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At least 343 records · Page 19Linked to original sources
PubMed2005

Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines.

Bicalutamide is a non-steroidal anti-androgen commonly used in the treatment of prostate carcinoma. We analysed the transcriptional response to bicalutamide treatment with the aim of explaining the inhibition of telomerase in the androgen-sensitive cell line LNCaP and the effects of bicalutamide on the androgen-insensitive cell line DU145. Cells treated with 80 muM bicalutamide in steroid-depleted medium for 1 day were analysed in duplicate by Affymetrix Human Genome Focus Arrays. Response to bicalutamide in LNCaP cells was represented by downregulation of androgen-regulated genes, activation of the p53 pathway and inhibition of telomerase, which was associated with downregulation of v-myc avian myelocytomatosis viral oncogene homologue (MYC) and telomerase reverse transcriptase subunit. In DU145 cells we observed the influence of cell density on bicalutamide effectivity such that highly confluent cells showed lesser sensitivity than low confluent ones. In conclusion, we provide an explanation for telomerase inhibition after androgen receptor blockade in LNCaP cells and we also report activation of the p53 pathway in LNCaP cells and in-vitro sensitivity to bicalutamide of low confluent androgen-insensitive DU145 cells. These findings might have implications for both experimental and clinical research into prostate cancer. In particular, activation of the p53 pathway after treatment with 80 microM bicalutamide could justify usage of bicalutamide dosages higher than 150 mg daily in androgen-sensitive carcinoma therapy.

Androgen Antagonists↗
PubMed2000

Trimethyltin reduces ATP levels and MTT reduction in the LRM55 rat astrocytoma cell line.

The LRM55 rat astrocytoma cell line was used to study the time and concentration effects of trimethyltin (TMT) exposure on intracellular adenosine triphosphate (ATP) levels, formazan production from (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and lactate dehydrogenase (LDH) release. TMT concentrations of > or =50 microM produced a delayed increase in extracellular LDH from approximately 20% at 24 h to almost 70%, at 72 h. Twenty-four hours before cell lysis was detectable ATP levels decreased to less than 30% and formazan production declined to 70% (50 microM), 31% (100 microM), and 21% (200 microM) of control values. Concentrations of TMT (5 and 10 microM) that produced little or no LDH release also decreased ATP levels (62 and 49% of control, respectively) and formazan production (63 and 52% of control, respectively) by 48 h. These data support the hypothesis that TMT exposure interferes with energy production and that this event likely contributes to the delayed cell death seen in this cell line. Moreover, the declines in ATP and formazan production can occur at subtoxic concentrations in LRM55 cells.

Adenosine Triphosphate↗
PubMed2002

Anticancer cytotoxicity and nephrotoxicity of the new platinum (II) complexes containing diaminocyclohexane and glycolic acid.

Cisplatin is an important antineoplastic agent, but dose-limiting nephrotoxicity prevents potential efficacy. There is interest in developing new platinum agents that have less toxicity. We have synthesized novel platinum (II) coordination complexes containing diaminocyclohexane as carrier ligands, and glycolic acid as a leaving group. In this study, new platinum (II) complex compounds were evaluated for cytotoxicity on cancer cell lines and nephrotoxicity. The new platinum complexes have demonstrated high efficacy in the cytotoxicity against human ovarian adenocarcinoma cell lines (SKOV-3/NIH.OVCAR-3) and human prostate carcinoma cell lines (DU-145/PC-3). The cytotoxicity of these compounds against rabbit proximal renal tubular cells and human renal cortical tissues was determined by MTT assay, the [3H]-thymidine uptake and glucose consumption test, and found to be considerably less than those of cisplatin. Based on our results, these novel platinum compounds appear to be valuable lead compounds with high efficacy and low nephrotoxicity.

Animals↗
PubMedDate not supplied

Ebselen attenuates oxidative stress in ischemic astrocytes depleted of glutathione. Comparison with glutathione precursors.

In this study, we investigated the protective effect of ebselen, a seleno-organic compound with antioxidant activity, towards astrocyte degeneration caused by exposure to simulated in vitro ischemic conditions and simultaneous depletion of glutathione (GSH). Depletion of GSH was induced by 24 h pretreatment with L-buthionine-(S,R)-sulfoximine (BSO). In this experimental paradigm, we examined the effects of ebselen (1-40 microM) on apoptosis, mitochondrial function, reactive oxygen species (ROS) production, intracellular GSH level and mitochondrial transmembrane potential (MTP). In addition, we also compared the antioxidant potential of ebselen with cystine and methionine as precursors of GSH synthesis as well as with GSH ethyl ester. Our study demonstrated that toxicity of simulated ischemia conditions was enhanced when intracellular GSH was depleted. Treatment with ebselen, especially at concentrations of 20 and 40 microM prevented ischemia-induced cytotoxicity. Our study has shown that antiapoptotic effect of ebselen is associated with its strong antioxidant properties, preservation of MTP and possibly conservation of mitochondrial GSH during cytoplasmatic GSH depletion caused by oxidative damage. Also, promoting GSH synthesis by the delivery of its substrates, like cystine or inhibition of the efflux by methionine may be a powerful strategy to minimize cell damage in the nervous tissue after ischemia.

Animals↗
PubMed1977

The effect of sodium azide on the chemiluminescence of granulocytes--evidence for the generation of multiple oxygen radicals.

It has been established that granulocytes generate superoxide (O-2) as well as hydrogen peroxide (H2O2) during phagocytosis. The chemiluminescence (CL) generated by phagocytes appears dependent on these oxygen radicals (or). however, recent studies suggest that oxygen molecules, including singlet oxygen (1O2) or hydroxyl radicals (OH-), may also be generated during phagocytosis and contribute to CL. We have tested this possibility by studying human granulocyte CL in the presence of 0.1 mM sodium azide, a known inhibitor of myeloperoxidase and catalase and a scavenger of 1O2. The effects of azide on CL were correlated with the effects of this compound on hexose monophosphate shunt (hmps) activity, nitroblue tetrazolium (NBT) dye reduction, formate oxidation, and cytochrome c reduction. CL generated by granulocytes during the phagocytosis of zymosan particles was markedly impaired by azide (24% to 47% of control values). On the other hand, phenomena dependent in part on the presence of O2 radicals, i.e., reduction of NBT dye and cytochrome c, were not impaired by the presence of azide. As would be expected, inhibition of catalase by azide virtually abolished the oxidation of formate, but the burst in HMPS activity associated with phagocytosis was augmented further. The latter observation indicated that azide did not impair generation of H2O2 but increased the relative amount detoxified via the HMPS. The experiment provides evidence that radicals other than O-2 and H2O2 are generated during phagocytosis and that these radicals are major contributors to the CL phenomenon.

Azides↗
PubMed1981

Some aspects of the use of tetrazolium salts in quantitative histochemistry.

The reduction of tetrazolium salts to highly coloured insoluble formazans is a reaction which has been widely exploited in histochemistry. This presentation considers three important aspects of the use of these compounds in quantitative studies, namely purity, intermediate reduction products, and calibration and measurement. Thin layer chromatography of tetrazolium salts from different suppliers has shown that standards of purity can vary widely, and that some samples are seriously contaminated. Studies with chromatographically pure compounds have demonstrated that the red diffuse colour seen in some reactions with di-tetrazolium salts is due to a half-reduced reduction intermediate. This "half-formazan" is part of the total activity, and cannot be disregarded in quantitative work. An understanding of the chemical nature of formazan end-products in tissue sections has made it possible to calibrate these reactions for microdensitometry.

Chromatography, Thin Layer↗
PubMed1991

Application of the MTT colorimetric assay to measure cytotoxic effects of phenolic compounds on established rat dental pulp cells.

The cytotoxicities of various phenolic compounds were examined using the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) colorimetric assay and established rat dental pulp cells (RPC-C2A). The ID50 (50% inhibition concentration) of the phenolic compounds ranged from 0.1 to 10 mmol/L, and the cytotoxicities of the phenolic compounds were related to their phenolic coefficients. The therapeutic index of each phenolic compound was calculated from the ID50 results and from the 50% inhibition concentration for prostaglandin synthesis that has been reported previously. Eugenol, guaiacol, and creosol had therapeutic indices much higher than those of other phenolic compounds examined. This experimental system could be used as a simple preliminary assay to test for toxicity of dental drugs and materials.

Animals↗
PubMed2004

Synthesis of aldehydo-sugar derivatives of pyrazoloquinoline as inhibitors of herpes simplex virus type 1 replication.

Synthesis of a novel series of structurally related pyrazoloquinoline nucleosides is described. All the newly synthesized compounds were examined for their in vitro antiviral activity against herpes simplex type-1 as shown by two different bioassays, namely; crystal violet staining or the MTS tetrazolium dye measurement. The acute toxicity (LD50) values of the biologically active compounds were determined.

Aldehydes↗
PubMed1980

The effect of local UVB skin irradiation on the rate of formazan deposition in the epidermis of hairless mice studied by means of a tetrazolium-reduction method.

One-hundred-and-twenty hairless mice were irradiated with UVB (310 nm, exposure 60 mJ/cm2) on a limited area of the dorsal skin. At different time intervals after irradiation, the rate of endogenous dehydrogenase activity per mg dry epidermis was measured by the tetrazolium reduction method. The amount of formazan deposited remained normal for 18 h, and then increased, reaching a peak significantly higher than normal at 24 h, and thereafter returned to normal. At day 8 there was a new, probably significant peak. The reaction was followed for 14 days. It was concluded that UVB irradiation provokes a period of increased formazan deposition in the epidermis, similar to what has been observed after ionizing radiation and chemical carcinogens. The validity of the tetrazolium test for skin carcinogenic irritaments was thus also confirmed.

Animals↗
PubMed1987

Functional integrity of intrinsic cardiac nerves located over an acute transmural myocardial infarction.

Acute transmural myocardial infarction has been reported to functionally denervate the normal myocardium distal to the infarcted zone by interrupting neurotransmission in axons coursing in the subepicardial region of the myocardial necrosis. To directly investigate the viability of such neurotransmission, the effects of acute transmural myocardial infarction on conduction in the intrinsic cardiac nerves overlying and distal to an experimentally induced acute transmural myocardial infarction were studied. In eight dogs, during control states electrical stimulation of the epicardium adjacent to a coronary artery produced compound action potentials in the more cranially located cardiopulmonary nerves. Thereafter, in four dogs an acute transmural myocardial infarction was produced by injecting rapidly hardening latex into a major diagonal branch of the left anterior descending coronary artery. Epicardial stimulation over the infarct, as well as proximal or distal to it, produced compound action potentials that conducted at normal velocities for at least 12 h postinfarction. The transmural extent of the infarct was verified with tetrazolium blue staining at the end of the experiment. In the other four dogs, compound action potentials were generated in cardiopulmonary nerves as described above and then ventricular fibrillation was produced to assess the effects of global anoxia on the function of axons coursing in cardiac nerves. Following the onset of ventricular fibrillation, compound action potentials were generated in these nerves in C fibers for up to 2 h, in B fibers for up to 4 h, and in A fibers for at least 12 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The differentiation of Brucella species by substrate specific tetrazolium reduction.

In the development of a tetrazolium reduction assay to replace substrate stimulated oxygen uptake for the identification of Brucella species, nine tetrazolium salts were evaluated. Only the more readily reduced compounds (MTT and INT) detected increased metabolic activity with the more fastidious, slow growing strains and with B. suis strains on L-arginine and DL-ornithine. The assay was optimised with MTT. MTT reduction profiles offered with the medium on which the cells were grown. Cells grown on TSA gave profiles more similar to the published respirometric results than those grown on SDA. The optimal substrate concentration was 0.84 g l-1 and prolonged (> 3 h) exposure to substrate was necessary before adding MTT. MTT concentration was not critical and the OD was proportional to the MTT concentration between 0.03 and > 0.5 g l-1. MTT reduction was linear for 60 min after its addition. The reaction was, therefore, stopped after 60 min by adding formaldehyde solution. The optimised assay was evaluated with 71 strains of Brucella, representing all the species and biovars of the genus. Each strain was assigned to its previously identified species and sub-groups were defined.

Amino Acids↗
PubMed1988

Superoxide modulates the activity of myeloperoxidase and optimizes the production of hypochlorous acid.

Myeloperoxidase catalyses the conversion of H2O2 and Cl- to hypochlorous acid (HOCl). It also reacts with O2- to form the oxy adduct (compound III). To determine how O2- affects the formation of HOCl, chlorination of monochlorodimedon by myeloperoxidase was investigated using xanthine oxidase and hypoxanthine as a source of O2- and H2O2. Myeloperoxidase was mostly converted to compound III, and H2O2 was essential for chlorination. At pH 5.4, superoxide dismutase (SOD) enhanced chlorination and prevented formation of compound III. However, at pH 7.8, SOD inhibited chlorination and promoted formation of the ferrous peroxide adduct (compound II) instead of compound III. We present spectral evidence for a direct reaction between compound III and H2O2 to form compound II, and for the reduction of compound II by O2- to regenerate native myeloperoxidase. These reactions enable compound III and compound II to participate in the chlorination reaction. Myeloperoxidase catalytically inhibited O2- -dependent reduction of Nitro Blue Tetrazolium. This inhibition is explained by myeloperoxidase undergoing a cycle of reactions with O2-, H2O2 and O2-, with compounds III and II as intermediates, i.e., by myeloperoxidase acting as a combined SOD/catalase enzyme. By preventing the accumulation of inactive compound II, O2- enhances the activity of myeloperoxidase. We propose that, under physiological conditions, this optimizes the production of HOCl and may potentiate oxidant damage by stimulated neutrophils.

Cyclohexanones↗
PubMed1992

Nitric oxide synthase in rat brain is predominantly located at neuronal endoplasmic reticulum: an electron microscopic demonstration of NADPH-diaphorase activity.

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) of the rat brain, apparently identical with nitric oxide (NO) synthase, was demonstrated at the electron microscopic level by means of the tetrazolium salt 2-(2'-benzothiazolyl)-5-styryl-3-(4'-phthalhydrazidyl)tetrazolium chloride (BSPT). BSPT is a non-osmiophilic compound that yields an insoluble, osmiophilic, and lipophobic formazan on reduction. The reaction product was deposited sharply on membranes of the endoplasmic reticulum including the nuclear envelope. Other membrane structures were, as a rule, free of reaction product, likewise mitochondria. Occasionally, however, the outer membrane of mitochondria was labeled, and their contents displayed a homogeneous, medium electron density. The findings suggest that NADPH-d, i.e. neuronal NO synthase, is a predominantly membrane-bound enzyme, which is ubiquitously distributed in cells of brain tissue, but highly concentrated in nerve cells described as 'NADPH-d-positive' at the light microscopic level.

Amino Acid Oxidoreductases↗
PubMed2003

Rapid in vitro chemosensitivity analysis of human colon tumor cell lines.

In oncology, diagnostic assays have the potential to individualize treatment. Due to a large number of chemotherapeutic agents available, a chemosensitivity assay would be of great value for patients receiving chemotherapy. However, no broadly accepted test exists to date. Our work aims at establishing a chemosensitivity test using a microphysiometer, a device that measures the extracellular acidification rate of cells. The test assesses chemosensitivity by comparing the acidification rate of cells treated with cytostatic agents with that of nontreated cells. We performed experiments with two human colon tumor cell lines, HCT 116 and SW620, and cytostatic agents commonly used in therapy of colon carcinoma. We showed that a chemosensitivity test can be reproducibly performed using a microphysiometer. Suitable media and conditions for the assay were found. Test results were further correlated with the crystal violet assay and a tetrazolium salt assay. In comparison, cytostatic effects were rapidly and most clearly displayed with the microphysiometer. Our results suggest that microphysiometry is a promising platform for chemosensitivity testing.

Antineoplastic Agents↗
PubMed1976

Acceleration of tetrazolium reduction by bacteria.

Conditions were assessed which would permit more rapid recognition of bacterial growth than has been previously reported using tetrazolium salts. Microtitration trays were used. 2-(p-Iodophenyl)-3(p-nitrophenyl)-5-phenyltetrazolium chloride is rapidly reduced by respiring cells in tissue homogenates but is more toxic than other tetrazoliums when added to growing bacterial cultures. Phenazine methosulfate (PMS), an intermediate electron carrier, potentiates tetrazolium reduction. Growth was readily detected by the addition of these compounds after 3 to 4 h of incubation in Schaedler broth. The final concentration prior to addition to tray wells was 1.0 mg/ml for 2-(p-iodophenyl)-3(p-nitrophenyl)-5-phenyltetrazolium chloride and 0.06 mg/ml for PMS. Addition of 0.5 to 0.8 g of agar per liter of broth enhanced subsequent tetrazolium reduction.

Bacteria↗
PubMed2006

Potential use of alexidine dihydrochloride as an apoptosis-promoting anticancer agent.

Despite advances in surgery, radiation, and chemotherapy, novel therapeutics are needed for head and neck cancer treatment. The objective of this current study was to evaluate alexidine dihydrochloride as a novel compound lead for head and neck cancers. Using a tetrazolium-based assay, the dose required to reduce cell viability by 50% (ED50) was found to be approximately 1.8 micromol/L in FaDu (human hypopharyngeal squamous cancer) and approximately 2.6 micromol/L in C666-1 (human undifferentiated nasopharyngeal cancer) cells. In contrast, the ED50 values were much higher in untransformed cells, specifically at approximately 8.8 micromol/L in GM05757 (primary normal human fibroblast), approximately 8.9 micromol/L in HNEpC (primary normal human nasal epithelial), and approximately 19.6 micromol/L in NIH/3T3 (mouse embryonic fibroblast) cells. Alexidine dihydrochloride did not interfere with the activities of cisplatin, 5-fluorouracil, or radiation, and interacted in a less-than-additive manner. DNA content analyses and Hoechst 33342 staining revealed that this compound induced apoptosis. Alexidine dihydrochloride-induced mitochondrial damage was visualized using transmission electron microscopy. Mitochondrial membrane potential (DeltaPsiM) depolarization was detectable after only 3 hours of treatment, and was followed by cytosolic Ca2+ increase along with loss of membrane integrity/cell death. Caspase-2 and caspase-9 activities were detectable at 12 hours, caspase-8 at 24 hours, and caspase-3 at 48 hours. FaDu cell clonogenic survival was reduced to < 5% with 1 micromol/L alexidine dihydrochloride, and, correspondingly, this compound decreased the in vivo tumor-forming potential of FaDu cells. Thus, we have identified alexidine dihydrochloride as the first bisbiguanide compound with anticancer specificity.

Animals↗