Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of the 3-substituent on the cytotoxicity of the 6-aziridinylpyrrolo[1,2-a]-benzimidazole quinones (PBIs), the 6-acetamidopyrrolo[1,2-alpha]benzimidazole quinones (APBIs), and the 6-acetamidopyrrolo[1,2-alpha]benzimidazole iminoquinones (imino-APBIs) was investigated by comparing LC50 mean graphs consisting of 60 cancer lines. Increasing lipophilicity of the 3-substituent of PBIs and APBIs increased the cytotoxicity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the 3-carbamate derivative which shows enhanced cleavage. This property of the 3-carbamate is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer cell lines; the correlation coefficient for log LC50 vs log lipophilicity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are activated by DT-diaphorase but that the APBIs and imino-APBIs are inactivated by this enzyme. Thus, the latter two agents are cytotoxic only as quinones. It was noted that APBIs possess a similar cytotoxic profile to three anthracycline analogues. This observation suggests mechanistic similarities between both types of cytotoxic agents. Major conclusions of this study pertain to the design of agents displaying cytotoxicity specifically against melanoma and renal cancers and to the use of 60-cell line mean graphs and COMPARE in cancer drug QSAR.
...
PMID:Pyrrolo[1,2-a]benzimidazole-based quinones and iminoquinones. The role of the 3-substituent on cytotoxicity. 783 21

In the present experiments we planned to ascertain whether an abnormal production of nitric oxide (NO) by human CHP100 neuroblastoma cells in culture following stimulation of N-methyl-D-aspartate (NMDA) receptors, produced lethal effects in co-cultured human BMEL melanoma cells. Human BMEL melanoma cells in culture were found to be positive to the nicotinamide adenine dinucleotide phosphate diaphorase (NADPH diaphorase) histochemical reaction and produced NO as revealed by measurements of nitrite under basal culture conditions. Exposure for 50 min to aspartate (1-2 mM) or to NMDA (0.5-1.5 mM) did not evoke significant melanoma cell death. The dose of 1.0 mM NMDA applied for 1 min to BMEL cell cultures did not increase significantly nitrite concentrations in comparison to controls. Incubation for 50 min of human CHP100 neuroblastoma cells with NMDA (0.5-1.5 mM) elicited dose-dependent death of BMEL melanoma cells co-cultured in trans-wells. Under these experimental conditions, nitrite levels in cell culture-inserts containing melanoma cells increased by 120% 1 min after application of the excitotoxin (1 mM) to CHP100 neuroblastoma cultures. The lethal effects produced in BMEL cell culture-inserts by application of NMDA (1.0 mM) to CHP100 cultures were prevented by pretreatment of neuroblastoma cultures with MK801 (200 nM). Similar protection was also afforded by N omega-nitro-L-arginine methyl ester (L-NAME; 0.2 mM) and N omega-monomethyl-L-arginine (L-NMMA; 0.2 mM), two inhibitors of nitric oxide synthase, and by haemoglobin (10 microM), a nitric oxide trapping agent.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:N-methyl-D-aspartate-induced excessive formation of nitric oxide in CHP100 neuroblastoma cells produces death of BMEL melanoma cells in co-culture. 783 19

Twelve x-ray-induced transcripts (xips), differentially expressed 8- to 230-fold in x-irradiated versus unirradiated radioresistant human melanoma (U1-Mel) cells, were isolated as cDNA clones (xip1 through xip12) after four rounds of differential hybridization. Northern analyses revealed rare, medium, and abundant xips, ranging in size from 1.2 to 10 kb. All transcripts were transiently expressed and induced by low, but not by high (> 600 cGy), doses of radiation. Three transcripts (xip4, -7, and -12) were induced only by ionizing radiation, and many (i.e., xip1, -2, -3, -5, -6, -8, -9, -10, and -11) were also induced by UV irradiation or phorbol 12-myristate 13-acetate. Heat shock did not induce any of the xips, but it decreased basal levels of xip4, -7, -11, and -12. Three xip cDNA clones were identified as encoding thymidine kinase, DT diaphorase, and tissue-type plasminogen activator. The remaining nine cDNA clones showed little homology to known genes. Three clones contained regions homologous to c-fes/fps protooncogene, recombination activating gene 1, or the human angiogenesis factor gene. X-ray-inducible genes may function in damaged cells to regulate DNA repair, apoptosis, mutagenesis, and carcinogenesis.
...
PMID:Isolation of x-ray-inducible transcripts from radioresistant human melanoma cells. 834 36

There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. The risk factors for women developing these cancers are all associated with longer estrogen exposure, as may be facilitated by early menses, late menopause and long-term estrogen replacement therapy. Equilenin (1,3,5(10),6,8-estrapentaen-3-ol-17-one) or its 17-hydroxylated analogs make up 15% of the most widely prescribed estrogen replacement formulation, Premarin, and yet there is very little information on the human metabolism of these estrogens. In this study, we synthesized the catechol metabolite of equilenin, 4-hydroxyequilenin, and examined how aromatization of the B ring affects the formation and reactivity of the o-quinone (3,5-cyclohexadien-1,2-dione). 4-Hydroxyequilenin-o-quinone is much more redox-active and longer-lived than the endogenous catechol estrone-o-quinones, which suggests that the mechanism(s) of toxicity of the former could be quite different. Interestingly, the rate of reduction of the 4-hydroxyequilenin-o-quinone is increased at least 13-fold in the presence of NAD(P)H:quinone oxidoreductase (DT-diaphorase). Once NADH is consumed however, the catechol auto-oxidized rapidly to the o-quinone. NADH consumption was accompanied by dicumarol-sensitive oxygen uptake both with the purified enzyme and with cytosol from human melanoma cells with high levels of DT-diaphorase activity. P450 reductase and rat liver microsomes also catalyzed NADPH consumption and oxygen uptake. 4-Hydroxyestrone-o-quinone was also rapidly reduced by NAD(P)H; however, this o-quinone does not auto-oxidize and once the o-quinone is reduced the reaction terminates. Including oxidative enzymes in the incubation completes the redox couple and 4-hydroxyestrone-o-quinone behaves like 4-hydroxyequilenin-o-quinone. These data suggest that reduction of estrogen-o-quinones may not result in detoxification. Instead this could represent a cytotoxic mechanism involving consumption of reducing equivalents (NADH/NADPH) as well as formation of superoxide and other reactive oxygen species leading to oxidative stress. Finally, we have compared the cytotoxicity of 4-hydroxyequilenin with that of the estrone catechols in human melanoma cells. 4-Hydroxyequilenin is 5-fold more toxic in these cells compared with 4-hydroxyestrone (ED50 = 7.8 versus 38 microM, respectively) suggesting that formation of the longer-lived redox-active 4-hydroxyequilenin-o-quinone was responsible for the cytotoxic differences. These results substantiate the conclusion that the involvement of quinoids in catechol estrogen toxicity depends on a combination of the rate of formation of the o-quinone, the lifetime of the o-quinone, and the electrophilic/redox reactivity of the quinoids.
...
PMID:Bioreductive activation of catechol estrogen-ortho-quinones: aromatization of the B ring in 4-hydroxyequilenin markedly alters quinoid formation and reactivity. 916 1

DT-diaphorase is a two-electron reducing enzyme that activates the bioreductive anti-tumour agent, mitomycin C (MMC). Cell lines having elevated levels of DT-diaphorase are generally more sensitive to MMC. We have shown that DT-diaphorase can be induced in human tumour cells by a number of compounds, including 1,2-dithiole-3-thione. In this study, we investigated whether induction of DT-diaphorase could enhance the cytotoxic activity of MMC in six human tumour cell lines representing four tumour types. DT-diaphorase was induced by many dietary inducers, including propyl gallate, dimethyl maleate, dimethyl fumarate and sulforaphane. The cytotoxicity of MMC was significantly increased in four tumour lines with the increase ranging from 1.4- to threefold. In contrast, MMC activity was not increased in SK-MEL-28 human melanoma cells and AGS human gastric cancer cells, cell lines that have high base levels of DT-diaphorase activity. Toxicity to normal human marrow cells was increased by 50% when MMC was combined with 1,2-dithiole-3-thione, but this increase was small in comparison with the threefold increase in cytotoxicity to tumour cells. This study demonstrates that induction of DT-diaphorase can increase the cytotoxic activity of MMC in human tumour cell lines, and suggests that it may be possible to use non-toxic inducers of DT-diaphorase to enhance the efficacy of bioreductive anti-tumour agents.
...
PMID:Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase. 1037 75

DT-diaphorase is an FAD-containing enzyme capable of a two-electron reduction of ortho- and paraquinones. Nicotinamide coenzymes (NADH + H+ and NADPH + H+) serve as hydrogen sources in these reactions. The role of DT-diaphorase has been thoroughly investigated in situations when the enzyme is able to reduce exogenous and endogenous quinones, hence protecting the cells against these reactive intermediates. The enzyme has also been studied in connection with its ability to activate some quinoid cytostatics. It is surprising that DT-diaphorase has never been investigated in pigment-producing cells that are known to generate considerable amounts of ortho-quinones. Using a spectrophotometric method we could readily measure the activity of DT-diaphorase in epidermis and various cultured pigment cells. The melanocytes isolated from dark skin showed generally higher DT-diaphorase activity than those from fair skin samples. Also, darkly pigmented congenital naevus cells exhibited higher activity of this enzyme. The most striking was the high DT-diaphorase activity in melanoma cell cultures. In these cells DT-diaphorase activity could be induced by incubation of the cells with 4-hydroxyanisole. A similar effect was seen when a catechol-O-methyltransferase (COMT) inhibitor (3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione (OR-462) was utilised. The induction was inhibited by cyclohexidine.
...
PMID:Study of DT-diaphorase in pigment-producing cells. 1064 8

The merits of N-unsubstituted indoles and cyclopent[b]indoles as DNA-directed reductive alkylating agents are described. These systems represent a departure from N-substituted and pyrrolo[1, 2-a]-fused systems such as the mitomycins and mitosenes. The cyclopent[b]indole-based aziridinylquinone system, when bearing an acetate leaving group with or without an N-acetyl group, was cytotoxic and displayed significant in vivo activity against syngeneic tumor implants. These analogues were superior to the others studied in terms of both high specificity for the activating enzyme DT-diaphorase and high percent DNA alkylation. Alkylation by a quinone methide intermediate as well as by the aziridinyl group could lead to cross-linking. The possible metabolites of the most active indole species were prepared and found to retain cytotoxicity, suggesting that in vivo activity could be sustained. The indole systems in the present study display selectivity for melanoma and, depending on the substituents present, selectivity for non-small-cell lung, colon, renal, and prostate cancers. The cancer specificities observed are believed to pertain to differential substrate specificities for DT-diaphorase.
...
PMID:Design of cancer-specific antitumor agents based on aziridinylcyclopent[b]indoloquinones. 1066 73

Described herein are the synthesis, cytotoxic properties, and topoisomerase II inhibition assays of benzodiimidazole and dipyrroloimidazobenzimidazole structural variants of the pyrrolo[1, 2-a]benzimidazole or APBI ring system. These ring variants were designed to inhibit topoisomerase II, much as the APBIs are able to do. Since only the quinone form of the APBIs can intercalate DNA, two-electron reduction to the hydroquinone by DT-diaphorase is known to deactivate these compounds. Indeed, the APBIs possess a high inverse correlation with the cellular concentration of DT-diaphorase. Therefore one feature of the ABPI structural variants is the excessive bulk about the quinone ring, which was predicted to diminish DT-diaphorase substrate activity. Another feature is the presence of one or two alkylating centers, which would permit alkylation of DNA and/or topoisomerase II. Inhibition assays for topoisomerase II-mediated relaxation of supercoiled DNA indicate that the benzodiimidazole and dipyrroloimidazobenzimidazole quinone ring systems are catalytic inhibitors of topoisomerase II. Both quinone systems exhibit cytotoxicity perhaps due to the lack of inactivation by DT-diaphorase as well as topoisomerase II inhibition. One quinone displayed the novel feature of cytotoxicity selectively against melanoma cell lines. In conclusion, the benzodiimidazole and dipyrroloimidazobenzimidazole quinone ring systems will be subjected to future analogue development and structure-activity studies.
...
PMID:Inhibitors of topoisomerase II based on the benzodiimidazole and dipyrroloimidazobenzimidazole ring systems: controlling DT-diaphorase reductive inactivation with steric bulk. 1069 89

The transcription factor nuclear factor-kappaB (NF-kappaB) is constitutively activated in malignancies from enhanced activity of inhibitor of NF-kappaB (IkappaB) kinase, with accelerated IkappaBalpha degradation. We studied whether redox signaling might stimulate these events. Cultured melanoma cells generated superoxide anions (O(2)(-)) without serum stimulation. O(2)(-) generation was reduced by the NAD(P)H:quinone oxidoreductase (NQO) inhibitor dicumarol and the quinone analog capsaicin, suggesting that electron transfer from NQO through a quinone-mediated pathway may be an important source of endogenous reactive oxygen species (ROS) in tumor cells. Treatment of malignant melanoma cells with the H(2)O(2) scavenger catalase, the sulfhydryl donor N-acetylcysteine, the glutathione peroxidase mimetic ebselen, or dicumarol decreased NF-kappaB activation. Catalase, N-acetylcysteine, ebselen, dicumarol, and capsaicin also inhibited growth of melanoma and other malignant cell lines. These results raise the possibility that ROS produced endogenously by mechanisms involving NQO can constitutively activate NF-kappaB in an autocrine fashion and suggest the potential for new antioxidant strategies for interruption of oxidant signaling of melanoma cell growth.
...
PMID:Reactive oxygen species from NAD(P)H:quinone oxidoreductase constitutively activate NF-kappaB in malignant melanoma cells. 1117 86

Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds detected in urine, central nervous system and some peripheral tissues in Mammalia. No data are at present available on TIQ levels in skin, although in vitro biochemical evidences indicate that they may undergo auto-oxidation with production of reactive oxygen species or may be enzymatically converted into melanin pigments. The effect of two catechol-bearing TIQs, salsolinol (SAL) and tetrahydropapaveroline (THP), on the viability of melanotic or amelanotic melanoma cell lines was investigated. Both SAL and THP were well tolerated up to roughly 30 microM and became overtly toxic at higher concentrations, with SAL being better tolerated than THP. Intracellular activity of some antioxidant enzymes, tyrosinase and alpha-ketoglutarate dehydrogenase was also evaluated to assess the cell response to oxidative and metabolic challenge of TIQs treatment. Catalase and superoxide dismutase pre-treatment only partially prevented TIQs toxicity while a complete protection was obtained with N-acetylcysteine and GSH. TIQs were able to provoke upregulation of the scavenging enzymes catalase and DT-diaphorase and to determine a decrease of the alpha-ketoglutarate dehydrogenase activity. SAL and THP enhanced tyrosinase activity and melanin production, suggesting that they were indeed tyrosinase substrates leading to melanin formation. The results support the evidence that TIQs were toxic toward melanoma cells, leading to their death by necrosis. TIQs toxicity was likely due to increased oxidative stress by generation of reactive oxygen species and oxidative metabolites. Our study represents an intent to furnish an additional contribution for the comprehension of catechol cytotoxicity.
...
PMID:Cytotoxicity of dopamine-derived tetrahydroisoquinolines on melanoma cells. 1241 63


1 2 3 4 5 Next >>

---