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Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species.Frontiers in Pharmacology 2019The United States Food and Drug Administration-approved antipsychotic drug, pimozide, has anticancer activities. However, the role of reactive oxygen species (ROS) in...
The United States Food and Drug Administration-approved antipsychotic drug, pimozide, has anticancer activities. However, the role of reactive oxygen species (ROS) in its effect on prostate cancer is not well-known. We examined cell proliferation, colony formation, migration, ROS production, and the expression of antioxidant-related genes after treatment of human prostate cancer PC3 and DU145 cells with pimozide. In addition, histopathology, ROS production, and superoxide dismutase (SOD) activity were analyzed after administering pimozide to TRAMP, a transgenic mouse with prostate cancer. Pimozide increased the generation of ROS in both cell lines and inhibited cell proliferation, migration, and colony formation. Oxidative stress induced by pimozide caused changes in the expression of antioxidant enzymes (SOD1, peroxiredoxin 6, and glutathione peroxidase 2) and CISD2. Co-treatment with glutathione, an antioxidant, reduced pimozide-induced ROS levels, and counteracted the inhibition of cell proliferation. Administration of pimozide to TRAMP mice reduced the progression of prostate cancer with increased ROS generation and decreased SOD activity. These results suggest that the antipsychotic drug, pimozide, has beneficial effects in prostate cancer and . The mechanism of pimozide may be related to augmenting ROS generation. We recommend pimozide as a promising anticancer agent.
PubMed: 32009948
DOI: 10.3389/fphar.2019.01517 -
Frontiers in Oncology 2020Drug repositioning is a promising strategy for discovering new therapeutic strategies for cancer therapy. We investigated psychotropic drugs for their antitumor...
Drug repositioning is a promising strategy for discovering new therapeutic strategies for cancer therapy. We investigated psychotropic drugs for their antitumor activity because of several epidemiological studies reporting lower cancer incidence in individuals receiving long term drug treatment. We investigated 27 psychotropic drugs for their cytotoxic activity in colorectal carcinoma, glioblastoma and breast cancer cell lines. Consistent with the cationic amphiphilic structure of the most cytotoxic compounds, we investigated their effect on mitochondrial and lysosomal compartments. Penfluridol, ebastine, pimozide and fluoxetine, fluspirilene and nefazodone showed significant cytotoxicity, in the low micromolar range, in all cell lines tested. In MCF7 cells these drugs caused mitochondrial membrane depolarization, increased the acidic vesicular compartments and induced phospholipidosis. Both penfluridol and spiperone induced AMPK activation and autophagy. Neither caspase nor autophagy inhibitors rescued cells from death induced by ebastine, fluoxetine, fluspirilene and nefazodone. Treatment with 3-methyladenine partially rescued cell death induced by pimozide and spiperone, whereas enhanced the cytotoxic activity of penfluridol. Conversely, inhibition of lysosomal cathepsins significantly reduced cell death induced by ebastin, penfluridol, pimozide, spiperone and mildly in fluoxetine treated cells. Lastly, Spiperone cytotoxicity was restricted to colorectal cancer and breast cancer and caused apoptotic cell death in MCF7 cells. The cytotoxicity of psychotropic drugs with cationic amphiphilic structures relied on simultaneous mitochondrial and lysosomal disruption and induction of cell death that not necessarily requires apoptosis. Since dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for cancer, particularly those in which the apoptotic machinery is defective, these data further support their clinical development for cancer therapy.
PubMed: 33194631
DOI: 10.3389/fonc.2020.562196 -
Journal of Neurology, Neurosurgery, and... Apr 1975Metoclopramide is an antiemetic drug which occasionally produced acute dystonic reactions. Although known to interfere with central dopamine mechanisms, it is frequently... (Clinical Trial)
Clinical Trial Comparative Study
Metoclopramide is an antiemetic drug which occasionally produced acute dystonic reactions. Although known to interfere with central dopamine mechanisms, it is frequently used in Parkinson's disease to prevent levodopa-induced nausea and vomiting. In this study metoclopramide did not increase Parkinsonism or reduce levodopa-induced involuntary movements in patients with Parkinson's disease. Pimozide, by contrast, increased Parkinsonism and reduced involuntary movements. The capacity of metoclopramide to produce acute dyskinesias while being apparently free of Parkinsonism effects is pharmacologically unique and differentiates this drug from the phenothiazines and butyrophenones.
Topics: Aged; Carbidopa; Clinical Trials as Topic; Drug Evaluation; Drug Interactions; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Metoclopramide; Middle Aged; Movement Disorders; Nausea; Parkinson Disease; Parkinson Disease, Secondary; Pimozide; Placebos; Promethazine
PubMed: 1095689
DOI: 10.1136/jnnp.38.4.331 -
Parkinsonism & Related Disorders 2008Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to... (Review)
Review
Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function.
Topics: Adenosine; Animals; Disease Models, Animal; Dopamine; Humans; Locomotion; Parkinson Disease; Tremor
PubMed: 18585081
DOI: 10.1016/j.parkreldis.2008.04.017 -
International Journal of Oncology Sep 2018Melanoma is one of the most fatal and therapy-resistant types of cancer; therefore, identifying novel therapeutic candidates to improve patient survival is an ongoing...
Melanoma is one of the most fatal and therapy-resistant types of cancer; therefore, identifying novel therapeutic candidates to improve patient survival is an ongoing effort. Previous studies have revealed that pimozide is not sufficient to treat melanoma; therefore, enhancing the treatment is necessary. Indoleamine 2, 3‑dioxygenase (IDO) is an immunosuppressive, intracellular rate-limiting enzyme, which contributes to immune tolerance in various tumours, including melanoma, and inhibition of IDO may be considered a novel therapeutic strategy when combined with pimozide. The present study aimed to assess the antitumour activities of pimozide in vitro, and to investigate the effects of pimozide combined with L‑methyl-tryptophan (L‑MT) in vivo. For in vitro analyses, the B16 melanoma cell line was used. Cell cytotoxicity assay, cell viability assay, wound‑healing assay and western blotting were conducted to analyse the effects of pimozide on B16 cells. Furthermore, B16 cell-bearing mice were established as the animal model. Haematoxylin and eosin staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labelling staining, western blotting and flow cytometry were performed to determine the effects of monotherapy and pimozide and L‑MT cotreatment on melanoma. The results demonstrated that pimozide exhibited potent antitumour activity via the regulation of proliferation, apoptosis and migration. Furthermore, the antitumour effects of pimozide were enhanced when combined with L‑MT, not only via regulation of proliferation, apoptosis and migration, but also via immune modulation. Notably, pimozide may regulate tumour immunity through inhibiting the activities of signal transducer and activator of transcription (Stat)3 and Stat5. In conclusion, the present study proposed the use of pimozide in combination with the IDO inhibitor, L‑MT, as a potential novel therapeutic strategy for the treatment of melanoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; Drug Synergism; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Pimozide; Skin Neoplasms; Tryptophan; Xenograft Model Antitumor Assays
PubMed: 30015838
DOI: 10.3892/ijo.2018.4473 -
Scientific Reports Oct 2021The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed...
The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.
Topics: Anti-Bacterial Agents; Antipsychotic Agents; Antitubercular Agents; Autophagy; Cell Line; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Repositioning; High-Throughput Screening Assays; Humans; Lysosomes; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Phagosomes; Pimozide; Salmonella Infections; Salmonella enterica; Small Molecule Libraries; Tuberculosis
PubMed: 34608194
DOI: 10.1038/s41598-021-98980-z -
Current Pharmaceutical Design 2004The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g.... (Review)
Review
The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na(+), Ca(2+) and K(+) channels often leading to life-threatening arrhythmia. To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors. Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na(+), Ca(2+) and K(+) channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders. The primary goal of this review is to shed light on the recently observed clinically important cardiovascular effects of new antidepressants and antipsychotics and discuss the mechanism beyond this phenomenon.
Topics: Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Attitude to Health; Cardiovascular Diseases; Humans; Selective Serotonin Reuptake Inhibitors
PubMed: 15320756
DOI: 10.2174/1381612043383872 -
Neuroscience and Biobehavioral Reviews Jul 2013We conducted a meta-analysis of randomized, placebo-controlled trials to determine the efficacy of antipsychotic and alpha-2 agonists in the treatment of chronic tic... (Review)
Review
We conducted a meta-analysis of randomized, placebo-controlled trials to determine the efficacy of antipsychotic and alpha-2 agonists in the treatment of chronic tic disorders and examine moderators of treatment effect. Meta-analysis demonstrated a significant benefit of antipsychotics compared to placebo (standardized mean difference (SMD)=0.58 (95% confidence interval (CI): 0.36-0.80). Stratified subgroup analysis found no significant difference in the efficacy of the 4 antipsychotic agents tested (risperidone, pimozide, haloperidol and ziprasidone). Meta-analysis also demonstrated a benefit of alpha-2 agonists compared to placebo (SMD=0.31 (95% confidence interval CI: 0.15-0.48). Stratified subgroup analysis and meta-regression demonstrated a significant moderating effect of co-occurring ADHD. Trials which enrolled subjects with tics and ADHD demonstrated a medium-to-large effect (SMD=0.68 (95%CI: 0.36-1.01) whereas trials that excluded subjects with ADHD demonstrated a small, non-significant benefit (SMD=0.15 (95%CI: -0.06 to 0.36). Our findings demonstrated significant benefit of both antipsychotics and alpha-2 agonists in treating tics but suggest alpha-2 agonists may have minimal benefit in tic patients without ADHD.
Topics: Adrenergic alpha-Agonists; Age Factors; Animals; Antidiarrheals; Attention Deficit Disorder with Hyperactivity; Clinical Trials as Topic; Humans; Meta-Analysis as Topic; PubMed; Tic Disorders
PubMed: 23099282
DOI: 10.1016/j.neubiorev.2012.09.008 -
British Journal of Pharmacology Oct 2010Glioblastoma treatment as now constituted offers increased survival measured in months over untreated patients. Because glioblastomas are active in synthesizing a... (Review)
Review
Glioblastoma treatment as now constituted offers increased survival measured in months over untreated patients. Because glioblastomas are active in synthesizing a bewildering variety of growth factors, a systematic approach to inhibiting these is being undertaken as treatment adjunct. The serotonin 7 receptor is commonly overexpressed in glioblastoma. Research documentation showing agonists at serotonin receptor 7 cause increased extracellular regulated kinase 1/2 activation, increased interleukin-6 synthesis, increased signal transducer and activator of transcription-3 activation, increased resistance to apoptosis and other growth enhancing changes in glioblastoma is reviewed in this paper. Because three drugs in wide use to treat thought disorders - paliperidone, pimozide and risperidone - are also potent and well-tolerated inhibitors at serotonin receptor 7, these drugs should be studied for growth factor deprivation in an adjunctive role in glioblastoma treatment.
Topics: Antipsychotic Agents; Chemotherapy, Adjuvant; Glioblastoma; Humans; Interleukin-6; Models, Biological; Receptors, Serotonin; Serotonin Antagonists; Signal Transduction
PubMed: 20880389
DOI: 10.1111/j.1476-5381.2010.00923.x -
Journal of Pain and Symptom Management Apr 1993Trigeminal neuralgia is not common, but is a debilitating pain syndrome. After the diagnosis is established, a stepwise approach to treatment is recommended....
Trigeminal neuralgia is not common, but is a debilitating pain syndrome. After the diagnosis is established, a stepwise approach to treatment is recommended. Carbamazepine is the drug of choice. When carbamazepine fails to relieve pain, baclofen and then phenytoin are used. A number of second-line drugs, such as clonazepam, divalproex sodium, chlorphenesine carbamate, and pimozide can also be tried. A large number of patients will respond to one or another drug or to a combination of two drugs. When medical treatment fails, several surgical procedures have been found to be effective. Percutaneous radiofrequency gangliolysis is the most widely used procedure with a high success rate. All surgical procedures must be performed by an experienced physician in order to achieve the lowest possible rate of serious complications.
Topics: Baclofen; Carbamazepine; Diagnosis, Differential; Humans; Phenytoin; Trigeminal Neuralgia
PubMed: 8326165
DOI: 10.1016/0885-3924(93)90143-j