of ACs, but an effect on enhanced protein expression and membrane localization of ACs was shown to underlie enhancement of cAMP production and, thus, reduction in cell migration by VILIP-1.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Atrial Natriuretic Factor; Blotting, Western; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cyclic AMP; Cyclic GMP; Dideoxyadenosine; Guanosine Monophosphate; Humans; Mice; Microscopy, Fluorescence; Neurocalcin; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Skin Neoplasms

Malignant melanoma is one of the most aggressive human neoplasms which develop from the malignant transformation of normal epithelial melanocytes and share the lineage with retinal cells. cGMP-phosphodiesterase 6 (PDE6) is one of the cancer-retina antigens newly identified in melanoma cells. Normally, PDE6 hydrolyzes the photoreceptor second messenger cGMP allowing the visual signal transduction in photoreceptor cells. cGMP also play an important signaling role in stimulating melanogenesis in human melanocytes. Here, we present evidence that PDE6 is a key enzyme regulating the cGMP metabolism in melanoma cells. Decrease in intracellular cGMP leads to calcium accumulation in melanoma cells. In these cells, cGMP-phosphodiesterase 6 can be activated by another cancer-retina antigen, transducin, through Wnt5a-Frizzled-2 cascade, which leads to a lowering of cGMP and an increase in intracellular calcium mobilization. Thus, the aberrant expression of PDE6 may control cGMP metabolism and calcium homeostasis in melanoma cells.

Topics: Calcium; Cell Line, Tumor; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 6; Frizzled Receptors; Homeostasis; Humans; Melanoma; Models, Biological; Protein Subunits; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Transducin; Wnt Proteins; Wnt-5a Protein

There will be an estimated 59,940 new cases of melanoma and 8,110 deaths from melanoma in the United States in 2007. There has been no improvement in survival with melanomas in the last 22 years, with current treatment indicating that new treatment(s) of melanoma are drastically needed. Four cardiac hormones ie, atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide, and kaliuretic peptide, have significant anticancer effects in adenocarcinomas.. Dose-response curves evaluated the effects of these cardiovascular hormones on cell death and DNA synthesis in several melanoma cell lines in culture for 96 hours. Receptors to mediate these peptide hormones effects were examined in the melanoma cells with Western blots. Their intracellular mediator-analog 8-bromo-cyclic GMP was used to determine if it could mimic their effects on decreasing melanoma cell number and DNA synthesis.. The four cardiac hormones caused cell death in up to 71% (P < 0.001) of the melanoma cells within 24 hours. Cardiac hormone receptors (NPR-A, -B, -C) were present on the melanoma cells, and each of the peptide hormones decreased DNA synthesis within the melanoma cells up to 73% (P < 0.001) at their 1-microM concentrations. 8-Bromo-cyclic GMP mimicked their effects, decreasing the number of melanoma cells up to 67% and their DNA synthesis by 58% (both at P < 0.01).. These results indicate that 4 cardiac hormones have potent beneficial effects by increasing cell death in up to 71% of melanoma cells within 24 hours mediated in part by a 73% decrease in their DNA synthesis.

Topics: Adult; Atrial Natriuretic Factor; Cell Death; Cell Line, Tumor; Cyclic GMP; DNA, Neoplasm; Guanylate Cyclase; Humans; Male; Melanoma; Middle Aged; Peptide Fragments; Protein Precursors; Receptors, Atrial Natriuretic Factor; Skin Neoplasms; Time Factors

Nitric oxide (NO) and the NO generating agent nitroprusside (SNP), inhibit the binding of [125I] vasoactive intestinal peptide (VIP) to its receptor at the surface of IGR39 human melanoma cells. Cysteine (10 mM) increases the sensitivity of the system to SNP while N-acetylcysteine (10 mM) decreases it. The NO gas as well as SNP inhibits the [125I]VIP binding capacity. These observations sustain an effect of SNP-generated NO rather than an effect of the SNP molecule per se or the cyanoferrate portion of the molecule. The inhibitory effect of NO is time and concentration dependent and is fully reversible. Affinity constants of high and low affinity VIP receptors of SNP-treated IGR39 cells are not modified while maximal binding capacity (Bmax) of both receptor types are decreased to the same extent. Production of cGMP by SNP-treated cells is time and concentration dependent and the maximum amount of cGMP obtained reaches 13 times the basal level. The cAMP production is not affected by SNP. However, the SNP effects on the [125I]VIP binding are not mimicked by the membrane permeant cGMP analogs dibutyryl cGMP and 8-bromo cGMP even at concentrations as high as 0.5 mM. Taken altogether, these data demonstrate a regulatory action of NO on VIP binding capacity of IGR39 melanoma cells which is not cGMP mediated. They also evidence a new step which could be involved in the NO-VIP interaction.

Topics: Cyclic AMP; Cyclic GMP; Dibutyryl Cyclic GMP; Humans; Melanoma; Neoplasm Proteins; Nitric Oxide; Nitroprusside; Protein Binding; Receptors, Vasoactive Intestinal Peptide; Skin Neoplasms; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Lymphocytes; Male; Middle Aged; Mycosis Fungoides; Reference Values; Skin Neoplasms

A dynamic complex evaluation of immunologic vigor was carried out in 17 cases of Kaposi's sarcoma. Immunologic disorders were found to be in a correlation with clinical course. Three groups were identified: (1) patients with favourable prognosis (OKT4+/OKT8+ ratio--1.46 +/- 0.09), (12) slowly advancing disease (OKT4+/OKT8+ ratio--0.87 +/- 0.13) and (3) unfavorable clinical course (OKT4+/OKT8+ ratio--0.47 +/- 0.04). The said variations are comparable to those of cyclic nucleotide level in blood lymphocytes.

Topics: B-Lymphocytes; Cell Migration Inhibition; Cyclic AMP; Cyclic GMP; Female; Humans; Immunoglobulins; Leukocyte Count; Lymphatic Metastasis; Male; Rosette Formation; Sarcoma, Kaposi; Skin Neoplasms; T-Lymphocytes; T-Lymphocytes, Helper-Inducer

Topics: Adenylyl Cyclases; Animals; Cocarcinogenesis; Cyclic GMP; Enzyme Activation; Epidermis; Isoproterenol; Mice; Neoplasms, Experimental; Papilloma; Phorbols; Receptors, Adrenergic; Receptors, Adrenergic, beta; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

Topics: 1-Methyl-3-isobutylxanthine; Administration, Topical; Animals; Cocarcinogenesis; Cyclic AMP; Cyclic GMP; DNA, Neoplasm; Dose-Response Relationship, Drug; Female; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Papilloma; Phorbols; Skin Neoplasms; Tetradecanoylphorbol Acetate; Theophylline

The effect of nucleotides on initiation-promotion skin carcinogenesis in Swiss mice was investigated. Cyclic AMP was given before initiation with DMBA, between initiation and promotion, and at the same time as promotion with croton oil. Cyclic AMP was more effective in inhibiting tumor development when injected at the same as promotion with croton oil. 5'-adenosine-monophosphate (5'-AMP) and cyclic GMP were as effective as cyclic AMP in inhibiting tumor development under these conditions. However, adenosine, dibutyryl-cyclic AMP and 5'-guanosine-monophosphate (5'-GMP) were ineffective.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenosine Monophosphate; Animals; Benz(a)Anthracenes; Cocarcinogenesis; Croton Oil; Cyclic AMP; Cyclic GMP; Female; Mice; Neoplasms, Experimental; Ribonucleotides; Skin Neoplasms; Time Factors

Topics: Adult; Carcinoma, Basal Cell; Cyclic AMP; Cyclic GMP; Eczema; Humans; Leukocytes; Melanoma; Middle Aged; Nevus; Nucleotides, Cyclic; Skin Neoplasms; T-Lymphocytes

Changes in the concentration of cyclic AMP as well as cyclic GMP were measured in different murine tumors and in human tumors of varying malignancy. The quotient of cAMP and cGMP seems to be an important parameter for the molecular-biological derangement. Because of the recently much discussed importance of cAMP and cGMP in the immune defence the changes in the concentration of both nucleotides were measured in the T-lymphocytes of tumor patients. Significant changes occurred in patients with malignant melanoma. Investigations of the stimulatibility of the cAMP and cGMP levels revealed a diminished activatibility of the cAMP level and a higher stimulatibility of the cGMP level in the T-lymphocytes of patients with malignant melanoma as compared with those of the controls. On the basis of the working hypothesis that there is a causal relationship between the deranged dualism of cAMP and cGMP in the T-lymphocytes and the failure of the immunological tumor cell defence, an increase in the cAMP level is offered as a possible therapy. Therapeutic results in tumor-bearing mice and first results in melanoma patients are discussed.

Topics: Animals; Carcinoma, Ehrlich Tumor; Cyclic AMP; Cyclic GMP; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Melanoma; Mice; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Nevus; Skin; Skin Neoplasms; T-Lymphocytes; Time Factors