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Biochimica Et Biophysica Acta Jan 1999NMDA receptor channel responses were recorded from acutely isolated rat hippocampal neurons, using whole-cell patch-clamp techniques. In the continuous presence of... (Comparative Study)
Comparative Study
NMDA receptor channel responses were recorded from acutely isolated rat hippocampal neurons, using whole-cell patch-clamp techniques. In the continuous presence of aspartate, tetraethylammonium, tetrabutylammonium, 1-amino-3-propyl-adamantane and 9-aminoacridine caused changes in the current through NMDA channels, which were described by two-exponential functions. It was established that depending on the behavior of the amplitude of the fast component for the recovery kinetics, the blocker action can be assigned to one of five types described by the simplest models. The effects of tetraethylammonium, tetrabutylammonium and 1-amino-3-propyl-adamantane were well described by these models. Using 9-aminoacridine as an example, it was shown that the simplest models cannot describe all possible types of the blocker-channel interaction. In such cases, the method of the simplest models combination can be used. The application of the simplest kinetic models analysis allowed to make the following conclusions: at least two molecules of 1-amino-3-propyl-adamantane or 9-aminoacridine can simultaneously bind to the open channel and block it; the occupation of 9-aminoacridine blocking sites in the channel can proceed in at least two different ways; the binding of tetrabutylammonium and 9-aminoacridine prevented the closure of the activation and/or desensitization gates of the channel, while that of tetraethylammonium did not.
Topics: Aminacrine; Animals; Cations; Kinetics; Patch-Clamp Techniques; Pyramidal Cells; Quaternary Ammonium Compounds; Rats; Receptors, N-Methyl-D-Aspartate; Tetraethylammonium
PubMed: 9889324
DOI: 10.1016/s0005-2736(98)00211-9 -
Journal of Virology Sep 2008Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of the aggressive and fatal disease adult T-cell leukemia. Previous studies have demonstrated that the...
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of the aggressive and fatal disease adult T-cell leukemia. Previous studies have demonstrated that the HTLV-1-encoded Tax protein inhibits the function of tumor suppressor p53 through a Tax-induced NF-kappaB pathway. Given these attributes, we were interested in the activity of small-molecule inhibitor 9-aminoacridine (9AA), an anticancer drug that targets two important stress response pathways, NF-kappaB and p53. In the present study, we have examined the effects of 9AA on HTLV-1-transformed cells. Treatment of HTLV-1-transformed cells with 9AA resulted in a dramatic decrease in cell viability. Consistent with these results, we observed an increase in the percentage of cells in sub-G(1) and an increase in the number of cells positive by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay following treatment of HTLV-1-transformed cells with 9AA. In each assay, HTLV-1-transformed cells C8166, Hut102, and MT2 were more sensitive to treatment with 9AA than control CEM and peripheral blood mononuclear cells. Analyzing p53 function, we demonstrate that treatment of HTLV-1-transformed cells with 9AA resulted in an increase in p53 protein and activation of p53 transcription activity. Of significance, 9AA-induced cell death could be blocked by introduction of a p53 small interfering RNA, linking p53 activity and cell death. These results suggest that Tax-repressed p53 function in HTLV-1-transformed cells is "druggable" and can be restored by treatment with 9AA. The fact that 9AA induces p53 and inhibits NF-kappaB suggests a promising strategy for the treatment of HTLV-1-transformed cells.
Topics: Aminacrine; Anticarcinogenic Agents; Apoptosis; Cell Cycle; Cell Death; Cell Line, Transformed; Cell Survival; Cell Transformation, Viral; Dose-Response Relationship, Drug; G1 Phase; Genes, Reporter; Human T-lymphotropic virus 1; Humans; In Situ Nick-End Labeling; Luciferases; NF-kappa B; Plasmids; RNA, Small Interfering; Time Factors; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53
PubMed: 18550670
DOI: 10.1128/JVI.00690-08 -
Journal of Lipid Research Sep 2010A method of direct lipid analysis by MALDI mass spectrometry in intact membranes, without prior extraction/separation steps, is described. The purple membrane isolated...
A method of direct lipid analysis by MALDI mass spectrometry in intact membranes, without prior extraction/separation steps, is described. The purple membrane isolated from the extremely halophilic archaeon Halobacterium salinarum was selected as model membrane. Lyophilized purple membrane were grinded with 9-aminoacridine (9-AA) as dry matrix, and the powder mixture was crushed in a mechanical die press to form a thin pellet. Small pieces of the pellet were then attached to the MALDI target and directly analyzed. In parallel, individual archaebacterial phospholipids and glycolipids, together with the total lipid extract of the purple membrane, were analyzed by MALDI-TOF/MS using 9-AA as the matrix in solution. Results show that 9-AA represents a suitable matrix for the conventional MALDI-TOF/MS analysis of lipid extracts from archaeal microorganisms, as well as for fast and reliable direct dry lipid analysis of lyophilized archaebacterial membranes. This method might be of general application, offering the advantage of quickly gaining information about lipid components without disrupting or altering the membrane matrix.
Topics: Aminacrine; Archaea; Fluorescent Dyes; Freeze Drying; Halobacterium salinarum; Lipids; Molecular Structure; Purple Membrane; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 20538644
DOI: 10.1194/jlr.D007328 -
Retrovirology Jun 2014Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of CD4+CD25+ lymphocytes caused by human T-cell lymphotropic virus type 1. While much progress has been...
BACKGROUND
Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of CD4+CD25+ lymphocytes caused by human T-cell lymphotropic virus type 1. While much progress has been made in understanding the mechanisms of cellular dysregulation, the prognosis for aggressive ATL still remains poor. Therefore, new therapeutic approaches need to be developed.
RESULTS
Previously, we demonstrated that the viral protein Tax inactivates p53 in HTLV-1-infected T-cells. Here we show that 9-aminoacridine (9AA) through p53 reactivation and NF-κB inhibition has selective toxicity for infected leukemic cells independent of their p53 status. We further demonstrate that 9AA activates caspase-3/7 resulting in PARP cleavage. Next we investigated the efficacy of 9AA in the MET-1 ATL model. Alone, 9AA did not cause significant drops in surrogate tumor markers, soluble IL-2Rα or β2-micorglobulin (β2μ) levels with only a slight increase in survival of MET-1-bearing mice. However, in combination with Campath-1H, 9AA treatment resulted in low soluble IL-2Rα and β2μ levels at 2 and 4 weeks. Consistent with reduced tumor cell burden, combination treatment significantly increased survival of MET-1-bearing mice compared to mice treated with either drug alone. Splenic cells isolated from 9AA or combination treated mice showed increased p53 protein levels and transcriptional activity. Consistent with increased tumor suppressor activity, we found increased PARP-1 cleavage in 9AA and combination treated cells.
CONCLUSION
Our results indicate that targeting reactivation of p53 and inhibition of NF-κB with acridine-derivatives in combination with other chemotherapeutics could result in increased efficacy and selective killing of tumor cells.
Topics: Alemtuzumab; Aminacrine; Animals; Antibodies, Monoclonal, Humanized; Caspase 3; Caspase 7; Cell Line, Tumor; Disease Models, Animal; Humans; Interleukin-2 Receptor alpha Subunit; Jurkat Cells; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Inbred NOD; Mice, SCID; NF-kappa B; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; T-Lymphocytes; Transcription, Genetic; Tumor Suppressor Protein p53
PubMed: 24890041
DOI: 10.1186/1742-4690-11-43 -
Journal of Neurochemistry Mar 2015Previous works have shown the interest of naturally fluorescent proflavine derivatives to label Abeta deposits in vitro. This study aimed to further characterize the...
Previous works have shown the interest of naturally fluorescent proflavine derivatives to label Abeta deposits in vitro. This study aimed to further characterize the properties of the proflavine 3-acetylamino-6-[3-(propargylamino)propanoyl]aminoacridine (COB231) derivative as a probe. This compound was therefore evaluated on human post-mortem and mice brain slices and in vivo in 18-month-old triple transgenic mice APPswe, PS1M146V and tauP301L (3xTgAD) mice presenting the main characteristics of Alzheimer's disease (AD). COB231 labelled amyloid plaques on brain slices of AD patients, and 3xTgAD mice at 10 and 0.1 μM respectively. However, no labelling of the neurofibrillary tangle-rich areas was observed either at high concentration or in the brain of fronto-temporal dementia patients. The specificity of this mapping was attested in mice using Thioflavin S and IMPY as positive controls of amyloid deposits. After intravenous injection of COB231 in old 3xTgAD mice, fluorescent amyloid plaques were detected in the cortex and hippocampus, demonstrating COB231 blood–brain barrier permeability. We also controlled the cellular localization of COB231 on primary neuronal cultures and showed that COB231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB231 (< 10%) for the highest concentration (100 μM).
Topics: Alzheimer Disease; Aminacrine; Animals; Autopsy; Brain; Disease Models, Animal; Female; Fluorescent Dyes; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Plaque, Amyloid; Proflavine; Sensitivity and Specificity; Staining and Labeling
PubMed: 25258048
DOI: 10.1111/jnc.12951 -
Environmental Health Perspectives Feb 1997
Topics: Aminacrine; Animals; Anti-Infective Agents, Local; Birth Weight; Body Weight; Dose-Response Relationship, Drug; Female; Kidney; Liver; Male; Mice; Organ Size; Pregnancy; Reproduction
PubMed: 9114319
DOI: No ID Found -
Virology Journal Jul 2009As part of a continued search for more efficient anti-HIV-1 drugs, we are focusing on the possibility that small molecules could efficiently inhibit HIV-1 replication...
As part of a continued search for more efficient anti-HIV-1 drugs, we are focusing on the possibility that small molecules could efficiently inhibit HIV-1 replication through the restoration of p53 and p21WAF1 functions, which are inactivated by HIV-1 infection. Here we describe the molecular mechanism of 9-aminoacridine (9AA) mediated HIV-1 inhibition. 9AA treatment resulted in inhibition of HIV LTR transcription in a specific manner that was highly dependent on the presence and location of the amino moiety. Importantly, virus replication was found to be inhibited in HIV-1 infected cell lines by 9AA in a dose-dependent manner without inhibiting cellular proliferation or inducing cell death. 9AA inhibited viral replication in both p53 wildtype and p53 mutant cells, indicating that there is another p53 independent factor that was critical for HIV inhibition. p21WAF1 is an ideal candidate as p21WAF1 levels were increased in both p53 wildtype and p53 mutant cells, and p21WAF1 was found to be phosphorylated at S146, an event previously shown to increase its stability. Furthermore, we observed p21WAF1 in complex with cyclin T1 and cdk9 in vitro, suggesting a direct role of p21WAF1 in HIV transcription inhibition. Finally, 9AA treatment resulted in loss of cdk9 from the viral promoter, providing one possible mechanism of transcriptional inhibition. Thus, 9AA treatment was highly efficient at reactivating the p53 - p21WAF1 pathway and consequently inhibiting HIV replication and transcription.
Topics: Aminacrine; Anti-HIV Agents; Cell Line; Cyclin-Dependent Kinase Inhibitor p21; HIV-1; Humans; T-Lymphocytes; Transcription, Genetic; Tumor Suppressor Protein p53; Virus Replication; tat Gene Products, Human Immunodeficiency Virus
PubMed: 19630958
DOI: 10.1186/1743-422X-6-114 -
Proceedings of the National Academy of... Oct 1988The antitumor drugs camptothecin and an anilinoacridine, 4'-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA), which act on DNA topoisomerase I and II, respectively,...
The antitumor drugs camptothecin and an anilinoacridine, 4'-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA), which act on DNA topoisomerase I and II, respectively, are shown to inhibit the growth of Saccharomyces cerevisiae mutants selected for their permeability to other inhibitors. In addition to growth inhibition, these drugs induce high levels of homologous recombination and induce the expression of a DNA damage-inducible gene DIN3. Cytotoxicity of the drugs is more pronounced in strains that also carry a rad52 mutation. An analog of mAMSA), which is ineffective as an inhibitor of DNA topoisomerase II in mammalian cells, is also ineffective in eliciting physiological responses in these yeast strains. The physiological effects of camptothecin, but not those of mAMSA, disappear if the TOP1 gene encoding DNA topoisomerase I is disrupted. This shows that DNA topoisomerase I is the sole target of camptothecin cytotoxicity and illustrates that a nonessential enzyme can nevertheless be the target for a cytotoxic drug.
Topics: Aminacrine; Aminoacridines; Antineoplastic Agents; Camptothecin; DNA Damage; DNA Topoisomerases, Type I; Gene Expression Regulation; Mutation; Recombination, Genetic; Saccharomyces cerevisiae
PubMed: 2845409
DOI: 10.1073/pnas.85.20.7501 -
Journal of Chromatographic Science Apr 2016Two sensitive and selective analytical methods were developed for simultaneous determination of aminoacridine hydrochloride and lidocaine hydrochloride in bulk powder...
Two sensitive and selective analytical methods were developed for simultaneous determination of aminoacridine hydrochloride and lidocaine hydrochloride in bulk powder and pharmaceutical formulation. Method A was based on HPLC separation of the cited drugs with determination of the toxic lidocaine-related impurity 2,6-dimethylaniline. The separation was achieved using reversed-phase column C18, 250 × 4.6 mm, 5 µm particle size and mobile phase consisting of 0.05 M disodium hydrogen phosphate dihydrate (pH 6.0 ± 0.2 adjusted with phosphoric acid) and acetonitrile (55 : 45, v/v). Quantitation was achieved with UV detection at 240 nm. Linear calibration curve was in the range of 1.00-10.00, 13.20-132.00 and 1.32-13.20 µg mL(-1) for aminoacridine hydrochloride, lidocaine hydrochloride and 2,6-dimethylaniline, respectively. Method B was based on TLC separation of the cited drugs followed by densitometric measurement at 365 nm on the fluorescent mode for aminoacridine hydrochloride and 220 nm on the absorption mode for lidocaine hydrochloride. The separation was carried out using ethyl acetate-methanol-acetic acid (65 : 30 : 5 by volume) as a developing system. The calibration curve was in the range of 25.00-250.00 ng spot(-1) and 0.99-9.90 µg spot(-1) for aminoacridine hydrochloride and lidocaine hydrochloride, respectively. The results obtained were statistically analyzed and compared with those obtained by applying the manufacturer's method.
Topics: Administration, Oral; Aminacrine; Chromatography, High Pressure Liquid; Drug Contamination; Gels; Lidocaine; Pharmaceutical Preparations
PubMed: 26671412
DOI: 10.1093/chromsci/bmv170 -
American Journal of Physiology. Cell... Oct 2011The F508del mutation, the most frequent in cystic fibrosis (CF), impairs the maturation of the CFTR chloride channel. The F508del defect can be partially overcome at low...
The F508del mutation, the most frequent in cystic fibrosis (CF), impairs the maturation of the CFTR chloride channel. The F508del defect can be partially overcome at low temperature (27°C) or with pharmacological correctors. However, the efficacy of correctors on the mutant protein appears to be dependent on the cell expression system. We have used a bronchial epithelial cell line, CFBE41o-, to determine the efficacy of various known treatments and to discover new correctors. Compared with other cell types, CFBE41o- shows the largest response to low temperature and the lowest one to correctors such as corr-4a and VRT-325. A screening of a small-molecule library identified 9-aminoacridine and ciclopirox, which were significantly more effective than corr-4a and VRT-325. Analysis with microarrays revealed that 9-aminoacridine, ciclopirox, and low temperature, in contrast to corr-4a, cause a profound change in cell transcriptome. These data suggest that 9-aminoacridine and ciclopirox act on F508del-CFTR maturation as proteostasis regulators, a mechanism already proposed for the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). However, we found that 9-aminoacridine, ciclopirox, and SAHA, in contrast to corr-4a, VRT-325, and low temperature, do not increase chloride secretion in primary bronchial epithelial cells from CF patients. These conflicting data appeared to be correlated with different gene expression signatures generated by these treatments in the cell line and in primary bronchial epithelial cells. Our results suggest that F508del-CFTR correctors acting by altering the cell transcriptome may be particularly active in heterologous expression systems but markedly less effective in native epithelial cells.
Topics: Aminacrine; Bacterial Proteins; Benzamides; Cell Line; Cell Membrane; Chlorides; Ciclopirox; Cold Temperature; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Gene Expression Profiling; Gene Expression Regulation; Humans; Hydroxamic Acids; Luminescent Proteins; Mutation; Piperazines; Protein Transport; Pyridones; Quinazolines; Thiazoles; Vorinostat
PubMed: 21753184
DOI: 10.1152/ajpcell.00507.2010