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Frontiers in Oncology 2021Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in...
Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance . Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.
PubMed: 34336684
DOI: 10.3389/fonc.2021.697950 -
Therapeutic Advances in Drug Safety 2021Retrospective analyses of large databases of treated patients can provide useful links to the presence of drug misuse or rare and infrequent adverse effects, such as...
BACKGROUND
Retrospective analyses of large databases of treated patients can provide useful links to the presence of drug misuse or rare and infrequent adverse effects, such as agranulocytosis, diabetic ketoacidosis or neuroleptic malignant syndrome. The aim of this study is to describe the adverse effects to antipsychotics reported in the Australian Database of Adverse Event Notifications (DAEN).
METHODS
Data were collected from the DAEN - a spontaneous reporting database. The database, which covered the period from January 2004 to December 2017, was obtained from the Therapeutic Goods Administration (TGA) website (www.TGA.gov). The drugs selected for this investigation are the following: aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, haloperidol and pimozide. All data were analysed descriptively. Comparison of reporting and management of adverse events between adults (older than 20 years) and children (5-19 years) was undertaken using chi squared test, where < 0.05 is significant.
RESULTS
A total of 7122 adverse events associated with the antipsychotics aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine and risperidone were reported to the TGA between January 2004 and December 2017. On average, there were 2.6 adverse events reported for each case. The most common adverse event reported for antipsychotics was neuroleptic malignant syndrome. There were no significant differences in the number of co-medications, formulations, indications, therapeutic dose, hospital admission and overdose among the antipsychotics between paediatric and adult populations. However, there were significant differences between causality, death and the management of adverse events between adult and paediatric populations (5-19 years) ( < 0.05, chi squared test).
CONCLUSION
The antipsychotic drug associated with the highest adverse events in adults was clozapine, followed by olanzapine. The most common adverse event in adults, and reported with a number of antipsychotic drugs, was neuroleptic malignant syndrome. In children, the highest numbers of adverse events reported in the database were associated with risperidone, clozapine and olanzapine.
PLAIN LANGUAGE SUMMARY
Adverse events reported of antipsychotics Retrospective analyses of large databases of treated patients can provide useful clues to the presence of drug misuse or rare and infrequent adverse effects associated with antipsychotics. The drugs selected for this investigation are the following: aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, haloperidol and pimozide. All data were analysed descriptively and investigated for any associations between the variables collected. Comparison of reporting and management of adverse events between adults (older than 20 years) and children (5-19 years) was undertaken using chi squared test, where < 0.05 is significant. The antipsychotic drug associated with the highest adverse events was clozapine, followed by olanzapine. In children, the highest numbers of adverse events reported in the database were associated with risperidone, clozapine and olanzapine. The most common adverse event in adults, and reported with a number of antipsychotic drugs, was neuroleptic malignant syndrome. There were significant differences between causality, death and the management of adverse events between adult and paediatric populations (5-19 years).Keywords: Antipsychotics, adverse effects, adverse events, safety.
PubMed: 34104400
DOI: 10.1177/20420986211012854 -
Canadian Medical Association Journal Jun 1984Tourette's syndrome is a widely misunderstood chronic disorder that develops in childhood and is usually lifelong. It is characterized by waxing and waning of...
Tourette's syndrome is a widely misunderstood chronic disorder that develops in childhood and is usually lifelong. It is characterized by waxing and waning of involuntary motor and phonic tics. The features and differential diagnosis are discussed in this paper. The estimated prevalence rate of Tourette's syndrome, 0.05%, implies that this disorder is not rare. The reasons for diagnostic confusion are outlined, and the genetic and neurotransmitter features discussed. The management of Tourette's syndrome has become more effective with the availability of at least two psychoactive drugs, haloperidol and pimozide. Although the cause of this syndrome is thought to be organic, these drugs and their adverse effects are best known to psychiatrists. Psychiatric and multidisciplinary intervention is often necessary because of the frequent association of psychosocial problems, cognitive and learning difficulties, and aggravation of the symptoms by stress. The understanding of Tourette's syndrome will probably increase significantly with the advent of the newer imaging techniques and the rapid progress of research in the neurosciences.
Topics: Adolescent; Child; Child, Preschool; Diagnosis, Differential; Diagnostic Errors; Diseases in Twins; Haloperidol; Humans; Hypersensitivity; Male; Mental Disorders; Pimozide; Sex Factors; Tourette Syndrome
PubMed: 6587930
DOI: No ID Found -
Oncotarget Oct 2018Pimozide, an antipsychotic drug of the diphenylbutylpiperidine class, has been shown to suppress cell growth of breast cancer cells . In this study we further explore...
Pimozide, an antipsychotic drug of the diphenylbutylpiperidine class, has been shown to suppress cell growth of breast cancer cells . In this study we further explore the inhibitory effects of this molecule in cancer cells. We found that Pimozide inhibited cell proliferation in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells and A549 lung cancer cells. Furthermore, we found that Pimozide also promoted apoptosis as demonstrated by cell cycle arrest and induction of double-strand DNA breaks but did not result in any effect in the non-transformed MCF10A breast cell line. In order to shed new lights into the molecular pathways affected by Pimozide, we show that Pimozide downregulated RAN GTPase and AKT at both protein and mRNA levels and inhibited the AKT signaling pathway in MDA-MB-231 breast cancer cells. Pimozide also inhibited the epithelial mesenchymal transition and cell migration and downregulated the expression of MMPs. Administration of Pimozide showed a potent antitumor activity in MDA-MB-231 xenograft animal model and reduced the number of lung metastases by blocking vascular endothelial growth factor receptor 2. Furthermore, Pimozide inhibited myofibroblast formation as evaluated by the reduction in α-smooth muscle actin containing cells. Thus, Pimozide might inhibit tumor development by suppressing angiogenesis and by paracrine stimulation provided by host reactive stromal cells. These results demonstrate a novel and antitumor activity of Pimozide against breast and lung cancer cells and provide the proof of concept for a putative Pimozide as a novel approach for cancer therapy.
PubMed: 30405882
DOI: 10.18632/oncotarget.26175 -
Biomedicines Feb 2023Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission...
Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission at the CNS by acting as a dopaminergic D receptor antagonist. Moreover, pimozide has been shown to block voltage-gated Ca and K channels in different cells. Despite its widespread clinical use, pimozide can cause several adverse effects, including extrapyramidal symptoms and cardiac arrhythmias. Dizziness and loss of balance are among the most common side effects of pimozide. By using the patch-clamp whole-cell technique, we investigated the effect of pimozide [3 μM] on K channels expressed by chicken embryo vestibular type-II hair cells. We found that pimozide slightly blocks a transient outward rectifying A-type K current but substantially increases a delayed outward rectifying K current. The net result was a significant hyperpolarization of type-II hair cells at rest and a strong reduction of their response to depolarizing stimuli. Our findings are consistent with an inhibitory effect of pimozide on the afferent synaptic transmission by type-II hair cells. Moreover, they provide an additional key to understanding the beneficial/collateral pharmacological effects of pimozide. The finding that pimozide can act as a K channel opener provides a new perspective for the use of this drug.
PubMed: 36831024
DOI: 10.3390/biomedicines11020488 -
Prostate Cancer and Prostatic Diseases Mar 2023The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for...
BACKGROUND
The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC.
METHODS
We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models.
RESULTS
We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression.
CONCLUSIONS
Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.
Topics: Male; Humans; Animals; Mice; Antineoplastic Agents; Prostatic Neoplasms, Castration-Resistant; Drug Resistance, Neoplasm; Pimozide; Early Detection of Cancer; Taxoids; Cell Line, Tumor
PubMed: 34593983
DOI: 10.1038/s41391-021-00426-0 -
Therapeutic Advances in Drug Safety 2019The US FDA has designated pimozide, thioridazine, and ziprasidone as contraindicated for patients at risk of QT interval prolongation, and assigned haloperidol,...
BACKGROUND
The US FDA has designated pimozide, thioridazine, and ziprasidone as contraindicated for patients at risk of QT interval prolongation, and assigned haloperidol, olanzapine, paliperidone, quetiapine, and risperidone as associated with a significant risk of QT prolongation. This study aimed to examine trends and hospital variations in concomitant prescribing among these eight selected antipsychotics, and coprescription with interacting drugs known to increase QT prolongation risk.
METHODS
Data on outpatient antipsychotic prescriptions during 2012-2015 were obtained from 16 general hospitals and 10 university hospitals nationwide. A time-series analysis was used for estimating trends in coprescription that led to drug interactions.
RESULTS
Coprescribing among the eight antipsychotics ranged from 7.5% for quetiapine to 33.1% for thioridazine. The rate of coprescription with contraindicated interacting drugs was 9.7% for thioridazine and 21.9% for pimozide, and increased by 1.1 and 1.4 percentage points (% pt.) yearly for thioridazine in general and university hospitals, respectively. Coprescribing with interacting drugs with precautions was 2.8% for quetiapine, 7.4% for ziprasidone, and 27.9% for risperidone; these percentages increased yearly by 1.7% pt. for ziprasidone and 2.6% pt. for risperidone in general hospitals, as well as by 1.0% pt. for risperidone in university hospitals. The median proportion of patients exposed to a QT-prolonging interaction was 12.3% across hospitals (interquartile range, 9.9-19.5%). Wide interhospital variation was found in percentages of drug interactions among patients receiving thioridazine, ziprasidone, paliperidone, or olanzapine in general hospitals, and among patients receiving paliperidone or pimozide in university hospitals.
CONCLUSIONS
Coprescription of antipsychotics with interacting drugs that could increase the risk of QT prolongation was common in Thailand, and thioridazine, ziprasidone, and risperidone showed increasing trends. We urge the incorporation of a unified list of QT-prolonging antipsychotics and interacting drugs into a computerized drug interaction warning system, and existing national rational drug use campaigns should cover this important issue.
PubMed: 31223470
DOI: 10.1177/2042098619854886 -
Cancer Science Dec 2019ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule....
ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD-1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system and explored gene signature-based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap-based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex-dependent actin polymerization and inhibited the vinculin-mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2 , ARPC2 and ARPC2 cells, were prepared using ARPC2 knockout cells prepared by gene-editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild-type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.
Topics: Actin-Related Protein 2-3 Complex; Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Movement; Humans; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Pimozide
PubMed: 31571309
DOI: 10.1111/cas.14205 -
Hospital Pharmacy Feb 2014This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a...
This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to [email protected].
PubMed: 24623867
DOI: 10.1310/hpj4902-134 -
Oncotarget Mar 2017Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug...
Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug resistance to chemotherapy, and the prognosis is poor due to the existence of liver cancer stem-like cells. In this study, we investigated the effect of the neuroleptic agent pimozide to inhibit stem-like cell maintenance and tumorigenicity in HCC. Our results showed that pimozide functioned as an anti-cancer drug in HCC cells or stem-like cells. Pimozide inhibited cell proliferation and sphere formation capacities in HCC cells by inducing G0/G1 phase cell cycle arrest, as well as inhibited HCC cell migration. Surprisingly, pimozide inhibited the maintenance and tumorigenicity of HCC stem-like cells, particularly the side population (SP) or CD133-positive cells, as evaluated by colony formation, sphere formation and transwell migration assays. Furthermore, pimozide was found to suppress STAT3 activity in HCC cells by attenuating STAT3-dependent luciferase activity and down-regulating the transcription levels of downstream genes of STAT3 signaling. Moreover, pimozide reversed the stem-like cell tumorigenic phenotypes induced by IL-6 treatment in HCC cells. Further, the antitumor effect of pimozide was also proved in the nude mice HCC xenograft model. In short, the anti-psychotic agent pimozide may act as a novel potential anti-tumor agent in treating advanced HCC.
Topics: Animals; Antineoplastic Agents; Antipsychotic Agents; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplastic Stem Cells; Pimozide; Real-Time Polymerase Chain Reaction; STAT3 Transcription Factor; Transcriptome; Xenograft Model Antitumor Assays
PubMed: 26061710
DOI: 10.18632/oncotarget.4307