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PloS One 2020Drug repurposing is an attractive and pragmatic way offering reduced risks and development time in the complicated process of drug discovery. In the past, drug...
Drug repurposing is an attractive and pragmatic way offering reduced risks and development time in the complicated process of drug discovery. In the past, drug repurposing has been largely accidental and serendipitous. The most successful examples so far have not involved a systematic approach. Nowadays, remarkable advances in drugs, diseases and bioinformatic knowledge are offering great opportunities for designing novel drug repurposing approach through comprehensive understanding of drug information. In this study, we introduced a novel drug repurposing approach based on transcriptomic data and chemical structures using deep learning. One strong candidate for repurposing has been identified. Pimozide is an anti-dyskinesia agent that is used for the suppression of motor and phonic tics in patients with Tourette's Disorder. However, our pipeline proposed it as a strong candidate for treating non-small cell lung cancer. The cytotoxicity of pimozide against A549 cell lines has been validated.
Topics: A549 Cells; Carcinoma, Non-Small-Cell Lung; Computational Biology; Deep Learning; Drug Discovery; Drug Repositioning; Gene Expression Profiling; Humans; Pimozide; Transcriptome
PubMed: 32525938
DOI: 10.1371/journal.pone.0233112 -
BioRxiv : the Preprint Server For... Jul 2020Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease...
Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (M). Of these tested small molecule medicines, six displayed an IC value in inhibiting M below 100 μM. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-2 entry into the human cell host and inhibiting M in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS-CoV-2 in Vero E6 cells completely at and dose-dependently below 5 μM and in A549 cells completely at and dose-dependently below 6.25 μM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.
PubMed: 32511370
DOI: 10.1101/2020.05.23.112235 -
Cancers Apr 2020Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most...
Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, V617F or mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, = 10), essential thrombocythemia (ET, = 15) and primary myelofibrosis (PMF, = 9), and in the V617F-positive cell lines HEL and SET-2. As assessed by immunohistochemistry, MPN cells displayed pSTAT5 in all patients examined. Phosphorylated STAT5 was also detected in putative CD34/CD38 MPN stem cells (MPN-SC) by flow cytometry. Immunostaining experiments and Western blotting demonstrated pSTAT5 expression in both the cytoplasmic and nuclear compartment of MPN cells. Confirming previous studies, we also found that JAK2-targeting drugs counteract the expression of pSTAT5 and growth in HEL and SET-2 cells. Growth-inhibition of MPN cells was also induced by the STAT5-targeting drugs piceatannol, pimozide, AC-3-019 and AC-4-130. Together, we show that CD34/CD38 MPN-SC express pSTAT5 and that pSTAT5 is expressed in the nuclear and cytoplasmic compartment of MPN cells. Whether direct targeting of pSTAT5 in MPN-SC is efficacious in MPN patients remains unknown.
PubMed: 32326377
DOI: 10.3390/cancers12041021 -
Cell Metabolism May 2020Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism...
Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.
Topics: Animals; Diet; Hyperglycemia; Hypoglycemic Agents; Ketones; Male; Mice; Muscle, Skeletal; Obesity; Oxidation-Reduction; Pimozide; Streptozocin
PubMed: 32275862
DOI: 10.1016/j.cmet.2020.03.017 -
Translational Pediatrics Feb 2020Tourette's disorder (TD) is one of the five American Psychiatric Association's 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifications of tic... (Review)
Review
Tourette's disorder (TD) is one of the five American Psychiatric Association's 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifications of tic disorders. Eponymously linked with the noted 19th century French physician, Gilles de la Tourette [1857-1904], this disorder is identified in 0.3% to 0.7% of the population. It is characterized as a familial neuropsychiatric condition with multiple motor tics and vocal tics (one or more) present for more than 1 year with varying severity. The underlying pathophysiology involves dysfunctional activity of the basal ganglia and circuitry of the frontal cortex as well as dorsolateral striatum deficits. Contributory factors include genetic features interacting with milieu influences. A number of comorbid disorders are seen including obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). Concepts of management are considered including behavioral therapy and pharmacologic approaches with alpha-adrenoceptor agonists, atypical antipsychotics (AAs), haloperidol, pimozide and others. Other management includes botulinum injections and deep brain stimulation in adults.
PubMed: 32206587
DOI: 10.21037/tp.2019.09.11 -
Cancer Biology & Therapy Jun 2020Triple-negative breast cancer (TNBC) displays an aggressive clinical course, heightened metastatic potential, and is linked to poor survival rates. Through its lack of...
Triple-negative breast cancer (TNBC) displays an aggressive clinical course, heightened metastatic potential, and is linked to poor survival rates. Through its lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), this subtype remains unresponsive to traditional targeted therapies. Undesirable and sometimes life-threatening side effects associated with current chemotherapeutic agents warrant the development of more targeted treatment options. Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor implicated in breast cancer (BCa) progression, has proven to be an efficient approach to halt cancer growth and . Currently, there are no FDA-approved STAT3 inhibitors for TNBC. Although pimozide, a FDA-approved antipsychotic drug, has been attributed a role as a STAT3 inhibitor in several cancers, its role on this pathway remains unexplored in TNBC. As a "one size fits all" approach cannot be applied to TNBC therapies due to the heterogeneous nature of this aggressive cancer, we hypothesized that STAT3 could be a novel biomarker of response to guide pimozide therapy. Using human cell lines representative of four TNBC subtypes (basal-like 1, basal-like 2, mesenchymal-like, mesenchymal stem-like), our current report demonstrates that pimozide significantly reduced their invasion and migration, an effect that was predicted by STAT3 phosphorylation on tyrosine residue 705 (Tyr705). Mechanistically, phosphorylated STAT3 (Tyr705) inhibition resulting from pimozide treatment caused a downregulation of downstream transcriptional targets such as matrix metalloproteinase-9 (MMP-9) and vimentin, both implicated in invasion and migration. The identification of biomarkers of response to TNBC treatments is an active area of research in the field of precision medicine and our results propose phosphorylated STAT3 (Tyr705) as a novel biomarker to guide pimozide treatment as an inhibitor of invasion and migration.
Topics: Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Dopamine Antagonists; Female; Humans; Phosphorylation; Pimozide; STAT3 Transcription Factor; Triple Negative Breast Neoplasms; Tumor Cells, Cultured
PubMed: 32164483
DOI: 10.1080/15384047.2020.1726718 -
Cell Death & Disease Feb 2020Osteosarcoma (OS) is the most common primary bone tumor that primarily affects children and adolescents. Studies suggested that dysregulation JAK/STAT signaling promotes...
Osteosarcoma (OS) is the most common primary bone tumor that primarily affects children and adolescents. Studies suggested that dysregulation JAK/STAT signaling promotes the development of OS. Cells treated with pimozide, a STAT5 inhibitor suppressed proliferation and colony formation and induced sub G0/G1 cell cycle arrest and apoptosis. There was a reduction in cyclin D1 and CDK2 expression and Rb phosphorylation, and activation of Caspase-3 and PARP cleavage. In addition, pimozide suppressed the formation of 3-dimensional osteospheres and growth of the cells in the Tumor in a Dish lung organoid system. Furthermore, there was a reduction in expression of cancer stem cell marker proteins DCLK1, CD44, CD133, Oct-4, and ABCG2. More importantly, it was the short form of DCLK1 that was upregulated in osteospheres, which was suppressed in response to pimozide. We further confirmed by flow cytometry a reduction in DCLK1+ cells. Moreover, pimozide inhibits the phosphorylation of STAT5, STAT3, and ERK in OS cells. Molecular docking studies suggest that pimozide interacts with STAT5A and STAT5B with binding energies of -8.4 and -6.4 Kcal/mol, respectively. Binding was confirmed by cellular thermal shift assay. To further understand the role of STAT5, we knocked down the two isoforms using specific siRNAs. While knockdown of the proteins did not affect the cells, knockdown of STAT5B reduced pimozide-induced necrosis and further enhanced late apoptosis. To determine the effect of pimozide on tumor growth in vivo, we administered pimozide intraperitoneally at a dose of 10 mg/kg BW every day for 21 days in mice carrying KHOS/NP tumor xenografts. Pimozide treatment significantly suppressed xenograft growth. Western blot and immunohistochemistry analyses also demonstrated significant inhibition of stem cell marker proteins. Together, these data suggest that pimozide treatment suppresses OS growth by targeting both proliferating cells and stem cells at least in part by inhibiting the STAT5 signaling pathway.
Topics: Animals; Apoptosis; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Humans; Neoplastic Stem Cells; Osteosarcoma; Pimozide; STAT5 Transcription Factor; Signal Transduction; Tumor Suppressor Proteins
PubMed: 32094348
DOI: 10.1038/s41419-020-2335-1 -
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 -
Scientific Reports Jan 2020Induction of autophagy can have beneficial effects in several human diseases, e.g. cancer and neurodegenerative diseases (ND). Here, we therefore evaluated the potential...
Induction of autophagy can have beneficial effects in several human diseases, e.g. cancer and neurodegenerative diseases (ND). Here, we therefore evaluated the potential of two novel autophagy-inducing compounds, i.e. STF-62247 and pimozide, to stimulate autophagy as well as autophagic cell death (ACD) using mouse embryonic fibroblasts (MEFs) as a cellular model. Importantly, both STF-62247 and pimozide triggered several hallmarks of autophagy in MEFs, i.e. enhanced levels of LC3B-II protein, its accumulation at distinct cytosolic sites and increase of the autophagic flux. Intriguingly, autophagy induction by STF-62247 and pimozide resulted in cell death that was significantly reduced in ATG5- or ATG7-deficient MEFs. Consistent with ACD induction, pharmacological inhibitors of apoptosis, necroptosis or ferroptosis failed to protect MEFs from STF-62247- or pimozide-triggered cell death. Interestingly, at subtoxic concentrations, pimozide stimulated fragmentation of the mitochondrial network, degradation of mitochondrial proteins (i.e. mitofusin-2 and cytochrome c oxidase IV (COXIV)) as well as a decrease of the mitochondrial mass, indicative of autophagic degradation of mitochondria by pimozide. In conclusion, this study provides novel insights into the induction of selective autophagy as well as ACD by STF-62247 and pimozide in MEFs.
Topics: Animals; Autophagic Cell Death; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Cell Line; Fibroblasts; Gene Knockout Techniques; Mice; Mitochondrial Proteins; Models, Biological; Pimozide; Proteolysis; Pyridines; Thiazoles
PubMed: 31959760
DOI: 10.1038/s41598-019-56990-y