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1.
Eur J Pharmacol ; 887: 173553, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949606

RESUMO

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.


Assuntos
Antipsicóticos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fenotiazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Animais , Antipsicóticos/uso terapêutico , Antivirais/uso terapêutico , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Flufenazina/farmacologia , Flufenazina/uso terapêutico , Humanos , Pandemias , Perfenazina/farmacologia , Perfenazina/uso terapêutico , Fenotiazinas/uso terapêutico , Proclorperazina/farmacologia , Proclorperazina/uso terapêutico , Tioridazina/farmacologia , Tioridazina/uso terapêutico
2.
Nat Commun ; 11(1): 4147, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811837

RESUMO

Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITD- or KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3- or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34+CD38- AML cells including AML initiating cells with MT-RTKs in vitro and in vivo. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Clorpromazina/farmacologia , Leucemia Mieloide Aguda/genética , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Monoméricas de Montagem de Clatrina/genética , Mutação Puntual , Transdução de Sinais/efeitos dos fármacos , Sequências de Repetição em Tandem/genética , Transplante Heterólogo , Adulto Jovem
3.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32817221

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China at the end of 2019 and has rapidly caused a pandemic, with over 20 million recorded COVID-19 cases in August 2020 (https://covid19.who.int/). There are no FDA-approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA-approved drugs. Rapid development and human testing of potential antivirals is urgently needed. Numerous drugs are already approved for human use, and subsequently, there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA-approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that 17 of these inhibit SARS-CoV-2 at non-cytotoxic concentrations. We directly followed up seven of these to demonstrate that all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found that both drugs protect mice from clinical disease.IMPORTANCE There are no FDA-approved antivirals for any coronavirus, including SARS-CoV-2. Numerous drugs are already approved for human use that may have antiviral activity and therefore could potentially be rapidly repurposed as antivirals. Here, we present data assessing the antiviral activity of 20 FDA-approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV in vitro We found that 17 of these inhibit SARS-CoV-2, suggesting that they may have pan-anti-coronaviral activity. We directly followed up seven of these and found that they all inhibit infectious-SARS-CoV-2 production. Moreover, we evaluated chloroquine and chlorpromazine in vivo using mouse-adapted SARS-CoV. We found that neither drug inhibited viral replication in the lungs, but both protected against clinical disease.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Células A549 , Animais , Cloroquina/farmacologia , Clorpromazina/farmacologia , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Pandemias , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Replicação Viral/efeitos dos fármacos
4.
PLoS One ; 15(8): e0238195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845920

RESUMO

Nosocomial infections caused by extensively drug-resistant (XDR) or Pan-Drug resistant (PDR) Acinetobacter (A.) baumannii have recently increased dramatically creating a medical challenge as therapeutic options became very limited. The aim of our study was to investigate the antibiotic-resistance profiles and evaluate the various combinations of ciprofloxacin (CIP) or levofloxacin (LEV) with antimicrobial agents and non-antimicrobial agents to combat antimicrobial resistance of XDR A. baumannii. A total of 100 (6.25%) A. baumannii clinical isolates were recovered from 1600 clinical specimens collected from hospitalized patients of two major university hospitals in Upper Egypt. Antimicrobial susceptibility tests were carried out according to CLSI guidelines. Antimicrobial susceptibility testing of the respective isolates showed a high percentage of bacterial resistance to 19 antimicrobial agents ranging from 76 to99%. However, a lower percentage of resistance was observed for only colistin (5%) and doxycycline (57%). The isolates were categorized as PDR (2; 2%), XDR (68; 68%), and multi-drug resistant (MDR) (30; 30%). Genotypic analysis using ERIC-PCR on 2 PDR and 32 selected XDR isolates showed that they were not clonal. Combinations of CIP or LEV with antibiotics (including, ampicillin, ceftriaxone, amikacin, or doxycycline) were tested on these A. baumannii non-clonal isolates using standard protocols where fractional inhibitory concentrations (-FICs) were calculated. Results of the respective combinations showed synergism in 23.5%, 17.65%, 32.35%, 17.65% and 26.47%, 8.28%, 14.71%, 26.47%, of the tested isolates, respectively. CIP or LEV combinations with either chlorpromazine (CPZ) 200 µg/ml, propranolol (PR) in two concentrations, 0.5 mg/ml and 1.0 mg/ml or diclofenac (DIC) 4 mg/ml were carried out and the MIC decrease factor (MDF) of each isolate was calculated and results showed synergism in 44%, 50%, 100%, 100% and 94%, 85%, 100%, 100%, of the tested isolates, respectively. In conclusion, combinations of CIP or LEV with CPZ, PR, or DIC showed synergism in most of the selected PDR and XDR A. baumannii clinical isolates. However, these combinations have to be re-evaluated in vivo using appropriate animal models infected by XDR- or PDR- A. baumannii.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Clorpromazina/farmacologia , Diclofenaco/farmacologia , Fluoroquinolonas/farmacologia , Propranolol/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Acinetobacter baumannii/isolamento & purificação , Ciprofloxacino/farmacologia , Infecção Hospitalar/microbiologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Egito , Humanos , Levofloxacino/farmacologia
6.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468014

RESUMO

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/classificação , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Bromoexina/farmacologia , Bromoexina/uso terapêutico , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Diminazena/farmacologia , Diminazena/uso terapêutico , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/normas , Reposicionamento de Medicamentos/tendências , Gabexato/análogos & derivados , Gabexato/farmacologia , Gabexato/uso terapêutico , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/uso terapêutico , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
7.
Encephale ; 46(3S): S35-S39, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32387014

RESUMO

OBJECTIVES: The ongoing COVID-19 pandemic comprises a total of more than 2,350,000 cases and 160,000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4%) compared to health care professionals (∼14%). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from severe forms of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition, to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20-200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (30-100 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19. METHODS: Our hypothesis is that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled clinical trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter time to response (TTR) to treatment in the CPZ+standard-of-care (CPZ+SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ+SOC group, compared to the SOC group: (A) superior clinical improvement; (B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); (C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); (D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; (E) to define the optimal dosage of CPZ and its tolerance; (F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines. CONCLUSION: This repositioning of CPZ as an anti-SARS-CoV-2 drug offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps and can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its "LARGe ACTion" properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Clorpromazina/uso terapêutico , Ensaios Clínicos Fase III como Assunto/métodos , Infecções por Coronavirus/tratamento farmacológico , Estudos Multicêntricos como Assunto/métodos , Pandemias , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Antivirais/farmacocinética , Antivirais/farmacologia , Biomarcadores , Barreira Hematoencefálica , Clorpromazina/farmacocinética , Clorpromazina/farmacologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Reposicionamento de Medicamentos , Endocitose/efeitos dos fármacos , França/epidemiologia , Humanos , Pulmão/metabolismo , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Seleção de Pacientes , Projetos Piloto , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Projetos de Pesquisa , Saliva/metabolismo , Índice de Gravidade de Doença , Método Simples-Cego , Distribuição Tecidual
8.
J Pharmacol Sci ; 143(2): 83-88, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32178942

RESUMO

Spontaneous locomotor activity (SLA) is a useful parameter reflecting physical and mental status of experimental animals. Here we aimed to establish a novel and simple method to assess mouse SLA using motion picture. Movement of C57BL/6 mice was continuously recorded by an infrared video camera connected with a single board computer. The geometric center of mouse outline in each frame was calculated using an image processing library, OpenCV in a programming language Python. Moving distance of the geometric center every second was utilized as an index of mouse SLA. Twenty-four hours assessment of SLA showed that mice repeated active and resting phase. Mice moved more actively during the dark period compared with the light period. Time-frequency analysis of SLA followed by unsupervised clustering classified their active and resting phase. Administration of a sedative, chlorpromazine (5 mg/kg) abolished mouse SLA for 8 h. In contrast, administration of a central nervous stimulant, caffeine (25 mg/kg) increased SLA for 3 h. In conclusion, we here established the automatic measurement system of mouse SLA using motion picture. This system is composed of common equipment and analysis software written in freely available programming language. We also confirmed that it is applicable for drug assessment.


Assuntos
Locomoção/fisiologia , Camundongos Endogâmicos C57BL/fisiologia , Camundongos Endogâmicos C57BL/psicologia , Filmes Cinematográficos , Atividade Motora/fisiologia , Animais , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Clorpromazina/farmacologia , Hipnóticos e Sedativos/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos
9.
Rev Sci Instrum ; 91(2): 025002, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113378

RESUMO

A high-throughput, automated screening platform has been developed for the assessment of biological membrane damage caused by nanomaterials. Membrane damage is detected using the technique of analyzing capacitance-current peak changes obtained through rapid cyclic voltammetry measurements of a phospholipid self-assembled monolayer formed on a mercury film deposited onto a microfabricated platinum electrode after the interaction of a biomembrane-active species. To significantly improve wider usability of the screening technique, a compact, high-throughput screening platform was designed, integrating the monolayer-supporting microfabricated electrode into a microfluidic flow cell, with bespoke pumps used for precise, automated control of fluid flow. Chlorpromazine, a tricyclic antidepressant, and a citrate-coated 50 nm diameter gold nanomaterial (AuNM) were screened to successfully demonstrate the platform's viability for high-throughput screening. Chlorpromazine and the AuNM showed interactions with a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) monolayer at concentrations in excess of 1 µmol dm-3. Biological validity of the electrochemically measured interaction of chlorpromazine with DOPC monolayers was confirmed through quantitative comparisons with HepG2 and A549 cytotoxicity assays. The platform also demonstrated desirable performance for high-throughput screening, with membrane interactions detected in <6 min per assay. Automation contributed to this significantly by reducing the required operating skill level when using the technique and minimizing fluid consumption.


Assuntos
Membrana Celular/metabolismo , Eletroquímica/instrumentação , Nanoestruturas , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Clorpromazina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Eletrodos , Desenho de Equipamento , Ouro/química , Ouro/farmacologia , Humanos , Dispositivos Lab-On-A-Chip , Fosfolipídeos/metabolismo
10.
Biochem Pharmacol ; 175: 113864, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32088265

RESUMO

Interleukin (IL)-1 signaling leads to production of pro-inflammatory mediators and is regulated by receptor endocytosis. Lysosomotropic drugs have been linked to increased pro-inflammatory responses under sterile inflammatory conditions but the underlying mechanisms have not been fully elucidated. Here, we report that lysosomotropic drugs potentiate pro-inflammatory effects in response to IL-1ß via a mechanism involving reactive oxygen species, p38 mitogen-activated protein kinase and reduced IL-1 receptor internalization. Chloroquine and hydroxychloroquine increased IL-1ß-induced CXCL8 secretion in macrophages which was critically dependent on the lysosomotropic character and inhibition of macroautophagy but independent from the NLRP3 inflammasome. Co-stimulation with the autophagy inducer interferon gamma attenuated CXCL8 release. Other lysosomotropic drugs like bafilomycin A1, fluoxetine and chlorpromazine but also the endocytosis inhibitor dynasore showed similar pro-inflammatory responses. Increased cell surface expression of IL-1 receptor suggests reduced receptor degradation in the presence of lysosomotropic drugs. Our findings provide new insights into a potentially crucial immunoregulatory mechanism in macrophages that may explain how lysosomotropic drugs drive sterile inflammation.


Assuntos
Autofagia/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lisossomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores de Interleucina-1/antagonistas & inibidores , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Clorpromazina/farmacologia , Endocitose/efeitos dos fármacos , Fluoxetina/farmacologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Lisossomos/imunologia , Macrófagos/imunologia , Transdução de Sinais , Células THP-1
11.
J Exp Clin Cancer Res ; 39(1): 26, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005270

RESUMO

BACKGROUND: Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY: The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS: On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Clorpromazina/uso terapêutico , Glioblastoma/tratamento farmacológico , Clorpromazina/farmacologia , Reposicionamento de Medicamentos , Feminino , Humanos , Masculino
12.
Biomolecules ; 9(8)2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344975

RESUMO

Electronegative low-density lipoprotein (LDL(-)) is a minor LDL subfraction that is present in blood with inflammatory and apoptotic effects. We aimed to evaluate the role of sphingolipids ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) in the LDL(-)-induced effect on monocytes. Total LDL was subfractioned into native LDL and LDL(-) by anion-exchange chromatography and their sphingolipid content evaluated by mass spectrometry. LDL subfractions were incubated with monocytes in the presence or absence of enzyme inhibitors: chlorpromazine (CPZ), d-erythro-2-(N-myristoyl amino)-1-phenyl-1-propanol (MAPP), and N,N-dimethylsphingosine (DMS), which inhibit Cer, Sph, and S1P generation, respectively. After incubation, we evaluated cytokine release by enzyme-linked immunosorbent assay (ELISA) and apoptosis by flow cytometry. LDL(-) had an increased content in Cer and Sph compared to LDL(+). LDL(-)-induced cytokine release from cultured monocytes was inhibited by CPZ and MAPP, whereas DMS had no effect. LDL(-) promoted monocyte apoptosis, which was inhibited by CPZ, but increased with the addition of DMS. LDL enriched with Sph increased cytokine release in monocytes, and when enriched with Cer, reproduced both the apoptotic and inflammatory effects of LDL(-). These observations indicate that Cer content contributes to the inflammatory and apoptotic effects of LDL(-) on monocytes, whereas Sph plays a more important role in LDL(-)-induced inflammation, and S1P counteracts apoptosis.


Assuntos
Lipoproteínas LDL/farmacologia , Monócitos/citologia , Esfingolipídeos/análise , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ceramidas/análise , Clorpromazina/farmacologia , Citocinas/metabolismo , Humanos , Lisofosfolipídeos/análise , Espectrometria de Massas , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Esfingosina/análogos & derivados , Esfingosina/análise , Esfingosina/farmacologia
13.
J Biol Chem ; 294(31): 11665-11674, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31217281

RESUMO

Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.


Assuntos
Clatrina/metabolismo , Endocitose , MicroRNAs/metabolismo , Doença Aguda , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Hipóxia Celular , Células Cultivadas , Clorpromazina/farmacologia , Meios de Cultivo Condicionados/farmacologia , Endocitose/efeitos dos fármacos , Exossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/veterinária , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo
14.
J Pharmacol Sci ; 140(2): 197-200, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31178327

RESUMO

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl-3H]scopolamine specific binding in mouse cerebral cortex. At 10-5 M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl-3H]scopolamine binding by > 45%. Furthermore, the pKi values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors.


Assuntos
Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Córtex Cerebral/metabolismo , Antagonistas Colinérgicos/metabolismo , Inibidores da Colinesterase/metabolismo , Receptores Muscarínicos/metabolismo , Escopolamina/metabolismo , Animais , Clorpromazina/farmacologia , Depressão Química , Interações Medicamentosas , Masculino , Metotrimeprazina/farmacologia , Camundongos Endogâmicos , Proclorperazina/farmacologia , Ligação Proteica
15.
Food Chem Toxicol ; 131: 110537, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150782

RESUMO

Programmed death ligand-1 (PD-L1) is an important immune checkpoint for cancer immunotherapy in clinic. In this study, we reported that platycodin D, a natural product isolated from an edible and medicinal plant Platycodon grandiflorus (Jacq.) A. DC., down-regulated the protein level of PD-L1 in lung cancer cells. Flow cytometry and immunofluorescence assay showed a weaker surface PD-L1 signal in NCI-H1975 cells after the incubation with platycodin D (10 µM) for 15 min compared to the control group. Jurkat T cells showed enhancive interleukin-2 secretion when co-cultured with platycodin D-treated NCI-H1975 cells, suggesting that platycodin D-induced PD-L1 reduction increases the activation of Jurkat T cells. An augmentation of PD-L1 protein was detected in the cell culture medium from platycodin D treatment group. Chlorpromazine (60 µM) almost abolished the platycodin D-mediated PD-L1 extracellular release and restored the membrane PD-L1. Finally, hemolysis assay exhibited that platycodin D-triggered PD-L1 extracellular release was independent of the hemolytic mechanism. Taken together, our study demonstrates that platycodin D reduces the protein level of PD-L1 in lung cancer cells via triggering its release into the cell culture medium, which sheds new light for the application of natural products in cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Linhagem Celular Tumoral , Clorpromazina/farmacologia , Humanos , Interleucina-2/metabolismo , Células Jurkat , Transporte Proteico/efeitos dos fármacos
16.
Virol J ; 16(1): 80, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196105

RESUMO

BACKGROUND: Rabies virus (RABV), a member of Lyssavirus of Rhabdoviridae family, is a kind of negative-strand RNA virus. The zoonosis caused by RABV leads to high mortality in animals and humans. Though with the extensive investigation, the mechanisms of RABV entry into cells have not been well characterized. METHODS: Chemical inhibitors and RNA interference (RNAi) were used to analysis RABV internalization pathway. The expression level of viral N protein was examined by quantitative PCR and western blot, and the virus infection in the cells was visualized by fluorescence microscopy. RESULTS: We firstly examined the endocytosis pathway of the challenge virus standard (CVS) -11 strain in N2a cells. Chlorpromazine treatment and knockdown of clathrin heavy chain (CHC) significantly reduced viral entry, which proved clathrin was required. Meanwhile neither nystatin nor knocking down caveolin-1 (Cav1) in N2a cells had an effect on CVS-11 infection, suggesting that caveolae was independent for CVS-11 internalization. And when cholesterol of cell membrane was extracted by MßCD, viral infection was strongly impacted. Additionally by using the specific inhibitor dynasore and ammonium chloride, we verified that dynamin and a low-pH environment were crucial for RABV infection, which was confirmed by confocal microscopy. CONCLUSIONS: Our results demonstrated that CVS-11 entered N2a cells through a clathrin-mediated, cholesterol-, pH-, dynamin-required, and caveolae-independent endocytic pathway.


Assuntos
Colesterol/metabolismo , Clatrina/metabolismo , Dinaminas/metabolismo , Endocitose , Vírus da Raiva/fisiologia , Internalização do Vírus , Linhagem Celular , Clorpromazina/farmacologia , Concentração de Íons de Hidrogênio , Proteínas do Nucleocapsídeo/genética , Interferência de RNA , Vírus da Raiva/efeitos dos fármacos
17.
Medicina (Kaunas) ; 55(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137751

RESUMO

Background and Objectives: Lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions by modest adjustments and offer many valuable opportunities in drug delivery. Chlorpromazine, an antipsychotic agent with poor aqueous solubility-with extensive first-pass metabolism-can be a suitable candidate for the development of SNEDDS. The current study was designed to develop triglyceride-based SNEDDS of chlorpromazine to achieve improved solubility, stability, and oral bioavailability. Materials and Methods: Fifteen SNEDDS formulations of each short, medium, and long chain, triglycerides were synthesized and characterized to achieve optimized formulation. The optimized formulation was characterized for several in vitro and in vivo parameters. Results: Particle size, zeta potential, and drug loading of the optimized SNEDDS (LCT14) were found to be 178 ± 16, -21.4, and 85.5%, respectively. Long chain triglyceride (LCT14) showed a 1.5-fold increased elimination half-life (p < 0.01), up to 6-fold increased oral bioavailability, and 1.7-fold decreased plasma clearance rate (p < 0.01) compared to a drug suspension. Conclusion: The findings suggest that SNEDDS based on long-chain triglycerides (LCT14) formulations seem to be a promising alternative for improving the oral bioavailability of chlorpromazine.


Assuntos
Disponibilidade Biológica , Clorpromazina/metabolismo , Emulsificantes/metabolismo , Administração Oral , Animais , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/normas , Emulsificantes/uso terapêutico , Ratos
18.
Dokl Biochem Biophys ; 484(1): 63-65, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012016

RESUMO

Using voltage-clamp technique, the involvement of sigma-1 receptors in the regulation of Na+ transport in frog skin by the immunomodulatory drug glutoxim was investigated. We have shown for the first time that preincubation of the frog skin with the sigma-1 receptor antagonists haloperidol and chlorpromazine attenuates the stimulatory effect of glutoxim on the Na+ transport. The results suggest the possible involvement of the sigma-1 receptors in the regulation of Na+ transport in frog skin epithelium by glutoxim.


Assuntos
Proteínas de Anfíbios/antagonistas & inibidores , Clorpromazina/farmacologia , Haloperidol/farmacologia , Oligopeptídeos/farmacologia , Receptores sigma/antagonistas & inibidores , Pele/metabolismo , Sódio/metabolismo , Proteínas de Anfíbios/metabolismo , Animais , Transporte de Íons/efeitos dos fármacos , Rana temporaria , Receptores sigma/metabolismo
19.
Nanoscale ; 11(13): 6377-6383, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30888365

RESUMO

Endogenous formaldehyde (FA) exists in many living cells and in inhomogeneous distribution in organelles. In particular, lysosomes play significant roles in FA generation and the biofunction of living cells. Herein, we developed a new ratiometric fluorescent nanoprobe, based on naphthalimide derivative (ND)-functionalized carbon dots (CDs), for monitoring endogenous FA in lysosomes. The fluorescence intensity (F535) of green-emitting ND at 535 nm serves as the response signal and the fluorescence intensity (F414) of blue-emitting CDs at 414 nm acts as the reference signal. The fluorescence intensity ratio (F535/F414) of the CD-ND probe is linearly correlated with FA concentration within the range of 1-40 µM in aqueous solution, and the detection limit (3σ/slope) is estimated to be 0.34 µM. As for practical application, this nanoprobe is utilized for the ratiometric fluorescence imaging of FA in live cells. Remarkably, this nanoprobe can specifically target and stain the lysosomes and detect exogenous and endogenous FA in HeLa cells. The new FA probe shows a superior lysosomal targeting ability with a Pearson's coefficient of 0.93, which is attributed to the macromolecular size and basic amine group functionalized surface of CD-ND.


Assuntos
Carbono/química , Corantes Fluorescentes/química , Formaldeído/análise , Lisossomos/metabolismo , Microscopia Confocal , Naftalimidas/química , Pontos Quânticos/química , Clorpromazina/farmacologia , Endocitose/efeitos dos fármacos , Células HeLa , Humanos , Limite de Detecção , Pontos Quânticos/metabolismo , Espectrometria de Fluorescência
20.
Chem Biol Interact ; 302: 28-35, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703373

RESUMO

The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.


Assuntos
Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Células MCF-7 , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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