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Cells Nov 2019Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the... (Review)
Review
Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues. Remarkably, we and others have previously showed that genetic inactivation of the gene antagonizes the growth of pancreatic cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The anticancer activity of the ZZW-115 was first validated on a large panel of cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins.
Topics: Adenocarcinoma; Animals; Basic Helix-Loop-Helix Transcription Factors; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Proteins; Pancreatic Neoplasms; Phenothiazines; Protein Transport; Xenograft Model Antitumor Assays
PubMed: 31744261
DOI: 10.3390/cells8111453 -
CNS Drug Reviews 2004Several studies have suggested that the antipsychotic compound, cyamemazine, possesses anxiolytic properties in humans. The original pharmacological profile of... (Review)
Review
Several studies have suggested that the antipsychotic compound, cyamemazine, possesses anxiolytic properties in humans. The original pharmacological profile of cyamemazine (D(2), 5-HT(2A), 5-HT(2C), and 5-HT(3) receptor antagonist), which was established by binding, microdialysis and behavioral studies, is consistent with these observations. In the light/dark exploration test, cyamemazine demonstrated anxiolytic-like activity by acute, but not chronic administration. By chronic administration, however, cyamemazine increased the time spent in the open arms of the elevated plus maze (EPM) test demonstrating anxiolytic-like activity. The discrepancy between the results obtained in these tests by acute and chronic administration, could be due to a combination of dopamine D(2) receptor antagonism with antagonism of the 5-HT(2C) and 5-HT(3) receptors. The action of cyamemazine on both the dopaminergic system and 5-HT(3) receptors could also explain the activity of cyamemazine in the management of alcohol withdrawal demonstrated in preclinical studies. This potential indication for cyamemazine and its activity in benzodiazepine withdrawal syndrome have recently been investigated in clinical trials and the results of these studies are presented in this review.
Topics: Alcohols; Animals; Anti-Anxiety Agents; Benzodiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Humans; Pharmacology, Clinical; Phenothiazines; Substance Withdrawal Syndrome
PubMed: 15492772
DOI: 10.1111/j.1527-3458.2004.tb00023.x -
Revista Brasileira de Psiquiatria (Sao... 2021
Topics: Antipsychotic Agents; Antiviral Agents; COVID-19; Humans; Phenothiazines; SARS-CoV-2
PubMed: 33440401
DOI: 10.1590/1516-4446-2020-0024 -
The Journal of Biological Chemistry Aug 2021Repair of damaged plasma membrane in eukaryotic cells is largely dependent on the binding of annexin repair proteins to phospholipids. Changing the biophysical...
Repair of damaged plasma membrane in eukaryotic cells is largely dependent on the binding of annexin repair proteins to phospholipids. Changing the biophysical properties of the plasma membrane may provide means to compromise annexin-mediated repair and sensitize cells to injury. Since, cancer cells experience heightened membrane stress and are more dependent on efficient plasma membrane repair, inhibiting repair may provide approaches to sensitize cancer cells to plasma membrane damage and cell death. Here, we show that derivatives of phenothiazines, which have widespread use in the fields of psychiatry and allergy treatment, strongly sensitize cancer cells to mechanical-, chemical-, and heat-induced injury by inhibiting annexin-mediated plasma membrane repair. Using a combination of cell biology, biophysics, and computer simulations, we show that trifluoperazine acts by thinning the membrane bilayer, making it more fragile and prone to ruptures. Secondly, it decreases annexin binding by compromising the lateral diffusion of phosphatidylserine, inhibiting the ability of annexins to curve and shape membranes, which is essential for their function in plasma membrane repair. Our results reveal a novel avenue to target cancer cells by compromising plasma membrane repair in combination with noninvasive approaches that induce membrane injuries.
Topics: Annexins; Antipsychotic Agents; Calcium; Cell Line, Tumor; Cell Membrane; Humans; Molecular Dynamics Simulation; Neoplasms; Phenothiazines; Phosphatidylserines; Phospholipids
PubMed: 34324830
DOI: 10.1016/j.jbc.2021.101012 -
Antimicrobial Agents and Chemotherapy Feb 2007The gram-negative soil bacillus Burkholderia pseudomallei is the causative agent of melioidosis, a severe and potentially fatal septicemic disease that is endemic to...
The gram-negative soil bacillus Burkholderia pseudomallei is the causative agent of melioidosis, a severe and potentially fatal septicemic disease that is endemic to Southeast Asia and northern Australia. Its intrinsic resistance to many antibiotics is attributed mainly to the presence of several drug efflux pumps, and therefore, inhibitors of such pumps are expected to restore the activities of many clinically important antimicrobial agents that are the substrates of these pumps. The phenothiazine antipsychotic and antihistaminic drugs prochlorperazine, chlorpromazine, and promazine have a synergistic interaction with a wide spectrum of antimicrobial agents, thereby enhancing their antimicrobial potency against B. pseudomallei. Antimicrobial agents that interacted synergistically with the phenothiazines include streptomycin, erythromycin, oleandomycin, spectinomycin, levofloxacin, azithromycin, and amoxicillin-clavulanic acid. The MICs of these antibiotics were reduced as much as 8,000-fold in the presence of the phenothiazines. Antimicrobial agents which did not interact synergistically with the phenothiazines include gentamicin, amoxicillin, and ampicillin. Omeprazole, a proton pump inhibitor, provided an augmentation of antimicrobial activities similar to that of the phenothiazines, suggesting that the phenothiazines might have interfered with the proton gradient at the inner membrane. B. pseudomallei cells accumulated more erythromycin in the presence of the phenothiazines, an effect similar to that of carbonyl cyanide m-chlorophenylhydrazone, a proton gradient uncoupler. In the presence of the phenothiazines, a much reduced concentration of erythromycin (0.06x MIC) also protected human lung epithelial cells and macrophage cells from B. pseudomallei infection and attenuated its cytotoxicity.
Topics: Anti-Infective Agents; Burkholderia pseudomallei; Cells, Cultured; Drug Synergism; Humans; Lung; Macrophages; Melioidosis; Microbial Sensitivity Tests; Phenothiazines; Proton Pump Inhibitors
PubMed: 17145801
DOI: 10.1128/AAC.01033-06 -
European Journal of Pharmacology Nov 2020In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not... (Review)
Review
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Topics: Animals; Antipsychotic Agents; Antiviral Agents; Betacoronavirus; COVID-19; Chlorpromazine; Coronavirus Infections; Fluphenazine; Humans; Pandemics; Perphenazine; Phenothiazines; Pneumonia, Viral; Prochlorperazine; RNA Viruses; SARS-CoV-2; Thioridazine; COVID-19 Drug Treatment
PubMed: 32949606
DOI: 10.1016/j.ejphar.2020.173553 -
Organic & Biomolecular Chemistry Jul 2022A two-step synthesis of phenothiazines has been developed using a dual-catalytic -thioarylation reaction of anilines as the key step. Activation of...
A two-step synthesis of phenothiazines has been developed using a dual-catalytic -thioarylation reaction of anilines as the key step. Activation of -(2-bromophenylthio)succinimide was achieved using the super Lewis acid, iron(III) triflimide and the Lewis base, diphenyl selenide, resulting in an accelerated and efficient -thioarylation reaction of various protected aniline derivatives and less reactive, unprotected analogues. The thioarylated adducts were then cyclised to the desired phenothiazines using either an Ullmann-Goldberg or Buchwald-Hartwig coupling reaction. The dual catalytic thioarylation and copper(I)-catalysed cyclisation approach was used for the four-step synthesis of methopromazine, a neuroleptic agent with antipsychotic activity.
Topics: Aniline Compounds; Catalysis; Copper; Ferric Compounds; Phenothiazines
PubMed: 35796590
DOI: 10.1039/d2ob01082h -
British Medical Journal Jul 1977
Topics: Antipsychotic Agents; Drug Resistance; Electroconvulsive Therapy; Humans; Phenothiazines; Schizophrenia
PubMed: 17450
DOI: 10.1136/bmj.2.6079.127-b -
British Journal of Clinical Pharmacology Nov 2007The emergence of multiresistant bacterial strains and the continuing burden of infectious disease globally point to the urgent need for novel affordable antimicrobial... (Review)
Review
The emergence of multiresistant bacterial strains and the continuing burden of infectious disease globally point to the urgent need for novel affordable antimicrobial drugs. Thioridazine is a phenothiazine antipsychotic drug with well-recognized antimicrobial activity, but this property has not been harnessed for clinical use as a result of its central nervous system and cardiac side-effects. The cardiotoxicity of thioridazine has recently been shown to be structurally specific at a molecular level, whereas its antimicrobial properties are shared by a number of phenothiazine analogues. This raises the possibility that its enantiomers or its inactive metabolite, the ring sulphoxide, may act as a lead compound in the future development of antimicrobial drugs to face the new challenges in infectious disease.
Topics: Anti-Infective Agents; Drug Approval; Drug Resistance, Microbial; Humans; Thioridazine; Treatment Outcome
PubMed: 17764469
DOI: 10.1111/j.1365-2125.2007.03021.x -
Cell Transplantation Mar 2019In vitro liver conservation is an issue of ongoing critical importance in graft transplantation. In this study, we investigated the possibility of augmenting the...
In vitro liver conservation is an issue of ongoing critical importance in graft transplantation. In this study, we investigated the possibility of augmenting the standard pre-transplant liver conservation protocol (University of Wisconsin (UW) cold solution) with the phenothiazines chlorpromazine and promethazine. Livers from male Sprague-Dawley rats were preserved either in UW solution alone, or in UW solution plus either 2.4, 3.6, or 4.8 mg chlorpromazine and promethazine (C+P, 1:1). The extent of liver injury following preservation was determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, the ratio of AST/ALT, morphological changes as assessed by hematoxylin-eosin staining, apoptotic cell death as determined by ELISA, and by expression of the apoptotic regulatory proteins BAX and Bcl-2. Levels of glucose (GLU) and lactate dehydrogenase (LDH) in the preservation liquid were determined at 3, 12, and 24 h after incubation to assess glucose metabolism. Oxidative stress was assessed by levels of superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA), and inflammatory cytokine expression was evaluated with Western blotting. C+P augmentation induced significant reductions in ALT and AST activities; the AST/ALT ratio; as well as in cellular swelling, vacuolar degeneration, apoptosis, and BAX expression. These changes were associated with lowered levels of GLU and LDH; decreased expression of SOD, MDA, ROS, TNF-α, and IL-1β; and increased expression of Bcl-2. We conclude that C+P augments hypothermic preservation of liver tissue by protecting hepatocytes from ischemia-induced oxidative stress and metabolic dysfunction. This result provides a basis for improvement of the current preservation strategy, and thus for the development of a more effective graft conservation method.
Topics: Animals; Cell Hypoxia; Cold Temperature; Gene Expression Regulation; Hepatocytes; Liver; Male; Organ Preservation; Organ Preservation Solutions; Oxidative Stress; Phenothiazines; Pilot Projects; Rats; Rats, Sprague-Dawley
PubMed: 30666889
DOI: 10.1177/0963689718824559