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Science Advances Oct 2023Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed...
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Topics: Humans; Glioblastoma; Trifluoperazine; Brain Neoplasms; Temozolomide; Chemoradiotherapy; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37878712
DOI: 10.1126/sciadv.adf1332 -
MBio Mar 2020Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier...
Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.
Topics: Amoxapine; Animals; Clostridioides difficile; Clostridium Infections; Doxapram; Drug Repositioning; Female; Immunity, Innate; Immunomodulation; Male; Mice; Mice, Inbred C57BL; Microbiota; RNA-Seq; Specific Pathogen-Free Organisms; Trifluoperazine
PubMed: 32156806
DOI: 10.1128/mBio.00053-20 -
PLoS Computational Biology Oct 2022Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many...
Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many downstream physiological responses, including muscle contraction, learning and depression. The antipsychotic drug trifluoperazine (TFP) is a known CaM inhibitor. By binding to various sites, TFP prevents CaM from associating to target-proteins. However, the molecular and state-dependent mechanisms behind CaM inhibition by drugs such as TFP are largely unknown. Here, we build a Markov state model (MSM) from adaptively sampled molecular dynamics simulations and reveal the structural and dynamical features behind the inhibitory mechanism of TFP-binding to the C-terminal domain of CaM. We specifically identify three major TFP binding-modes from the MSM macrostates, and distinguish their effect on CaM conformation by using a systematic analysis protocol based on biophysical descriptors and tools from machine learning. The results show that depending on the binding orientation, TFP effectively stabilizes features of the calcium-unbound CaM, either affecting the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the bound domain. The conclusions drawn from this work may in the future serve to formulate a complete model of pharmacological modulation of CaM, which furthers our understanding of how these drugs affect signaling pathways as well as associated diseases.
Topics: Calmodulin; Trifluoperazine; Antipsychotic Agents; Calcium; Protein Binding; Binding Sites
PubMed: 36206305
DOI: 10.1371/journal.pcbi.1010583 -
Archives of Virology Nov 2022Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the...
Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the increased incidence of DENV infection, there are no antiviral drugs available for treatment or prevention. Phenothiazines are heterocyclic compounds with various pharmacological properties that are very adaptable for drug repurposing. In the present report, we analyzed the antiviral activity against DENV and the related Zika virus (ZIKV) of trifluoperazine (TFP), a phenothiazine derivative in clinical use as an antipsychotic and antiemetic agent. TFP exhibited dose-dependent inhibitory activity against the four DENV serotypes and ZIKV in monkey Vero cells at non-cytotoxic concentrations with 50% effective concentration values in the range 1.6-6.4 µM. A similar level of antiviral efficacy was exhibited by TFP against flavivirus infection in the human cell lines A549 and HepG2. Mechanistic studies, performed using time-dependent infectivity assays, real-time RT-PCR, Western blot, and immunofluorescence techniques, indicated that uncoating of the virus during penetration into the cell was the main target for TFP in infected cells, but the compound also exerted a minor effect on a late stage of the virus multiplication cycle. This study demonstrates that TFP, a pharmacologically active phenothiazine, is a selective inhibitor of DENV multiplication in cell culture. Our findings open perspectives for the repositioning of phenothiazines like TFP with a wide spectrum of antiviral efficacy as potential agents for the control of pathogenic flaviviruses.
Topics: Animals; Antiemetics; Antipsychotic Agents; Antiviral Agents; Chlorocebus aethiops; Dengue; Dengue Virus; Humans; Phenothiazines; Trifluoperazine; Vero Cells; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 35920983
DOI: 10.1007/s00705-022-05555-y -
Molecular Pharmacology 2015Because cancer cell invasion is a critical determinant of metastasis, targeting invasion is a viable approach to prevent metastasis. Utilizing a novel three-dimensional...
Because cancer cell invasion is a critical determinant of metastasis, targeting invasion is a viable approach to prevent metastasis. Utilizing a novel three-dimensional high-throughput invasion assay, we screened a National Cancer Institute compound library and discovered compounds demonstrating inhibitory effects on cancer cell invasion. One hit, trifluoperazine, suppresses invasion of human cancer cell lines while displaying a limited cytotoxicity profile. This inhibition is due to the interference with cancer cell migratory ability but not proteolytic activity. Treatment of cancer cells with trifluoperazine significantly reduces angiogenesis and prevents cancer cell invasion through a chorioallantoic basement membrane. Mechanistically, treatment results in decreased phosphorylated AKT (Ser(473) and Thr(308)) and β-catenin (Ser(552)). Lack of phosphorylation of Ser(552) of β-catenin prevents β-catenin nuclear relocation, resulting in decreased expression of vascular endothelial growth factor, likely mediated through dopamine receptor D2. Taken together, we demonstrated that trifluoperazine is responsible for reducing the angiogenic and invasive potential of aggressive cancer cells through dopamine receptor D2 to modulate the β-catenin pathway and propose that trifluoperazine may be used as an antimetastasis chemotherapeutic.
Topics: Animals; Antineoplastic Agents; Antipsychotic Agents; Cell Line, Tumor; Chick Embryo; Human Umbilical Vein Endothelial Cells; Humans; Mice; NIH 3T3 Cells; Neoplasm Invasiveness; Trifluoperazine
PubMed: 25552486
DOI: 10.1124/mol.114.096941 -
The Cochrane Database of Systematic... Jun 2011Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment.
OBJECTIVES
To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders.
SEARCH STRATEGY
We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data.
SELECTION CRITERIA
Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment.
DATA COLLECTION AND ANALYSIS
Working independently, we critically appraised records from 681studies, of which five studies met inclusion criteria. John Rathbone from the Schizophrenia Group supported us with the data extraction. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate.
MAIN RESULTS
Five studies with a combined N = 998 met inclusion criteria. Four studies (N = 724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs N = 353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT N = 240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT N = 236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT N = 94, RR 0.96 CI 0.3 to 3.6). Two studies (Cole 1964; May 1976) contributed data to assessment of side effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. Rappaport 1978 suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (N = 80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison, as this difference becomes non-significant in a sensitivity analysis on intent-to-treat participants (N = 127, RR 1.69 CI 0.9 to 3.0). One study (May 1976) contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (N = 92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One study (Mosher 1995) contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (N = 89, MD 0.01 CI -0.6 to 0.6) and global improvement (N = 89, MD -0.03 CI -0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria.
AUTHORS' CONCLUSIONS
With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia.
Topics: Antipsychotic Agents; Chlorpromazine; Fluphenazine; Humans; Patient Dropouts; Randomized Controlled Trials as Topic; Schizophrenia; Thioridazine; Trifluoperazine
PubMed: 21678355
DOI: 10.1002/14651858.CD006374.pub2 -
FEBS Letters Nov 1983Trifluoperazine, chlorpromazine and other drugs known to inhibit calmodulin-dependent processes are also known to inhibit protein kinase C. The effect of these agents on...
Trifluoperazine, chlorpromazine and other drugs known to inhibit calmodulin-dependent processes are also known to inhibit protein kinase C. The effect of these agents on secretion evoked by known activators of C-kinase has been studied in human platelets loaded with the fluorescent Ca indicator, quin2 and preincubated with aspirin. The secretory response stimulated by phorbol ester and exogenous diacylglycerol, at basal levels of cytoplasmic free Ca2+, [Ca2+]i, was suppressed by trifluoperazine, chlorpromazine and W-7, as was the secretion evoked by collagen that occurs without a change in [Ca2+]i. The response to thrombin, which is accompanied by elevated [Ca2+]i was barely affected. Modest elevation of [Ca2+]i by Ca ionophore was able to overcome the inhibitory effect of these drugs on the response to phorbol ester, diacylglycerol, and collagen.
Topics: Blood Platelets; Calcimycin; Calcium; Chlorpromazine; Collagen; Enzyme Activation; Humans; Kinetics; Protein Kinase C; Protein Kinase Inhibitors; Tetradecanoylphorbol Acetate; Thrombin; Trifluoperazine
PubMed: 6228439
DOI: 10.1016/0014-5793(83)80015-5 -
International Journal of Molecular... Jun 2018The inhibition of mesangial cell (MC) proliferation has become an important therapy in preventing glomerular proliferation diseases. Trifluoperazine (TFP) has been...
Trifluoperazine induces apoptosis through the upregulation of Bax/Bcl‑2 and downregulated phosphorylation of AKT in mesangial cells and improves renal function in lupus nephritis mice.
The inhibition of mesangial cell (MC) proliferation has become an important therapy in preventing glomerular proliferation diseases. Trifluoperazine (TFP) has been reported to inhibit the proliferation of several types of cancer cell, however, the effects of TFP in renal proliferation diseases remain to be fully elucidated. The present study examined the effects of TFP on the proliferation of MCs and quantified cell apoptosis progression in vivo and in vitro. The effects of various TFP concentrations and treatment durations on cell proliferation and cell apoptosis in vitro were analyzed using flow cytometry in conjunction with a Cell Counting kit‑8 assay. Cell proliferation in vivo was determined using hematoxylin and eosin staining and immunohistochemistry of Ki67. The expression of the two cell apoptosis‑related proteins, B‑cell lymphoma-2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax), were estimated using western blot analysis and immunohistochemistry in vivo and in vitro. TFP‑induced phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathways were also estimated using western blot analysis. These results suggested that TFP inhibited MC proliferation in a dose‑ and time‑dependent manner. It was found that TFP inhibited the abnormal proliferation of MCs, which was stimulated by 20% fetal bovine serum in vitro and in lupus MRL/lpr mice. TFP promoted cell apoptosis, downregulated the expression of Bcl‑2 and upregulated the expression of Bax in a dose‑dependent manner at mRNA and protein levels. In addition, TFP inhibited phosphorylated AKT, potentially leading to the suppressed activation of PI3K/AKT signaling pathways. TFP treatment significantly decreased the levels of blood urea nitrogen and serum creatinine, but had no significant effects on the body weight and liver function of the lupus mice. These results validated and reinforced the potential of TFP in the treatment of mesangial proliferative diseases.
Topics: Animals; Apoptosis; Cell Proliferation; Female; Lupus Nephritis; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Trifluoperazine; bcl-2-Associated X Protein
PubMed: 29568865
DOI: 10.3892/ijmm.2018.3562 -
Progress in Biophysics and Molecular... 1984
Review
Topics: Actins; Adenosine Triphosphate; Animals; Calcium; Calmodulin; Cattle; Fishes; Magnesium; Magnetic Resonance Spectroscopy; Muscle Proteins; Myosins; Parvalbumins; Protein Binding; Protein Conformation; Rabbits; Trifluoperazine; Tropomyosin; Troponin; Troponin C
PubMed: 6377387
DOI: 10.1016/0079-6107(84)90005-1 -
The Tohoku Journal of Experimental... Jul 2022Multiple myeloma (MM) is a common hematological malignancy. Bortezomib (BTZ) is a traditional medicine for MM treatment, but there are limitations for current treatment...
Multiple myeloma (MM) is a common hematological malignancy. Bortezomib (BTZ) is a traditional medicine for MM treatment, but there are limitations for current treatment methods. Trifluoperazine (TFP) is a clinical drug for acute and chronic psychosis therapy. Lately, researchers have found that TFP can suppress tumor growth in many cancers. We attempted to study the effects of BTZ and TFP on MM in vivo and in vitro. We concentrated on the individual and combined impact of BTZ and TFP on the proliferation and apoptosis of MM cells via Cell Counting kit-8 assay, EdU assay, western blot, and flow cytometry. We found that combination therapy has a strong synergistic impact on MM cells. Combination therapy could induce cell arrest during G2/M phase and induce apoptosis in MM cells. Meanwhile, BTZ combined with TFP could play a better role in the anti-MM effect in vivo through MM.1s xenograft tumor models. Furthermore, we explored the mechanism of TFP-induced apoptosis in MM, and we noticed that TFP might induce MM apoptosis by inhibiting p-P38 MAPK/NUPR1. In summary, our findings suggest that TFP could synergistically enhance the BTZ-induced anti-cancer effect in multiple myeloma, which might be a promising therapeutic strategy for MM treatment.
Topics: Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Bortezomib; Cell Line, Tumor; Cell Proliferation; Humans; Multiple Myeloma; Neoplasm Proteins; Trifluoperazine; p38 Mitogen-Activated Protein Kinases
PubMed: 35644544
DOI: 10.1620/tjem.2022.J044