Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Violacein is the main pigment produced by Chromobacterium violaceum, a saprophytic gram-negative bacillus. Violacein is formed by the condensation of two modified tryptophan molecules and has potential anti-neoplastic effects. The purpose of this pilot study was to investigate the in vitro activity of violacein in human uveal melanoma cell lines. Human uveal melanoma cell lines 92.1 and OCM-1 were incubated with five different concentrations of violacein (10(-5)-10(-9) M), and the total cellular protein content was measured by means of the sulphorhodamine B assay. Dose-response curves were obtained and the concentration inhibiting cell growth by 50% (IC50) together with the concentration inhibiting the net cell growth by 50% (GI50) were calculated for both cell lines. Violacein IC50 and GI50 concentrations to cell line 92.1 were 2.78 x 10(-6) M and 1.69 x 10(-6) M, respectively. The IC50 and GI50 concentrations to cell line OCM-1 were 3.69 x 10(-6) M and 2.12 x 10(-6) M, respectively. Previous studies using the same methodology have revealed violacein to have a GI50 in the range (3-6) x 10(-8) M for MOLT-4 leukaemia, NCI-H460 large cell lung cancer and KM12 colon cancer cell lines. Violacein displayed borderline cytotoxic activity in human uveal melanoma cell lines 92.1 and OCM-1, as measured by the sulphorhodamine B assay, and further studies are necessary to define its suitability as a potential therapeutic agent for metastatic uveal melanoma.
Melanoma Res 2004 Oct
PMID:Cytotoxic effects of violacein in human uveal melanoma cell lines. 1545

A potential approach to activate tumor-specific T cells is to use live bacterial vectors to deliver appropriate antigens in a highly immunostimulatory context. We constructed a recombinant strain of Listeria monocytogenes (rLM) expressing murine tyrosinase-related protein-2 (TRP-2), a nonmutated melanocyte-derived differentiation antigen highly expressed in melanomas. Immunization of C57Bl/6 mice with this rLM strain efficiently primed CD8 T cells to recognize the MHC class I-restricted TRP-2180-188 epitope and express IFN-gamma upon in vitro peptide stimulation. Peptide-loaded target cells were lysed in vitro by TRP-2-specific T cells in cytotoxicity assays, and mice immunized and boosted with rLM expressing TRP-2 were functionally protected from subcutaneous challenge with B16 melanoma cells. These results identify and characterize the anti-"self" T-cell responses induced by recombinant L. monocytogenes expressing an endogenous, nonmutated tumor antigen.
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PMID:Characterization of anti-self CD8 T-cell responses stimulated by recombinant Listeria monocytogenes expressing the melanoma antigen TRP-2. 1591 53

Melatonin has been experimentally implicated in skin functions such as hair growth cycling, fur pigmentation, and melanoma control, and melatonin receptors are expressed in several skin cells including normal and malignant keratinocytes, melanocytes, and fibroblasts. Melatonin is also able to suppress ultraviolet (UV)-induced damage to skin cells and shows strong antioxidant activity in UV exposed cells. Moreover, we recently uncovered expression in the skin of the biochemical machinery involved in the sequential transformation of l-tryptophan to serotonin and melatonin. Existence of the biosynthetic pathway was confirmed by detection of the corresponding genes and proteins with actual demonstration of enzymatic activities for tryptophan hydroxylase, serotonin N-acetyl-transferase, and hydroxyindole-O-methyltransferase in extracts from skin and skin cells. Initial evidence for in vivo synthesis of melatonin and its metabolism was obtained in hamster skin organ culture and in one melanoma line. Therefore, we propose that melatonin (synthesized locally or delivered topically) could counteract or buffer external (environmental) or internal stresses to preserve the biological integrity of the organ and to maintain its home-ostasis. Furthermore, melatonin could have a role in protection against solar radiation or even in the management of skin diseases.
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PMID:On the role of melatonin in skin physiology and pathology. 1621 27

Level and persistence of antigenic peptides presented by APCs on MHC class I (MHC-I) molecules influence the magnitude and quality of the ensuing CTL response. We recently demonstrated the unique immunological properties conferred on APCs by expressing beta2-microglobulin (beta2m) as an integral membrane protein. In this study, we explored membrane-anchored beta2m as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. We expressed in mouse RMA-S cells two H-2Kb binding peptides from MO5, OVA257-264, and TRP-2181-188, each genetically fused with the N terminus of membranal beta2m via a short linker. Specific Ab staining and T cell hybridoma activation confirmed that OVA257-264 was properly situated in the MHC-I binding groove. In vivo, transfectants expressing both peptides elicited stronger CTLs and conferred better protection against MO5 than peptide-saturated RMA-S cells. Cells expressing OVA257-264/beta2m were significantly superior to OVA257-264-charged cells in their ability to inhibit the growth of pre-established MO5 tumors. Our results highlight the immunotherapeutic potential of membranal beta2m as a universal scaffold for optimizing Ag presentation by MHC-I molecules.
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PMID:Induction of antitumor immunity by CTL epitopes genetically linked to membrane-anchored beta2-microglobulin. 1636 13

Production of indoleamine 2,3-dioxygenase (IDO) by tumor cells, leading to tryptophan depletion and production of immunosuppressive metabolites, may facilitate immune tolerance of cancer. IDO gene is also expressed in dendritic cells (DC) upon maturation induced by lipopolysaccarides or IFN. We investigated IDO gene expression in melanoma cell lines and clinical specimens as compared to mature DC (mDC). Furthermore, we explored effects of L-kynurenine (L-kyn) and 3-hydroxyanthranilic acid (3-HAA) on survival and antigen-dependent and independent proliferation of CD8(+) cells. We observed that IDO gene expression in cultured tumor cells and freshly excised samples is orders of magnitude lower than in mDC, providing highly efficient antigen presentation to CD8(+) T cells. Non toxic concentrations of L-kyn or 3-HAA did not significantly inhibit antigen-specific CTL responses. However, 3-HAA, but not L-kyn markedly inhibited antigen-independent proliferation of CD8(+) T cells induced by common receptor gamma-chain cytokines IL-2, -7 and -15. Our data suggest that CD8(+) T cell activation induced by antigenic stimulation, a function exquisitely fulfilled by mDC, is unaffected by tryptophan metabolites. Instead, in the absence of effective T cell receptor triggering, 3-HAA profoundly affects homeostatic proliferation of CD8(+) T cells.
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PMID:Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines. 1638 30

1. Kynurenic (KYNA) and quinolinic (QUIN) acids are neuroactive tryptophan metabolites formed along the kynurenine pathway: the first is considered a non-competitive antagonist and the second an agonist of glutamate receptors of NMDA type. The affinity of these compounds for glutamate receptors is, however, relatively low and does not explain KYNA neuroprotective actions in models of post-ischemic brain damage. 2. We evaluated KYNA effects on the release of fibroblast growth factor (FGF)-1, a potent neurotrophic cytokine. Because KYNA exhibits a neuroprotective profile in vitro and in vivo, we anticipated that it could function as an autocrine/paracrine inducer of FGF-1 release. Studies were performed in several models of FGF-1 secretion (FGF-1 transfected NIH 3T3 cells exposed to heat shock, A375 melanoma cells exposed to serum starvation, growth factor deprived human endothelial cells). To our surprise, KYNA, at low concentration, inhibited FGF-1 release in all cellular models. QUIN, a compound having opposite effects on glutamate receptors, also reduced this release, but its potency was significantly lower than that of KYNA. 3. KYNA and QUIN also displayed a major stimulatory effect on the proliferation rate of mouse microglia and human glioblastoma cells, in vitro. 4. Our data suggest that minor changes of local KYNA concentration may modulate FGF-1 release, cell proliferation, and ultimately tissue damage in different pathological conditions.
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PMID:Kynurenic acid inhibits the release of the neurotrophic fibroblast growth factor (FGF)-1 and enhances proliferation of glia cells, in vitro. 1639 31

Neuropsychiatric symptoms are commonly related to interferon alpha treatment. The paper summarises the current knowledge about their aetiology, course, and treatment. Interferon alpha is a cytokine with antiviral and antineoplasmatic activity. It is commonly used in the treatment of chronic hepatitis C and B, malignant melanoma, Kaposi sarcoma, renal cancers, and some haematological malignancies. Treatment with interferon alpha is associated with depressive symptoms, cognitive disturbances, chronic fatigue syndrome, dysphoria, anxiety symptoms, anorexia, mania and psychotic states. Up to a half of the patients need psychiatric consultations, 10-25% of them need psychiatric treatment. Neuropsychiatric symptoms are the results of direct affection of CNS by interferon and induced cytokines. They increase hypothalamic-pituitary-adrenal (HPA) activity, alter thyroid function and lead to a behavioural syndrome called 'sickness behaviour'. Moreover interferon induces the activity of 2, 3 indoloamine dioxygenase, the enzyme which converts tryptophan into kynurenine, leads to a reduced level of tryptophan, and thus to a reduced level of central serotonin and to an increased level of neurotoxic kynurenine metabolites. Interferon also affects central opioid receptors and changes dopaminergic and noradrenergic neurotransmission. Serotonin selective reuptake inhibitors (SSRI), other antidepressants i.e. nortriptyline, benzodiazepines, naltrexone, and neuroleptics (for maniac and psychotic states) are used to treat interferon associated psychiatric symptoms. Psychological therapy may also be useful, as well as psychoeducation and behavioural interventions.
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PMID:[Neuropsychiatric symptoms related to interferon alpha]. 1706 50

Arginine deiminase (ADI) catalyzes the irreversible hydrolysis of arginine to citrulline and ammonia. It belongs to a newly classified superfamily of guanidino-group-modifying enzymes. Located in the catalytic center of Mycoplasma hominis ADI, some crucial sites (Asp160, Glu212, His268, and Asp270) are highly conserved among these enzymes. Here, we constructed five ADI single mutants D160E, E212D, H268F, H268Y, and D270E, and three double mutants D160E/D270E, D160E/E212D, and E212D/D270E, aiming to evaluate the contributions of these crucial residues to the structure, stability, and enzymatic activity of ADI, and to elucidate their roles in the catalytic process of this family of enzymes. Tryptophan emission fluorescence and circular dichroism were used to analyze the different effects of mutagenesis on these conserved residues on the secondary and tertiary structures of ADI. Urea-induced unfolding and trypsin digestion were applied to measure their stabilities against denaturants and proteases, respectively. Additionally, the enzymatic activities of ADI and its mutants were measured. Here, we report that all the mutations have little effect on the native structure of ADI. However, the substitutions on these crucial sites still interfere with the stability of ADI to different degrees. As these mutations impair both the substrate binding and the substrate induced conformational changes of ADI to different extents, most of the mutants except D160E (preserves about 30% of the enzymatic activity of wild type) have totally lost the enzymatic activity in the hydrolysis of arginine and the inhibitory ability on the proliferation of mouse melanoma cells.
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PMID:Insight into the catalytic mechanism of arginine deiminase: functional studies on the crucial sites. 1708 Apr 55

Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyl-tryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the D and L stereoisomers exhibit important cell type-specific variations in activity. The L isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell-based assays. However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the d isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of D-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability of D-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block host-mediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens.
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PMID:Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. 1723 91

The progression of cells from a normal differentiated state in which rates of proliferation and apoptosis are balanced to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signalling proteins and the evolution and clonal selection of more aggressive cell phenotypes. These events are associated with changes in the expression of numerous other proteins. This process of tumorigenesis involves the altered expression of one or more TRP proteins, depending on the nature of the cancer. The most clearly described changes are those involving TRPM8, TRPV6 and TRPM1. Expression of TRPM8 is substantially increased in androgen-dependent prostate cancer cells, but is decreased in androgen independent and metastatic prostate cancer. TRPM8 expression is regulated, in part, by androgens, most likely through androgen response elements in the TRPM8 promoter region. TRPM8 channels are involved in the regulation of cell proliferation and apoptosis. Expression of TRPV6 is also increased in prostate cancer and in a number of other cancers. In contrast to TRPM8, expression of TRPV6 is not directly regulated by androgens. TRPM1 is highly expressed in early stage melanomas but its expression declines with increases in the degree of aggressiveness of the melanoma. The expression of TRPV1, TRPC1, TRPC6, TRPM4, and TRPM5 is also increased in some cancers. The level of expression of TRPM8 and TRPV6 in prostate cancer, and of TRPM1 in melanomas, potentially provides a good prognostic marker for predicting the course of the cancer in individuals. The Drosophila melanogaster, TRPL, and the TRPV1 and TRPM8 proteins, have been used to try to develop strategies to selectively kill cancer cells by activating Ca(2+) and Na(+) entry, producing a sustained increase in the cytoplasmic concentration of these ions, and subsequent cell death by apoptosis and necrosis. TRPV1 is expressed in neurones involved in sensing cancer pain, and is a potential target for pharmacological inhibition of cancer pain in bone metastases, pancreatic cancer and most likely in other cancers. Further studies are required to assess which other TRP proteins are associated with the development and progression of cancer, what roles TRP proteins play in this process, and to develop further knowledge of TRP proteins as targets for pharmaceutical intervention and targeting in cancer.
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PMID:TRP channels in cancer. 1761 60


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