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PubMed2005

Gefitinib induces myeloid differentiation of acute myeloid leukemia.

Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.

Biomarkers, Tumor↗

PubMed1998

Electron transfer processes in the reactivity of nonsteroidal anti-inflammatory drugs in the ground and excited states.

The nonsteroidal anti-inflammatory drugs (NSAID), naproxen, sulindac and indomethacin, were shown to donate electrons to nitro blue tetrazolium (NBT) when irradiated with UV light in deoxygenated aqueous buffer solution (pH 7.4, 30 degrees C). The reaction was monitored spectrophotometrically by the appearance of the diformazan reduction product from NBT. The electron transfer process facilitates the decomposition of the drugs. Naproxen in the presence of NBT is photodegraded principally to the alcohol (2-[1-hydroxyethyl]-6-methoxynaphthalene) at a rate approximately 20-fold faster than when irradiated alone in deoxygenated conditions. The photoproduct from naproxen also participates in the electron transfer to NBT but at a much slower rate than naproxen. Irradiation of sulindac or indomethacin in the presence of NBT caused the slow photoreduction of NBT to diformazan. In the absence of NBT, indomethacin and sulindac are essentially unreactive when irradiated in aqueous solution. The ability of a number of NSAID to act as electron donors in their ground state was studied by observing their oxidation by potassium peroxodisulfate in pH 7.0 phosphate buffer at 50 degrees C. The HPLC analysis of the drug remaining showed that the 2-arylpropionic acid NSAID (naproxen, ibuprofen, ketoprofen and suprofen) reacted at a rate equivalent to the thermal decomposition of peroxodisulfate. The major products were the same as detected in the photooxidation of these drugs, resulting from decarboxylation and oxygen addition but also included a dimeric compound. On the other hand, the NSAID that do not contain the propionic acid substituent all reacted more slowly with peroxodisulfate, enabling specific reaction rate constants to be evaluated.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Synthesis of 6-aziridinylbenzimidazole derivatives and their in vitro antitumor activities.

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a-d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a-c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a-d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a-c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a-d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters 10d and 13e-h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of 10a-d or 11a-d against SNU-16 were superior to those of 13e-h, and were equal to or slightly higher than that of mitomycin C. Compounds 11a-d were slightly more cytotoxic than 10a-d in all cell lines tested.

Animals↗

PubMed2001

Striatal dopaminergic pathways as a target for the insecticides permethrin and chlorpyrifos.

Because insecticide exposure has been linked to both Parkinsons disease and Gulf War illness, the neurotoxic actions of pyrethroid and organophosphate insecticides on behavior and striatal dopaminergic pathways were investigated in C57BL/6 mice treated with permethrin (three i.p. doses at 0.2-200 mg/kg) or chlorpyrifos (three s.c. doses at 25-100 mg/kg) over a 2-week period. Permethrin altered maximal [3H]dopamine uptake in striatal synaptosomes from treated mice, with changes in Vmax displaying a bell-shaped curve. Uptake was increased to 134% of control at a dose of 1.5 mg/kg. At higher doses of PM (25 mg/kg), dopamine uptake declined to a level significantly below that of control (50% of control at 200 mg/kg, P < 0.01). We also observed a small, but statistically significant decrease in [3H]dopamine uptake by chlorpyrifos, when given at a dose of 100 mg/kg. There was no significant effect on the Km for dopamine transport. Evidence of cell stress was observed in measures of mitochondrialfunction, which were reduced in mice given high-end doses of chlorpyrifos and permethrin. Although cytotoxicity was not reflected in decreased levels of striatal dopamine in either 200 mg/kg PM or 100 mg/kg CPF treatment groups, an increase in dopamine turnover at 100 mg/kg CPF was indicated by a significant increase in titers of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid. Both permethrin and chlorpyrifos caused a decrease in open field behavior at the highest doses tested. Although frank Parkinsonism was not observed, these findings confirm that dopaminergic neurotransmission is affected by exposure to pyrethroid and organophosphorus insecticides, and may contribute to the overall spectrum of neurotoxicity caused by these compounds.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1975

The effects of polyanions on NBT Reductions hexose monophosphate shunt activity, and ultrastructure of polymorphonuclear leukocytes.

Heparin causes enhanced nitroblue tetrazolium (NBT) reduction by polymorphonuclear leukocytes (PMN's). To determine the mechanism of this stimulation, samples of 1 to 3 x 10(7) PMN's were incubated with various concentrations of heparin, chondroitin sulfate A (CSA), and chondroitin sulfate B (CSB), with and without NBT. The effect of the polyanions (PA) on PMN hexose monophosphate shunt (HMPS) activity was determined by the production of 14CO2 from glucose-1-14C by the leukocytes. NBT reduction was evaluated histochemically and spectrophotometrically at 515 mmu. Samples of PMN's in heparin and heparin-NBT mixtures were examined by electron microscopy after various incubation periods. Increased NBT reductions by PMN's was found when leukocytes were incubated with heparin, CSA, and CSB, but these compounds had no effect on the HMPS activity of PMN's unless NBT was added. Electron microscopy of samples that contained heparin-NBT revealed an insoluble complex that was phagocytosed by the leukocytes. The stimulation of PMN oxidative metabolism and NBT reduction that follows incubation with PA-NBT appears to be directly related to ingestion of this particulate complex by the leukocytes.

Carbon Dioxide↗

PubMedDate not supplied

Anxiolytic agent, dihydrohonokiol-B, recovers amyloid beta protein-induced neurotoxicity in cultured rat hippocampal neurons.

The effects of anxiolytic honokiol derivative, dihydrohonokiol-B (DHH-B), on amyloid beta protein (Abeta(25-35), 10 nM)-induced changes in Cl(-)-ATPase activity, intracellular Cl- concentration ([Cl-]i) and glutamate neurotoxicity were examined in cultured rat hippocampal neurons. DHH-B (10 ng/ml) recovered Abeta-induced decrease in neuronal Cl(-)-ATPase activity without any changes in the activities of Na+/K+-ATPase and anion-insensitive Mg2+-ATPase. A GABA(C) receptor antagonist (1,2,5,6,-tetrahydropyridin-4-yl) methyl-phosphinic acid (TPMPA, 15 microM), inhibited the protective effects of DHH-B on Cl(-)-ATPase activity. DHH-B reduced Abeta-induced elevation of [Cl-]i as assayed using a Cl(-)-sensitive fluorescent dye, and prevented Abeta-induced aggravation of glutamate neurotoxicity. These data suggest that DHH-B exerts the neuroprotective action against Abeta through GABA(C) receptor stimulation.

Adenosine Triphosphatases↗

PubMed2003

Effects of mineral trioxide aggregate (MTA) extracts on mitogen-activated protein kinase activity in human osteosarcoma cell line (U2OS).

Extracellular regulated kinases (ERKs)-1 and -2 are members of the MAPK family of protein kinases involved in the proliferation, differentiation and apoptosis of bone cells. The purpose of the present study investigated the biocompatibility role, and signaling pathways of components of mineral trioxide aggregate (MTA) by culturing human osteosarcoma cell line (U2OS) in the presence of materials. Biocompatibility effects were assessed using the MTT assay for mitochondrial enzyme activity. The statistical analysis of the survival rate was performed using one-way analysis of variance (ANOVA) with p<0.05 shown statistical difference. The signaling pathway of MTA-treated U2OS cells were assessed by the western blotting methods. Dose-dependent and time-dependent tests were conducted. The results showed that the survival rates of the MTA extract experimental groups were higher than that of the control group (p<0.05). ERKs activity was dose-dependent, decreasing as the concentrations of the MTA extract decreased, and was time-dependent, decreasing as the treatment time increased. Suppression of ERK pathway by PD98059 resulted in dose-dependent and time-dependent decreases. The findings suggest that MTA is a biocompatible material to U2OS cells, and the ERK kinase pathway plays a signal transduction role in the MTA treated U2OS cells.

Aluminum Compounds↗

PubMed2002

Cytotoxicity and oxidative mechanisms of different forms of chromium.

Chromium exists mostly in two valence states in nature: hexavalent chromium [chromium(VI)] and trivalent chromium [chromium(III)]. Chromium(VI) is commonly used in industrial chrome plating, welding, painting, metal finishes, steel manufacturing, alloy, cast iron and wood treatment, and is a proven toxin, mutagen and carcinogen. The mechanistic cytotoxicity of chromium(VI) is not completely understood, however, a large number of studies demonstrated that chromium(VI) induces oxidative stress, DNA damage, apoptotic cell death and altered gene expression. Conversely, chromium(III) is essential for proper insulin function and is required for normal protein, fat and carbohydrate metabolism, and is acknowledged as a dietary supplement. In this paper, comparative concentration- and time-dependent effects of chromium(VI) and chromium(III) were demonstrated on increased production of reactive oxygen species (ROS) and lipid peroxidation, enhanced excretion of urinary lipid metabolites, DNA fragmentation and apoptotic cell death in both in vitro and in vivo models. Chromium(VI) demonstrated significantly higher toxicity as compared with chromium(III). To evaluate the role of p53 gene, the dose-dependent effects of chromium(VI) were assessed in female C57BL/6Ntac and p53-deficient C57BL/6TSG p53 mice on enhanced production of ROS, lipid peroxidation and DNA fragmentation in hepatic and brain tissues. Chromium(VI) induced more pronounced oxidative damage in multiple target organs in p53 deficient mice. Comparative studies of chromium(III) picolinate and niacin-bound chromium(III), two popular dietary supplements, reveal that chromium(III) picolinate produces significantly more oxidative stress and DNA damage. Studies have implicated the toxicity of chromium picolinate in renal impairment, skin blisters and pustules, anemia, hemolysis, tissue edema, liver dysfunction; neuronal cell injury, impaired cognitive, perceptual and motor activity; enhanced production of hydroxyl radicals, chromosomal aberration, depletion of antioxidant enzymes, and DNA damage. Recently, chromium picolinate has been shown to be mutagenic and picolinic acid moiety appears to be responsible as studies show that picolinic acid alone is clastogenic. Niacin-bound chromium(III) has been demonstrated to be more bioavailable and efficacious and no toxicity has been reported. In summary, these studies demonstrate that a cascade of cellular events including oxidative stress, genomic DNA damage and modulation of apoptotic regulatory gene p53 are involved in chromium(VI)-induced toxicity and carcinogenesis. The safety of chromium(III) is largely dependent on the ligand, and adequate clinical studies are warranted to demonstrate the safety and efficacy of chromium(III) for human consumption.

Animals↗

PubMed2000

Effects of cerivastatin on human arterial smooth muscle cell proliferation and migration in transfilter cocultures.

Statins competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity reducing mevalonate synthesis. In this study, antiproliferative and antimigratory effects of the new compound cerivastatin were analyzed and compared with classic statins of the first and second generation using mono- and cocultures of human arterial smooth muscle (haSMC) and endothelial (haEC) cells. Effects on the mitotic index and mitochondrial activity of haEC and haSMC monocultures were tested using BrdU enzyme-linked immunosorbent assay (ELISA) and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) tests, respectively. In lactate dehydrogenase (LDH) assays, cytotoxicity of statins was studied. Transfilter cocultures were performed for 14 days to evaluate haSMC growth under the stimulatory effect of proliferating haEC, which release growth factors [e.g., platelet-derived growth factor (PDGF)]. The hydrophobic statins simvastatin, lovastatin, and atorvastatin significantly inhibited haSMC and haEC growth in monocultures at 0.5-50 microM. However, most potent effects were exerted by cerivastatin in 10- to 30-fold lower doses without any significant cytotoxicity. More important, cerivastatin showed also significant effects on haSMC proliferation and migration in transfilter cocultures at extremely low doses (IC50, 0.04-0.06 microM), even when applied exclusively to the endothelial side and in the presence of low-density lipoprotein (LDL). Addition of mevalonate abolished the effects of cerivastatin completely. Even in the presence of growth-stimulating haEC and LDL, cerivastatin was found to be the most potent inhibitor of haSMC proliferation and migration in doses that also can be reached in human serum after oral drug administration. The results support the concept that statins seems to influence additional cellular mechanisms beyond cholesterol reduction, which might also have a relevance for the prevention of restenosis.

Analysis of Variance↗

PubMed1990

Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines.

The National Cancer Institute (NCI) is implementing a large-scale in vitro drug-screening program that requires a very efficient automated assay of drug effects on tumor cell viability or growth. Many laboratories worldwide have adopted a microculture assay based on metabolic reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). However, because of certain technical advantages to use of the protein-binding dye sulforhodamine B (SRB) in a large-scale screening application, a detailed comparison of data generated by each type of assay was undertaken. The MTT and SRB assays were each used to test 197 compounds, on simultaneous days, against up to 38 human tumor cell lines representing seven major tumor categories. On subsequent days, 38 compounds were retested with the SRB assay and 25 compounds were retested with the MTT assay. For each of these three comparisons, we tabulated the differences between the two assays in the ratios of test group values to control values (T/C) for cell survival; calculated correlation coefficients for various T/C ratios; and estimated the bivariate distribution of the values for IC50 (concentration of drug resulting in T/C values of 50%, or 50% growth inhibition) for the two assays. The results indicate that under the experimental conditions used and within the limits of the data analyses, the assays perform similarly. Because the SRB assay has practical advantages for large-scale screening, however, it has been adopted for routine use in the NCI in vitro antitumor screen.

Antineoplastic Agents↗

PubMed2006

Synthesis of diacetoxy acetal derivatives of santonin and their enhancing effects on HL-60 leukemia cell differentiation.

Several diacetoxy acetal analogues have been synthesized from santonin and assessed for their ability of inducing or enhancing the differentiation of human HL-60 leukemia cells. The compounds themselves had little effect on HL-60 cell differentiation. However, three analogues, 2a, 3a, and 5b, synergistically enhanced 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-induced HL-60 cell differentiation when combined with 5 nM of dihydroxyvitamin D3 [1,25-(OH)2D3], a well-known differentiation inducer. Especially, the compound 5b profoundly enhanced the 1,25-(OH)2D3]-induced HL-60 cell differentiation.

Calcitriol↗

PubMed1995

Ruthenium Red potently inhibits immune responses both in vitro and in vivo.

Targeted drug screening revealed a compound, Ruthenium Red, which potently blocked proliferation of human T-cells. This compound is not generally cytotoxic or cytostatic, as judged by its lack of effect on the proliferation of a panel of transformed cell lines, but it exhibits true immunosuppressive properties. Ruthenium Red inhibits the T-cell proliferative response (with an IC50 approximately 100 nM) to a wide variety of agents, including viral antigens from herpes simplex virus, tetanus toxoid, alloantigens and IL-2. This compound did not alter the growth of an M-CSF-dependent cell line (M-NFS-60) in response to added growth factor. Time course studies revealed that Ruthenium Red could be added as late as 24 h after the initiation of T-cell stimulation by antigen and still produce maximal inhibition, indicating that later stages of signaling events are being effected. Ruthenium REd was then tested for its ability to abrogate immune response in vivo. It was discovered that this compound dramatically reduced the expansion of lymphocytes in draining lymph nodes of mice immunized with cytochrome c in adjuvants. Furthermore, Ruthenium Red also suppressed specific antibody production in mice following challenge with this antigen. The functional properties of Ruthenium Red have been compared with other immunosuppressive agents and reveal that this compound is most similar to rapamycin in its overall profile. The chemical structure of Ruthenium Red is quite different from these other agents; therefore, it may be extremely useful in helping dissect the activation pathway of T-cells. It will be important to explore further the therapeutic potential of this unique compound.

Animals↗

PubMed1994

Chemical and bioactive constituents from Zanthoxylum simulans.

Two new benzo[c]phenanthridine alkaloids, 6-methyldihydrochelerythrine [1] and 6-methylnorchelerythrine [2], together with 23 known compounds, were isolated from the root bark of Zanthoxylum simulans. Structures were elucidated by spectral analysis. Among them, the pyranoquinoline alkaloids, zanthosimuline [3], and huajiaosimuline [4], exhibited cytotoxic activity. In addition, compound 4 showed significant antiplatelet aggregation activity and induced terminal differentiation with cultured HL-60 cells.

Animals↗

PubMed2005

Multiparametric assay to screen and dissect the mode of action of anti-human immunodeficiency virus envelope drugs.

A flow cytometry-based assay was used to simultaneously quantify X4 and R5 human immunodeficiency virus (HIV) envelope-mediated cell-to-cell viral transfer, cell death, and cell-to-cell fusion. In this assay, different anti-HIV envelope drugs showed characteristic inhibitory profiles for each measured parameter, allowing for the rapid identification of the mode of action of active compounds.

Anti-HIV Agents↗

PubMed2006

In vitro apoptotic activity of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones in L5178Y cells.

Compounds containing B-N bonds have shown interesting biological activity. One class of such molecules is the 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones (3a-j), which contain a B-N bond, have an alpha-amino acid moiety in the heterocycle, and have an exocyclic moiety related to an amino acid. The purpose of this work was to determine the inhibitory effects of 3a-j on the proliferation of murine L5178Y lymphoma cells. A new five-membered heterocyclic nucleus with apoptotic activity was found. The target products showed potent cytotoxicity in the L5178Y cell line. Among them, 3a exhibited the highest antineoplastic activity in L5178Y cells with an IC(50) value of 22.5+/-0.2 microM.

Animals↗

PubMedDate not supplied

Effect of daidzein on cell growth, cell cycle, and telomerase activity of human cervical cancer in vitro.

Phytoestrogens are some plant compounds exhibiting estrogen-like activities. However, some studies have shown that they also affect the growth of some nonhormone-dependent diseases. In this study, daidzein--one of the most common phytoestrogens--was used to investigate its effects on human cervical cancer cells HeLa in vitro. First, the cell growth was measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Then, the distributions of cell cycle and apoptosis were analyzed with the help of flow cytometry. Finally, the telomerase activity was detected by using real-time quantitative reverse transcription-polymerase chain reaction. The results showed that at the concentrations from 6.25 to 100 micro mol/l, daidzein inhibited the growth of HeLa cells. Flow cytometric analysis showed that cancer cells were arrested at G(0)/G(1) or G(2)/M phase with daidzein. The inductive effects of apoptosis were more obviously observed in low-concentration groups. After HeLa cells were treated with daidzein, the expression of human telomerase catalytic subunit mRNA decreased. These meant that daidzein affected human nonhormone-dependent cervical cancer cells in several ways, including cell growth, cell cycle, and telomerase activity in vitro.

Apoptosis↗

PubMed2005

Inhibition of the nuclear factor-kappaB signaling pathway by leflunomide or triptolide also inhibits the anthralin-induced inflammatory response but does not affect keratinocyte growth inhibition.

We performed this study to determine the relationship between activation of nuclear factor (NF)-kappaB and inhibition of keratinocyte growth by anthralin, which not only might be useful for a better understanding of the role of NF-kappaB in the pathogenesis of psoriasis, but also indicate whether the inflammatory reaction induced by anthralin is inseparable from its antipsoriatic activity. The involvement of NF-kappaB was assessed using the antipsoriatic drugs leflunomide and triptolide (T0) as effectors, since they can inhibit NF-kappaB activation induced by anthralin. The results showed that the inhibition of keratinocyte growth by anthralin was not related to the activation of NF-kappaB. Using sodium salicylate, a known NF-kappaB inhibitor, further confirmed this conclusion. Thus it might be possible to inhibit the inflammatory response induced by anthralin via repression of NF-kappaB activation. We found that leflunomide or T0 could significantly inhibit the mRNA overexpression of interleukin-8 and intercellular adhesion molecule-1 in keratinocytes induced by anthralin. Taken together, our data indicate that the growth inhibition of anthralin is related to the NF-kappaB-independent signaling pathway, and that leflunomide or T0 could control proinflammatory cytokine expression induced by anthralin via inhibiting the activation of NF-kappaB.

Anthralin↗

PubMed2005

Antioxidant effects of aqueous extract of Terminalia chebula in vivo and in vitro.

The ripe fruit of Terminalia chebula RETZIUS (T. chebula RETZ) (Combretsceae), which is a native plant in India and Southeast Asia, has traditionally been used as a popular folk medicine for homeostatic, antitussive, laxative, diuretic, and cardiotonic treatments. The objective of this study was to evaluate the protective effects of an aqueous extract of fruit of T. chebula on the tert-butyl hydroperoxide (t-BHP)-induced oxidative injury observed in cultured rat primary hepatocytes and rat liver. Both treatment and pretreatment of the hepatocytes with the T. chebula extract (TCE) significantly reversed the t-BHP-induced cell cytotoxicity and lactate dehydrogenase leakage. In addition, TCE exhibited in vitro ferric-reducing antioxidant activity and 2,2-diphenyl-1-picryhydrazyl free radical-scavenging activities. The in vivo study showed that pretreatment with TCE (500 or 1000 mg/kg) by gavage for 5 d before a single dose of t-BHP (0.1 mmol/kg i.p.) significantly lowered the serum levels of the hepatic enzyme markers aspartate aminotransferase and alanine aminotransferase and reduced the indicators of oxidative stress in the liver, such as the glutathine disulfide content and lipid peroxidation, in a dose-dependent manner. Histopathologic examination of the rat livers showed that TCE reduced the incidence of liver lesions, including hepatocyte swelling and neutrophilic infiltration, and repaired necrosis induced by t-BHP. Based on the results described above, we speculate that TCE has the potential to play a role in the hepatic prevention of oxidative damage in living systems.

Animals↗