-
Cancer Biology & Therapy Dec 2024The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this...
The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.
Topics: Humans; Female; MAP Kinase Signaling System; Breast Neoplasms; Antipsychotic Agents; Pimozide; Cell Proliferation; Apoptosis; Autophagy; Cell Line, Tumor
PubMed: 38356266
DOI: 10.1080/15384047.2024.2302413 -
IScience Feb 2024Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We...
Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We previously devised a traveling wave (TW) system to promote maturation in 3D cardiac tissue. To align with current drug assessment paradigms (CiPA and JiCSA), necessitating a 2D monolayer cardiac tissue, we integrated the TW system with a multi-electrode array. This gave rise to a hiPSC-derived closed-loop cardiac tissue (iCT), enabling spontaneous TW initiation and swift pacing of cardiomyocytes from various cell lines. The TW-paced cardiomyocytes demonstrated heightened sarcomeric and functional maturation, exhibiting enhanced response to isoproterenol. Moreover, these cells showcased diminished sensitivity to verapamil and maintained low arrhythmia rates with ranolazine-two drugs associated with a low risk of torsades de pointes (TdP). Notably, the TW group displayed increased arrhythmia rates with high and intermediate risk TdP drugs (quinidine and pimozide), underscoring the potential utility of this system in drug assessment applications.
PubMed: 38333703
DOI: 10.1016/j.isci.2024.108992 -
BMC Public Health Feb 2024Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory... (Review)
Review
Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide. Ceramide molecules aggregate/assemble on the plasma membrane to form "platforms" that facilitate the viral intake into the cell. Impairing the ASMase activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids' role in cell signal transduction cascades, and viral infection mechanisms. Also, we outlined ASMase structure and underlying mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico molecular docking analyses of FIASMAs with inhibitors revealed that dilazep (S = - 12.58 kcal/mol), emetine (S = - 11.65 kcal/mol), pimozide (S = - 11.29 kcal/mol), carvedilol (S = - 11.28 kcal/mol), mebeverine (S = - 11.14 kcal/mol), cepharanthine (S = - 11.06 kcal/mol), hydroxyzin (S = - 10.96 kcal/mol), astemizole (S = - 10.81 kcal/mol), sertindole (S = - 10.55 kcal/mol), and bepridil (S = - 10.47 kcal/mol) have higher inhibition activity than the candidate drug amiodarone (S = - 10.43 kcal/mol), making them better options for inhibition.
Topics: Humans; COVID-19; Molecular Docking Simulation; SARS-CoV-2; Sphingomyelin Phosphodiesterase; Ceramides; Sphingolipids
PubMed: 38321448
DOI: 10.1186/s12889-024-17747-z -
MedComm Dec 2023Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a consistently low 5-year survival rate. Therefore, we aim to identify key genes involved in LUAD...
Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a consistently low 5-year survival rate. Therefore, we aim to identify key genes involved in LUAD progression to pave the way for targeted therapies in the future. BDH1 plays a critical role in the conversion between acetoacetate and β-hydroxybutyrate. The presence of β-hydroxybutyrate is essential for initiating lysine β-hydroxybutyrylation (Kbhb) modifications. Histone Kbhb at the H3K9 site is attributed to transcriptional activation. We unveiled that β-hydroxybutyrate dehydrogenase 1 (BDH1) is not only conspicuously overexpressed in LUAD, but it also modulates the overall intracellular Kbhb modification levels. The RNA sequencing analysis revealed leucine-rich repeat-containing protein 31 (LRRC31) as a downstream target gene regulated by BDH1. Ecologically expressed BDH1 hinders the accumulation of H3K9bhb in the transcription start site of LRRC31, consequently repressing the transcriptional expression of LRRC31. Furthermore, we identified potential BDH1 inhibitors, namely pimozide and crizotinib, which exhibit a synergistic inhibitory effect on the proliferation of LUAD cells exhibiting high expression of BDH1. In summary, this study elucidates the molecular mechanism by which BDH1 mediates LUAD progression through the H3K9bhb/LRRC31 axis and proposes a therapeutic strategy targeting BDH1-high-expressing LUAD, providing a fresh perspective for LUAD treatment.
PubMed: 38098610
DOI: 10.1002/mco2.449 -
Annals of Nuclear Medicine Feb 2024The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HTR is the newest member of this family and contributes to different...
BACKGROUND
The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HTR is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, glioblastoma multiform (GBM) overexpresses 5-HTR; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HTR imaging agents. METHODS: Compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[Tc(CO)(HO)] and Tc(CO)-[6] and Tc(CO)-[7] were obtained with high radiochemical purity (RCP > 94%). The stability of the radiotracers was evaluated in both saline and mouse serum. Specific binding on different cell lines including U-87 MG, MCF-7, SKBR3, and HT-29 was performed. The biodistribution of these radiotracers was evaluated in normal and U-87 MG Xenografted models. Finally, Tc(CO)-[6] and Tc(CO)-[7] were applied for in vivo imaging in U-87 MG Xenografted models.
RESULTS
Specific binding study indicates that Tc(CO)-[6] and Tc(CO)-[7] can recognize 5-HTR of U87-MG cell line. The biodistribution study in normal mice indicates that the brain uptake of Tc(CO)-[6] and Tc(CO)-[7] is the highest at 30 min post-injection (0.8 ± 0.25 and 0.64 ± 0.18%ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38 ± 0.65 and 3.27 ± 0.5%ID/g, respectively). The injection of pimozide can block the tumor's radiotracer uptake, indicating the binding of these radiotracers to the 5-HTR. The imaging study in the xenograft model also confirms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for Tc(CO)-[6] and Tc(CO)-[7] at 60 min was 3.33 and 3.88, respectively. CONCLUSIONS: Tc(CO)-[6] and Tc(CO)-[7] can visualize tumor in the U87-MG xenograft model due to their affinity toward 5-HTR.
Topics: Mice; Humans; Animals; Serotonin; Tissue Distribution; Neoplasms; Radiopharmaceuticals; Piperazines; Technetium; Cell Line, Tumor
PubMed: 38032496
DOI: 10.1007/s12149-023-01885-2 -
Clinical and Experimental Dermatology Mar 2024Patients with delusional infestation (DI) frequently refuse to be treated with psychoactive drugs. In the past, pimozide was commonly used as a first-line agent but is...
BACKGROUND
Patients with delusional infestation (DI) frequently refuse to be treated with psychoactive drugs. In the past, pimozide was commonly used as a first-line agent but is now prescribed more rarely. Risperidone was first used to treat DI in 1995. A recent review identified 12 studies that evaluated the use of risperidone in 43 patients with DI.
OBJECTIVES
To study the characteristics of and therapeutic results in patients with DI treated with risperidone at a university medical centre in São Paulo, Brazil.
METHODS
We performed a retrospective study of patients with DI treated with risperidone at a dermatological university clinic since 2016. Records were reviewed for personal data and findings related to treatment.
RESULTS
Twenty-seven patients were studied (20 women and 7 men). The maintenance dose of risperidone varied from 1 mg three times weekly to 8 mg daily. Control of symptoms was achieved in the majority of patients. A reduction in dosage due to side-effects was seen in four patients; risperidone had to be switched to another antipsychotic in three cases, despite a good response. Only one patient did not respond to risperidone.
CONCLUSIONS
Risperidone is an effective, well-tolerated and safe treatment for delusional parasitosis. Adequate follow-up is mandatory in order to obtain long-term control of symptoms.
Topics: Male; Humans; Female; Risperidone; Retrospective Studies; Brazil; Antipsychotic Agents; Academic Medical Centers
PubMed: 38001055
DOI: 10.1093/ced/llad411 -
Biomedicines Sep 2023This umbrella review aimed to determine the various drugs used to treat trigeminal neuralgia (TN) and to evaluate their efficacies as well as side effects by surveying... (Review)
Review
This umbrella review aimed to determine the various drugs used to treat trigeminal neuralgia (TN) and to evaluate their efficacies as well as side effects by surveying previously published reviews. An online search was conducted using PubMed, CRD, EBSCO, Web of Science, Scopus, and the Cochrane Library with no limits on publication date or patients' gender, age, and ethnicity. Reviews and meta-analyses of randomized controlled trials pertaining to drug therapy for TN, and other relevant review articles added from their reference lists, were evaluated. Rapid reviews, reviews published in languages other than English, and reviews of laboratory studies, case reports, and series were excluded. A total of 588 articles were initially collected; 127 full-text articles were evaluated after removing the duplicates and screening the titles and abstracts, and 11 articles were finally included in this study. Except for carbamazepine, most of the drugs had been inadequately studied. Carbamazepine and oxcarbazepine continue to be the first choice for medication for classical TN. Lamotrigine and baclofen can be regarded as second-line drugs to treat patients not responding to first-line medication or for patients having intolerable side effects from carbamazepine. Drug combinations using carbamazepine, baclofen, gabapentin, ropivacaine, tizanidine, and pimozide can yield satisfactory results and improve the tolerance to the treatment. Intravenous lidocaine can be used to treat acute exaggerations and botulinum toxin-A can be used in refractory cases. Proparacaine, dextromethorphan, and tocainide were reported to be inappropriate for treating TN. Anticonvulsants are successful in managing trigeminal neuralgia; nevertheless, there have been few studies with high levels of proof, making it challenging to compare or even combine their results in a statistically useful way. New research on other drugs, combination therapies, and newer formulations, such as vixotrigine, is awaited. There is conclusive evidence for the efficacy of pharmacological drugs in the treatment of TN.
PubMed: 37892981
DOI: 10.3390/biomedicines11102606 -
ACS Infectious Diseases Dec 2023The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using...
The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in . From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in . Seven compounds, including ivacaftor (), butenafine (), naftifine (), pimozide (), thioridazine (), trifluoperazine (), and meloxicam (), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor () inhibited efflux dose dependently, had no effect on an strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 μg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.
Topics: Escherichia coli; Escherichia coli Proteins; Ligands; Membrane Transport Proteins; Bacterial Outer Membrane Proteins; Multidrug Resistance-Associated Proteins; Anti-Bacterial Agents; Carrier Proteins
PubMed: 37888944
DOI: 10.1021/acsinfecdis.3c00350 -
Cureus Sep 2023Tics are sudden, repetitive, non-rhythmic movements and/or vocalizations. Generally, tics begin during childhood as a part of Tourette syndrome (TS) and rarely have an...
Tics are sudden, repetitive, non-rhythmic movements and/or vocalizations. Generally, tics begin during childhood as a part of Tourette syndrome (TS) and rarely have an onset during adulthood. We describe a 30-year-old male who presented with multiple motor and vocal tics two weeks following a closed head injury with alteration of consciousness as a result of being crushed against the wall by a 4,100-pound air-conditioning unit. He started having motor tics that developed in a rostrocaudal distribution, followed by simple and complex vocal tics. His tics increased in severity over several months following the injury until presentation. He was started on pimozide and received hyperbaric oxygen treatment which improved both motor and vocal tics.
PubMed: 37876411
DOI: 10.7759/cureus.45741 -
Journal of Clinical Pharmacology Jan 2024The inhibition of human ether-a-go-go-related gene (hERG) channels is a known cause of QT prolongation triggered by antipsychotic drugs. Our previous studies suggest...
P-Glycoprotein-Mediated Interaction Is a Risk Factor for QT Prolongation in Concomitant Use of Antipsychotics and SSRIs as P-Glycoprotein-Mediated Inhibitors: Analysis of the Japanese Adverse Drug Event Report Database.
The inhibition of human ether-a-go-go-related gene (hERG) channels is a known cause of QT prolongation triggered by antipsychotic drugs. Our previous studies suggest that P-glycoprotein (P-gp)-mediated drug interactions may lead to increased gastrointestinal absorption of pimozide and its accumulation in cardiomyocytes, thereby enhancing the inhibitory effect of hERG channels. There is a paucity of epidemiological studies examining the risk of QT prolongation by antipsychotic drugs in terms of P-gp-mediated interactions with concomitant drugs. Therefore, using the Japanese Adverse Event Reporting Database, we investigated whether the risk of QT prolongation triggered by antipsychotic drugs associated with hERG inhibition is affected by the concomitant use of selective serotonin reuptake inhibitors (SSRIs) associated with P-gp inhibition. The results showed that the frequency of QT prolongation increased when the antipsychotic drugs quetiapine and sulpiride, which are P-gp substrates, were combined with SSRIs with P-gp inhibition. In contrast, no association with QT prolongation was observed in patients on non-P-gp-substrate antipsychotics, irrespective of the P-gp inhibitory effect of the concomitant SSRI. These results suggest that P-gp-mediated interactions are a risk factor for antipsychotic-induced QT prolongation. There is a need for further investigation into the risks of specific drug combinations.
Topics: Humans; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug-Related Side Effects and Adverse Reactions; Ether-A-Go-Go Potassium Channels; Japan; Long QT Syndrome; Risk Factors; Selective Serotonin Reuptake Inhibitors
PubMed: 37658631
DOI: 10.1002/jcph.2343