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Autophagy Nov 2021Increasing evidence suggests that induction of lethal macroautophagy/autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of...
Increasing evidence suggests that induction of lethal macroautophagy/autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of previous work, we demonstrate that pimozide and loperamide trigger an ATG5- and ATG7 (autophagy related 5 and 7)-dependent type of cell death that is significantly reduced with cathepsin inhibitors and the lipid reactive oxygen species (ROS) scavenger α-tocopherol in MZ-54 GBM cells. Global proteomic analysis after treatment with both drugs also revealed an increase of proteins related to lipid and cholesterol metabolic processes. These changes were accompanied by a massive accumulation of cholesterol and other lipids in the lysosomal compartment, indicative of impaired lipid transport/degradation. In line with these observations, pimozide and loperamide treatment were associated with a pronounced increase of bioactive sphingolipids including ceramides, glucosylceramides and sphingoid bases measured by targeted lipidomic analysis. Furthermore, pimozide and loperamide inhibited the activity of SMPD1/ASM (sphingomyelin phosphodiesterase 1) and promoted induction of lysosomal membrane permeabilization (LMP), as well as release of CTSB (cathepsin B) into the cytosol in MZ-54 wild-type (WT) cells. Whereas LMP and cell death were significantly attenuated in and knockout (KO) cells, both events were enhanced by depletion of the lysophagy receptor VCP (valosin containing protein), supporting a pro-survival function of lysophagy under these conditions. Collectively, our data suggest that pimozide and loperamide-driven autophagy and lipotoxicity synergize to induce LMP and cell death. The results also support the notion that simultaneous overactivation of autophagy and induction of LMP represents a promising approach for the treatment of GBM.: ACD: autophagic cell death; AKT1: AKT serine/threonine kinase 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; CERS1: ceramide synthase 1; CTSB: cathepsin B; CYBB/NOX2: cytochrome b-245 beta chain; ER: endoplasmatic reticulum; FBS: fetal bovine serum; GBM: glioblastoma; GO: gene ontology; HTR7/5-HT7: 5-hydroxytryptamine receptor 7; KD: knockdown; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAP: LC3-associated phagocytosis; LMP: lysosomal membrane permeabilization; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; RB1CC1: RB1 inducible coiled-coil 1; ROS: reactive oxygen species; RPS6: ribosomal protein S6; SMPD1/ASM: sphingomyelin phosphodiesterase 1; VCP/p97: valosin containing protein; WT: wild-type.
Topics: Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Brain Neoplasms; Cathepsins; Cell Death; Cell Line, Tumor; Ceramides; Gene Knockout Techniques; Glioblastoma; Humans; Lipid Metabolism; Loperamide; Lysosomes; Permeability; Pimozide; Proteome; Sphingomyelin Phosphodiesterase
PubMed: 33461384
DOI: 10.1080/15548627.2021.1874208 -
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 -
International Journal of Molecular... Jan 2021As hyperprolactinemia is observed in patients with bromocriptine‑resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine...
As hyperprolactinemia is observed in patients with bromocriptine‑resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase‑2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine‑resistant prolactinoma cells. A reduction in phospho‑STAT5, cyclin D1 and B‑cell lymphoma extra‑large (Bcl‑xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem‑like cells, and reduced the protein expression of the cancer stem cell markers, CD133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5‑knockdown primary culture cells of human bromocriptine‑resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. Collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl‑xL and STAT5/cyclin D1 signaling pathways.
Topics: Animals; Bromocriptine; Cell Line, Tumor; Cyclin D1; Humans; Mice; Mice, Nude; Pimozide; Pituitary Neoplasms; Prolactinoma; Rats; STAT5 Transcription Factor; Signal Transduction; Xenograft Model Antitumor Assays; bcl-X Protein
PubMed: 33155660
DOI: 10.3892/ijmm.2020.4784 -
PloS One 2020Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole...
Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy. Here, we investigated the possible involvement of P-glycoprotein (P-gp)-mediated interaction among these drugs, using in vitro methods. ATPase assay confirmed that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The maximum transport rate (Jmax) and half-saturation concentration (Kt) for the carrier-mediated transport estimated by means of pimozide efflux assay using P-gp-overexpressing LLC-GA5-CoL150 cells were 84.9 ± 8.9 pmol/min/mg protein, and 10.6 ± 4.7 μM, respectively. These results indicate that pimozide is a good P-gp substrate, and it appears to have the potential to cause drug-drug interactions in the digestive tract at clinically relevant gastrointestinal concentrations. Moreover, sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in LLC-GA5-CoL150 cells. Transport studies using Caco-2 cell monolayers were consistent with the results in LLC-GA5-CoL150 cells, and indicate that P-gp-mediated drug-drug interaction may occur in the gastrointestinal tract. Thus, P-gp inhibition by sertraline and/or aripiprazole may increase the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which is known to be associated with an increased risk of QT prolongation, a life-threatening side effect.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Aripiprazole; Biological Transport; Caco-2 Cells; Drug Interactions; Gastrointestinal Absorption; Humans; LLC-PK1 Cells; Pimozide; Sertraline; Swine
PubMed: 33119612
DOI: 10.1371/journal.pone.0232438 -
Blood Advances Oct 2020Whole genomic and transcriptomic analyses of MEITL revealed multiple potential therapeutic targets. Synergistic effects of pimozide and romidepsin are shown in a...
Whole genomic and transcriptomic analyses of MEITL revealed multiple potential therapeutic targets. Synergistic effects of pimozide and romidepsin are shown in a well-characterized MEITL PDX model.
Topics: Humans; Lymphoma, T-Cell
PubMed: 33017466
DOI: 10.1182/bloodadvances.2020001782 -
Cells Sep 2020Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of...
Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
Topics: Adenine; Animals; Antineoplastic Agents; Antipsychotic Agents; Autophagy; Autophagy-Related Protein 5; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Repositioning; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Microtubule-Associated Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Pimozide; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; RNA, Small Interfering; STAT3 Transcription Factor; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 32971907
DOI: 10.3390/cells9092141 -
Drug Metabolism and Disposition: the... Nov 2020Pimozide is a dopamine receptor antagonist indicated for the treatment of Tourette syndrome. Prior in vitro studies characterized dealkylation of pimozide to...
Pimozide is a dopamine receptor antagonist indicated for the treatment of Tourette syndrome. Prior in vitro studies characterized dealkylation of pimozide to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI) via CYP3A4 and, to a lesser extent, CYP1A2 as the only notable routes of pimozide biotransformation. However, drug-drug interactions between pimozide and CYP2D6 inhibitors and genotype-dependent effects have since been observed. To reconcile these incongruities between the prior in vitro and in vivo studies, we characterized two novel pimozide metabolites: 5-hydroxypimozide and 6-hydroxypimozide. Notably, 5-hydroxypimozide was the major metabolite produced by recombinant CYP2D6 (K ∼82 nM, ∼0.78 pmol/min per picomoles), and DHPBI was the major metabolite produced by recombinant CYP3A4 (apparent K ∼1300 nM, ∼2.6 pmol/min per picomoles). Kinetics in pooled human liver microsomes (HLMs) for the 5-hydroxylation (K ∼2200 nM, ∼59 pmol/min per milligram) and dealkylation (K ∼3900 nM, ∼600 pmol/min per milligram) reactions were also determined. Collectively, formation of DHPBI, 5-hydroxypimozide, and 6-hydroxypimozide accounted for 90% of pimozide depleted in incubations of NADPH-supplemented pooled HLMs. Studies conducted in HLMs isolated from individual donors with specific cytochrome P450 isoform protein abundances determined via mass spectrometry revealed that 5-hydroxypimozide ( = 0.94) and 6-hydroxypimozide ( = 0.86) formation rates were correlated with CYP2D6 abundance, whereas the DHPBI formation rate ( = 0.98) was correlated with CYP3A4 abundance. Furthermore, the HLMs differed with respect to their capacity to form 5-hydroxypimozide relative to DHPBI. Collectively, these data confirm a role for CYP2D6 in pimozide clearance via 5-hydroxylation and provide an explanation for a lack of involvement when only DHPBI formation was monitored in prior in vitro studies. SIGNIFICANCE STATEMENT: Current genotype-guided dosing information in the pimozide label is discordant with available knowledge regarding the primary biotransformation pathways. Herein, we characterize the CYP2D6-dependent biotransformation of pimozide to previously unidentified metabolites. In human liver microsomes, formation rates for the novel metabolites and a previously identified metabolite were determined to be a function of CYP2D6 and CYP3A4 content, respectively. These findings provide a mechanistic basis for observations of genotype-dependent pimozide clearance in vivo.
Topics: Adult; Aged; Antipsychotic Agents; Biotransformation; Child; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Drug Interactions; Female; Humans; Male; Microsomes, Liver; Middle Aged; Pimozide; Recombinant Proteins; Tourette Syndrome; Young Adult
PubMed: 32847865
DOI: 10.1124/dmd.120.000188 -
PloS One 2020Despite enzalutamide's efficacy in delaying the progression of metastatic castration-resistant prostate cancer (CRPC), resistance to this anti-androgen inevitably...
Despite enzalutamide's efficacy in delaying the progression of metastatic castration-resistant prostate cancer (CRPC), resistance to this anti-androgen inevitably occurs. Several studies have revealed that the signal transducer and activator of transcription (STAT) 5 plays a role in tumour progression and development of drug resistance such as enzalutamide. Data mining revealed heterogeneous expression of STAT5 in enzalutamide-treated mCRPC patients and enzalutamide-resistant prostate cancer (PCa). Isobologram analysis revealed that the STAT5 inhibitor pimozide combined with enzalutamide has? additive and synergistic inhibitory effects on cell viability in the used models. Functional analysis with siRNA-mediated STAT5 knockdown yielded divergent results. The LNCaP-derived cell line MR49F could be resensitised to enzalutamide by siRNA-mediated STAT5b-knock-down. In contrast, neither STAT5a nor STAT5b knockdown resensitised enzalutamide-resistant LAPC4-EnzaR cells to enzalutamide. In conclusion, our results indicate that STAT5 may be a possible target in a subgroup of enzalutamide-resistant PCa. However, based on the data presented here, a general role of STAT5 in enzalutamide-resistance and its potential as a therapeutic target could not be shown.
Topics: Antineoplastic Agents; Benzamides; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; STAT5 Transcription Factor; Tumor Suppressor Proteins
PubMed: 32790723
DOI: 10.1371/journal.pone.0237248 -
Cureus Jun 2020Neurotic or psychogenic excoriation (PE) is one of the most commonly diagnosed skin disorders associated with a primary psychiatric condition. PE is characterized by...
Neurotic or psychogenic excoriation (PE) is one of the most commonly diagnosed skin disorders associated with a primary psychiatric condition. PE is characterized by excessive picking and scratching of normal-appearing skin, and is often comorbid or is an inherent manifestation of affective disturbance and psychosis itself in schizophrenia. Evidence in the literature has demonstrated the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRI) in treating PE. Other pharmacological treatments that have shown therapeutic benefits in case reports include doxepin, clomipramine, naltrexone, pimozide, and olanzapine. However, using adjunct therapeutic methods or augmentation in the treatment of neurogenic excoriation in the setting of schizophrenia is still not well explored. In this study, we discuss the case of a 59-year-old medically complex paraplegic male with schizophrenia comorbid with severe refractory PE. The patient had poor adherence to psychopharmacological treatment. Consequently, the patient was repeatedly hospitalized due to acute exacerbations of schizophrenic episodes and self-mutilation due to PE. After several failed treatment approaches, olanzapine 10 mg PO BID was added as an adjunct therapy to the Haldol® Decanoate (Janssen Pharmaceutica, Beerse, Belgium) at a dosage of 100 mg/month intramuscularly to control the acute PE symptoms. This treatment modality proved successful in this case, and the patient has been free from PE relapse for over one year of close follow-up. Olanzapine along with Haldol Decanoate long-acting injectable (LAI), might, therefore, be a useful adjunct therapeutic modality for patients with refractory PE with a comorbid diagnosis of schizophrenia and warrants further research.
PubMed: 32742822
DOI: 10.7759/cureus.8772 -
Indian Dermatology Online Journal 2020Psychodermatological (PD) conditions encountered in dermatologic practice include primary psychiatric conditions such as delusions of parasitosis or secondary... (Review)
Review
Psychodermatological (PD) conditions encountered in dermatologic practice include primary psychiatric conditions such as delusions of parasitosis or secondary psychiatric conditions such as anxiety and depression due to dermatologic disease. The psychotropics include antipsychotic agents, anti-anxiety agents, antidepressants, and miscellaneous drugs such as anti convulsants. Anti psychotics are further divided into first-generation and second-generation drugs. Currently, second-generation drugs e.g., risperidone are preferred over first-generation drugs e.g., pimozide in delusional infestation owing to the side effect profile of the latter. Anti-anxiety agents include benzodiazepines used in acute anxiety and buspirone in chronic anxiety disorders. They are frequently prescribed along with antidepressants. Although dependence and necessity of tapering is a problem with benzodiazepines, delayed onset of action is a feature of buspirone. The commonly used antidepressants in dermatology include selective serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), selective serotonin norepinephrine reuptake inhibitors (venlafaxine, desvenlefaxine, and duloxetine), norepinephrine dopamine reuptake inhibitors (bupropion), tricyclic antidepressants (doxepin, amitriptyline, imipramine, and clomipramine), and tetracyclic antidepressants (mirtazapine). Miscellaneous drugs include anticonvulsants such as gabapentin and pregabalin, naltrexone, and N-acetyl cysteine. The principles of PD treatment are first establish the psychiatric diagnosis, followed by initiating drug treatment. The choice of drugs is dependent on multiple factors such as side-effect profile, drug interactions, and co-morbid conditions. Usually, drugs are started at a low dose and gradually increased. A literature search was done in Pubmed, Google Scholar, and Medline databases, and articles on treatment were analyzed.
PubMed: 32695685
DOI: 10.4103/idoj.IDOJ_330_19