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)

Despite extensive study on biological activities of chitosan and chitooligosaccharides (COS), there is no experimental evidence available as to COS mediated inhibition of free radical damage in cellular oxidizing systems. In this study, radical scavenging efficacies of different molecular weight bearing COS were assessed and their intracellular radical scavenging effects were tested employing B16F1, murine melanoma cell line. The results exhibited appreciable suppression in occurrence of intracellular radical species in the presence of low molecular weight bearing COS (<1 kDa) confirming low molecular weight is important for observed activities in biological systems. However, DNA oxidation carried out in the presence of COS clearly exhibited that COS exert protective effect on oxidative damage of purified genomic DNA regardless of molecular weight. Low molecular weight bearing COS was observed to be successively participated in suppression of NF-kappaB gene promoter activity suggesting its capability to prevent oxidative stress related disease complications. Moreover, induction of intracellular glutathione (GSH) level in the presence of COS promoted the effectiveness of COS to act against cellular oxidative stress.
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PMID:An in vitro cellular analysis of the radical scavenging efficacy of chitooligosaccharides. 1747 86

To find novel skin-whitening agents, the melanogenesis inhibitory action of gallic acid (GA) was investigated. In this current study, the effects of GA on mushroom tyrosinase, tyrosinase inhibitory activity, and melanin content were assessed in B16 melanoma cells (B16 cells). Results indicated that GA has a strong antityrosinase activity (IC50=3.59x10(-6) M). Furthermore, data on murine tyrosinase activity and melanin biosynthesis revealed that GA effectively suppressed murine tyrosinase action and the amount of melanin. To investigate the relation between GA's inhibition of melanogenesis and antioxidant activity, the effect of GA on reactive species (RS) generation and the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in were determined in B16 cells. Results indicated that GA effectively down-regulated the RS generation and enhanced the GSH/GSSG ratio. Based on these results, I propose that GA exerts antimelanogenic activity coupled with antioxidant properties by suppressing RS generation and maintaining a higher GSH/GSSG ratio.
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PMID:Antimelanogenic and antioxidant properties of gallic acid. 1754 Nov 53

The metabolism and toxicity of ethyl 4-hydroxybenzoate (4-HEB) were investigated in vitro using tyrosinase enzyme, a melanoma molecular target, and CYP2E1 induced rat liver microsomes, and in human SK-MEL-28 melanoma cells. The results were compared to 4-hydroxyanisole (4-HA). At 90 min, 4-HEB was metabolized 48% by tyrosinase and 26% by liver microsomes while the extent of 4-HA metabolism was 196% and 88%, respectively. The IC50 (day 2) of 4-HEB and 4-HA towards SK-MEL-28 cells were 75 and 50 microM, respectively. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased 4-HEB toxicity towards SK-MEL-28 cells indicating o-quinone formation played an important role in 4-HEB induced cell toxicity. Addition of ascorbic acid and GSH to the media was effective in preventing 4-HEB cell toxicity. Cyclosporin A and trifluoperazine, inhibitors of permeability transition pore in mitochondria, were significantly potent in inhibiting 4-HEB cell toxicity. 4-HEB caused time-dependent decline in intracellular GSH concentration which preceded cell death. 4-HEB also led to reactive oxygen species (ROS) formation in melanoma cells which exacerbated by dicoumarol and 1-bromoheptane whereas cyclosporin A and trifluoperazine prevented it. Our findings suggest that the mechanisms of 4-HEB toxicity in SK-MEL-28 were o-quinone formation, intracellular GSH depletion, ROS formation and mitochondrial toxicity.
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PMID:Metabolic bioactivation and toxicity of ethyl 4-hydroxybenzoate in human SK-MEL-28 melanoma cells. 1784 68

In our efforts to find new skin lightening agents, piceatannol (PICE) was investigated for its antioxidative property and ability to inhibit melanogenesis. In this study, PICE's effect on inhibition of mushroom tyrosinase, and tyrosinase inhibiting activity and melanin content were assessed utilizing the B16F10 melanoma cell (B16 cell) culture system. Results indicated that PICE has a strong antityrosinase activity (IC(50)=1.53 microM). To evaluate the relative efficacy of PICE compared to other tyrosinase inhibitors, its inhibitory effect was compared and showed that PICE was significantly stronger than kojic acid (IC(50)=50.1 microM) and resveratrol (IC(50)=63.2 microM). Furthermore, PICE was shown to down-regulate melanin content. To document PICE's antioxidative property, which is known to influence melanogenic activity, we assessed reactive species (RS) generation, reduced glutathione (GSH) and oxidized glutathione (GSSG) levels in these B16 cells. The results showed that PICE suppressed RS generation and enhanced the GSH/GSSG ratio. In conclusion, our results indicated that the antimelanogenic action of PICE is likely exhibited by the combined effect of PICE's antioxidative property and its ability to suppress RS generation while increasing the GSH/GSSG ratio.
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PMID:Piceatannol inhibits melanogenesis by its antioxidative actions. 1797 67

Tyrosinase is expressed in melanoma cells and catalyzes the formation of 3,3',4',5,7-pentahydroxyflavone (quercetin) into reactive quinone species and subsequent glutathionyl adducts. Therefore, we examined the effect of quercetin metabolism on the glutathione (GSH) bioreduction pathway and cell viability in DB-1 melanoma cells that express varying levels of tyrosinase (Tyr+). In a cell-free system, GSH was significantly decreased by quercetin, which coincided with the formation of glutathionyl adducts. In Tyr+ clones, quercetin decreased bioreduction capacity and increased reactive oxygen species (ROS) to a greater degree compared to control cells. The antioxidant/electrophile response element-induced enzymes, glutathione-S-transferase (GST), and nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 were expressed at high levels in Tyr+ cells and contributed to pro-oxidant quercetin metabolism. The basal level of ROS and apoptosis was higher in Tyr+ cells and were selectively increased after exposure to quercetin. The increase in apoptosis following quercetin exposure was p53/Bax mediated and correlated with a decrease in GST-driven bioreduction capacity and an increase in ROS. In conclusion, quercetin can selectively sensitize Tyr+ expressing melanoma cells to apoptosis and may serve as an adjuvant to chemotherapy by enhancing cell death and interfering with GST-mediated drug resistance.
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PMID:Quercetin selectively inhibits bioreduction and enhances apoptosis in melanoma cells that overexpress tyrosinase. 1800 Dec 20

Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenicmelanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hcy), an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by increase in glutathione (GSH) levels and methylated DNA content. Furthermore, a significant increase in dnmt1 and 3b expression was identified along melan-a anchorage blockade. L(G)-Nitro-L-arginine methyl esther (L-NAME), known as a nitric oxide synthase (NOS) inhibitor, and N-acetyl-L-cysteine (NAC) prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO) production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.
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PMID:Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. 1808 18

The extracellular gamma-glutamyltransferase-mediated metabolism of glutathione has been implicated in prooxidant events which may have impact on cellular functions including drug resistance. This study was performed in two GGT-transfected melanoma clones to explore the hypothesis that GGT expression in tumour cells is implicated in modulation of cell behaviour under stress conditions. Our results show that GGT-overexpression in melanoma cells was associated with resistance to oxidative stress produced by prooxidant agents such as hydrogen peroxide and ascorbic acid. In GGT-overexpressing cells, ability to tolerate oxidative stress was evidenced by the presence of a moderate level of ROS and lack of DNA damage response following treatment with H(2)O(2). Cellular response to oxidative stress induced by ascorbic acid was detectable only in the clone with low GGT activity which also exhibited an increased susceptibility to apoptosis. The increased resistance of the GGT-overexpressing clone was not related to intracellular GSH content but rather to the increased expression of catalase and to a reduced efficiency of iron-mediated formation of toxic free radicals. Taken together, these findings are consistent with a contribution of GGT in the mechanisms of drug resistance, because induction of oxidative stress is a relevant event in the apoptotic response to cytotoxic agents.
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PMID:Cellular response to oxidative stress and ascorbic acid in melanoma cells overexpressing gamma-glutamyltransferase. 1831 25

Metastatic spread, not primary tumor burden, is the leading cause of cancer death. Glutathione (L-gamma-glutamyl-L-cysteinyl-glycine; GSH) is the most prevalent non-protein thiol in mammalian cells, and in cancer cells is particularly relevant in regulating mutagenic mechanisms, DNA synthesis, growth, and multidrug and radiation resistance. In malignant tumors, as compared with normal tissues, that resistance associates in most cases with higher GSH levels. Interaction of metastatic cells with the vascular endothelium activates local release of proinflammatory cytokines, which act as signals promoting cancer cell adhesion, extravasation, and proliferation. A high% of metastatic cells with high GSH levels survive the nitrosative and oxidative stresses elicited by the endothelium and possibly by macrophages and granulocytes. Gamma-glutamyl transpeptidase overexpression and an interorgan flow of GSH, by increasing cysteine availability for tumor GSH synthesis, promote metastatic growth. The mechanism of NO- and H(2)O(2)-induced tumor cytotoxicity has been examined during murine B16 melanoma (B16M) adhesion to the vascular endothelium. H(2)O(2) was not cytotoxic in the absence of NO. But, NO-induced tumor cytotoxicity was increased by H(2)O(2) due to the formation of potent oxidants, likely (.)OH and ((-))OONO radicals, via a trace metal-dependent process. B16M cells with high GSH content were more resistant to NO and H(2)O(2). Cancer cell survivors showed higher Bcl-2 and GSH levels. Metastatic invaders, after surviving attack by tissue macrophages, may further enhance their resistance.
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PMID:Tumoricidal activity of endothelium-derived NO and the survival of metastatic cells with high GSH and Bcl-2 levels. 1847 63

We previously reported that melanogenic enzyme TRP-2 (or DCT for DOPAchrome tautomerase) expression in WM35 melanoma cells resulted in increased intracellular GSH levels, reduction in DNA damage induced by free radicals, and decreased cell sensitivity to oxidative stress. These effects seemed to depend on a particular cellular context, because none of them were found to occur in HEK epithelial cells. We postulated that the TRP-2 beneficial effect observed in WM35 cells in the oxidative stress situation may relate to quinone metabolization and, more precisely, to the ability of TRP-2 to clear off related toxic metabolites, resulting in a global redox status modification. Here, a comparative protein expression profiling of catecholamine biosynthesis enzymes and detoxification enzymes was conducted in WM35 melanoma cells and in HEK epithelial cells, in comparison with normal human melanocytes. Results showed that WM35 cells, but not HEK cells, expressed enzymes involved in catecholamine biosynthesis, suggesting that their quinone-related toxic metabolites were present in WM35 cells but not in HEK cells. To address the issue of a possible TRP-2 beneficial effect toward quinone toxicity, cell survival experiments were then conducted in HEK cells using dopamine and hydroquinone at toxic concentrations. We showed that TRP-2 expression significantly reduced HEK cell sensitivity to both compounds. This beneficial property of TRP-2 was likely to depend on the integrity of its DOPAchrome tautomerase catalytic site, because both TRP-2(R194Q) and TRP-2(H189G), which have lost their DOPAchrome tautomerase activity, failed to modify the HEK cell response to dopamine and hydroquinone. These results suggest that TRP-2 acts on quinone metabolites other than DOPAchrome, e.g., in the catecholamine pathway, and limits their deleterious effects.
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PMID:TRP-2 expression protects HEK cells from dopamine- and hydroquinone-induced toxicity. 1867 12

Permeabilization of the mitochondrial membrane has been extensively associated with necrotic and apoptotic cell death. Similarly to what had been previously observed for B16F10-Nex2 murine melanoma cells, PdC (palladacycle compounds) obtained from the reaction of dmpa (N,N-dimethyl-1-phenethylamine) with the dppe [1,2-ethanebis(diphenylphosphine)] were able to induce apoptosis in HTC (hepatoma, tissue culture) cells, presenting anticancer activity in vitro. To elucidate cell site-specific actions of dmpa:dppe that could respond to the induction of apoptosis in cancer cells in the present study, we investigated the effects of PdC on isolated RLM (rat liver mitochondria). Our results showed that these palladacycles are able to induce a Ca2+-independent mitochondrial swelling that was not inhibited by ADP, Mg2+ and antioxidants. However, the PdC-induced mitochondrial permeabilization was partially prevented by pre-incubation with CsA (cyclosporin A), NEM (N-ethylmaleimide) and bongkreic acid and totally prevented by DTT (dithiothreitol). A decrease in the content of reduced thiol groups of the mitochondrial membrane proteins was also observed, as well as the presence of membrane protein aggregates in SDS/PAGE without lipid and GSH oxidation. FTIR (Fourier-transform IR) analysis of PdC-treated RLM demonstrated the formation of disulfide bonds between critical thiols in mitochondrial membrane proteins. Associated with the mitochondrial permeabilization, PdC also induced the release of cytochrome c, which is sensitive to inhibition by DTT. Besides the contribution to clarify the pro-apoptotic mechanism of PdC, this study shows that the catalysis of specific protein thiol cross-linkage is enough to induce mitochondrial permeabilization and cytochrome c release.
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PMID:Palladacycles catalyse the oxidation of critical thiols of the mitochondrial membrane proteins and lead to mitochondrial permeabilization and cytochrome c release associated with apoptosis. 1875 68


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