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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 -
Critical Reviews in Oncology/hematology Aug 2018Pimozide is currently being used in clinic as a neuroleptic and exerts versatile biological actions. Pimozide is a cationic amphiphilic drug (CAD); CADs block the... (Review)
Review
Pimozide is currently being used in clinic as a neuroleptic and exerts versatile biological actions. Pimozide is a cationic amphiphilic drug (CAD); CADs block the synthesis of neutral lipids, impair cholesterol homeostasis of cancer cells and increase accumulation of diacylglycerol-3-phosphate. Pimozide exerts tumoricidal activity which was first shown for melanoma and neuroblastoma via proposed anti- dopaminergic effects. Recently, pancreas cancers are shown to elevate dopamine receptor-2 synthesis, which is blocked by pimozide leading growth inhibition. Besides binding to inner mitochondrial membrane and reducing cellular respiration, pimozide also inhibits calmodulin, T-type calcium channels and σ-receptors which all correlate with tumor-inhibitory functions. Pimozide also exerts chemotherapy and radiotherapy-sensitizing effects in cancer cells and acts as an inhibitor of STAT-3 and STAT-5 signaling proteins with potential activity in leukemia, liver and prostate cancer. Pimozide also blocks stem cell features and Wnt-β/catenin signaling in liver cancer. Pimozide interferes with Fatty Acid Protein Binding-4 and activates PPAR-γ and it was proposed to alleviate cancer cachexia. Besides mechanisms of calmodulin and σ-receptor associated pathways, pimozide was proposed to inhibit glioblastoma via serotonin receptor 5-HT7. Pimozide is a selective inducer of autophagy and also inhibits ubiquitine specific protease (USP-1) which may associate with its chemosensizing potential in lung cancer and glioblastoma. Via versatile mechanisms of tumoricidal actions and due to its highly traversing capability through the blood-brain barrier, pimozide highly deserves to be studied in animal models of drug resistant refractory cancers and glioblastoma, which have very poor prognosis.
Topics: Animals; Antineoplastic Agents; Antipsychotic Agents; Drug Resistance, Neoplasm; Glioblastoma; Humans; Neoplasms; Pimozide; Schizophrenia; Signal Transduction
PubMed: 29958636
DOI: 10.1016/j.critrevonc.2018.06.004 -
Journal of Clinical Psychopharmacology Feb 1993
Topics: Delusions; Depressive Disorder; Dose-Response Relationship, Drug; Humans; Pimozide
PubMed: 8486820
DOI: 10.1097/00004714-199302000-00010 -
The American Journal of Psychiatry Jan 1981
Topics: Child; Drug Administration Schedule; Enuresis; Humans; Male; Pimozide; Tourette Syndrome
PubMed: 6934699
DOI: 10.1176/ajp.138.1.123a -
Southern Medical Journal Mar 1993One of the more difficult psychopharmacologic aspects of current clinical psychiatry is finding a neuroleptic drug that adequately treats delusional states. Furthermore,... (Review)
Review
One of the more difficult psychopharmacologic aspects of current clinical psychiatry is finding a neuroleptic drug that adequately treats delusional states. Furthermore, many chronic schizophrenics remain resistant to standard antipsychotic medication, and clozapine is effective in only 30% to 50% of refractory cases. In addition, clozapine has several serious side effects and is expensive. We have determined that pimozide is clearly effective in Tourette's syndrome, maintenance schizophrenia, and some delusional disorders. We further demonstrate that the drug is likely to be effective in the treatment of the negative symptoms of schizophrenia and other delusional states. In addition, we suggest that a trial of pimozide may be indicated before giving clozapine to treatment-resistant schizophrenic patients. The side effect that probably most limits pimozide's current use is the possible production of ECG abnormalities. This side effect does not seem to be a realistic clinical concern, however, if the patients are properly screened and the pimozide dose is maintained at or below 20 mg/day.
Topics: Clinical Protocols; Clinical Trials as Topic; Delusions; Drug Monitoring; Drug Resistance; Drug Utilization; Electrocardiography; Humans; Pimozide; Schizophrenia; Tourette Syndrome; United States; United States Food and Drug Administration
PubMed: 8451677
DOI: 10.1097/00007611-199303000-00019 -
The Journal of Dermatological Treatment May 2022
Topics: Antipsychotic Agents; Delusions; Dermatology; Humans; Pimozide
PubMed: 32940111
DOI: 10.1080/09546634.2020.1825611 -
The Journal of Dermatological Treatment Aug 2022
Topics: Antipsychotic Agents; Delusions; Humans; Pimozide
PubMed: 35373694
DOI: 10.1080/09546634.2022.2062283 -
The American Journal of Psychiatry Nov 1993
Topics: Adult; Delusions; Drug Interactions; Drug Therapy, Combination; Female; Fluoxetine; Humans; Pimozide; Receptors, Dopamine
PubMed: 8214191
DOI: 10.1176/ajp.150.11.1751b -
Journal of the Indian Medical... Nov 1984
Topics: Humans; Pimozide; Psychotic Disorders
PubMed: 6535809
DOI: No ID Found -
Archives of Neurology Sep 1989Pimozide was compared with carbamazepine in a double-blind crossover trial in 48 patients with trigeminal neuralgia who were refractory to medical therapy. Pimozide... (Clinical Trial)
Clinical Trial Comparative Study
Pimozide was compared with carbamazepine in a double-blind crossover trial in 48 patients with trigeminal neuralgia who were refractory to medical therapy. Pimozide treatment produced greater reduction in trigeminal neuralgia symptoms than carbamazepine treatment. All of the pimozide-treated patients improved, while only 56% of carbamazepine-treated patients were relieved of their pain. Although both drugs provoked some adverse effects, it was not necessary to interrupt the trial in any case. After this 24-week trial, all patients began receiving pimozide and were followed up according to an open-label study design. In all cases, the pimozide dosage was progressively reduced until the minimal effective dose was reached. Central and peripheral mechanisms that may underlie pimozide-induced improvement are discussed.
Topics: Carbamazepine; Double-Blind Method; Female; Humans; Male; Multicenter Studies as Topic; Pimozide; Random Allocation; Time Factors; Trigeminal Neuralgia
PubMed: 2673161
DOI: 10.1001/archneur.1989.00520450030015