-
Antimicrobial Agents and Chemotherapy Mar 1996Cryptococcus neoformans is an opportunistic fungal pathogen which becomes heavily melanized in the presence of phenolic substrates such as L-dopa. Various drugs are...
Cryptococcus neoformans is an opportunistic fungal pathogen which becomes heavily melanized in the presence of phenolic substrates such as L-dopa. Various drugs are known to bind to melanin with high affinity, including the antipsychotic agent trifluoperazine and the antimalarial agent chloroquine. We hypothesized that drugs which bind melanin may have different toxicities for melanized and nonmelanized C. neoformans cells. The effects of trifluoperazine and chloroquine or C. neoformans were determined by measuring cell viability after exposure to these drugs. Cell viability was measured by CFU determination and flow cytometry with propidium iodide staining. Melanized cells were more susceptible than nonmelanized cells to the fungicidal effects of trifluoperazine. Chloroquine had no fungicidal effect on either melanized or nonmelanized C. neoformans under the conditions studied. Flow cytometry of trifluoperazine-treated C. neoformans cells stained with the mitochondrial stain dihydrorhodamine 123 revealed fluorescence changes consistent with mitochondrial damage. Our results indicate that melanized and nonmelanized C. neoformans cells can differ in susceptibility to certain drugs and suggest that strategies which target melanin may be productive for antifungal-drug discovery.
Topics: Chloroquine; Cryptococcus neoformans; DNA, Fungal; Dopamine Agents; Dopamine Antagonists; Flow Cytometry; Levodopa; Melanins; Microbial Sensitivity Tests; Trifluoperazine
PubMed: 8851567
DOI: 10.1128/AAC.40.3.541 -
The AAPS Journal Jun 2018The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The... (Comparative Study)
Comparative Study
The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term. TFP fully inhibited growth of cells (I = 1) with an IC = 9887 nM. Near-maximum inhibition was achieved for GEM (I = 0.825) and PTX (I= 0.844) with an IC = 17.4 nM for GEM and IC = 7.08 nM for PTX. Estimates of an interaction term ψ revealed that the combination of TFP-GEM was apparently synergistic; close to additivity, the combination TFP-PTX was antagonistic. The interaction of GEM-PTX was additive, and TFP-GEM-PTX was synergistic but close to additive. The combination of TFP IC-GEM IC-PTX IC seemed optimal in producing inhibition of PANC-1 cells with an inhibitory effect of 82.1-90.2%. The addition of ψ terms to traditional interaction equations allows assessment of the degree of perturbation of assumed mechanisms.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Dose-Response Relationship, Drug; Drug Interactions; Humans; Inhibitory Concentration 50; Models, Biological; Neoplastic Stem Cells; Paclitaxel; Pancreatic Neoplasms; Trifluoperazine; Gemcitabine
PubMed: 29951754
DOI: 10.1208/s12248-018-0235-4 -
Biochimica Et Biophysica Acta.... May 2021Stroke is the second leading cause of death and the third leading cause of disability globally. Edema is a hallmark of stroke resulting from dysregulation of water...
Stroke is the second leading cause of death and the third leading cause of disability globally. Edema is a hallmark of stroke resulting from dysregulation of water homeostasis in the central nervous system (CNS) and plays the major role in stroke-associated morbidity and mortality. The overlap between cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema. Water balance in the brain is tightly regulated, primarily by aquaporin 4 (AQP4) channels, which are mainly expressed in perivascular astrocytic end-feet. Targeting AQP4 could be a useful therapeutic approach for treating brain edema; however, there is no approved drug for stroke treatment that can directly block AQP4. In this study, we demonstrate that the FDA-approved drug trifluoperazine (TFP) effectively reduces cerebral edema during the early acute phase in post-stroke mice using a photothrombotic stroke model. This effect was combined with an inhibition of AQP4 expression at gene and protein levels. Importantly, TFP does not appear to induce any deleterious changes on brain electrolytes or metabolic markers, including total protein or lipid levels. Our results support a possible role for TFP in providing a beneficial extra-osmotic effect on brain energy metabolism, as indicated by the increase of glycogen levels. We propose that targeting AQP4-mediated brain edema using TFP is a viable therapeutic strategy during the early and acute phase of stroke that can be further investigated during later stages to help in developing novel CNS edema therapies.
Topics: Animals; Aquaporin 4; Biomarkers; Brain; Disease Models, Animal; Glycogen; Male; Mice; Mice, Inbred BALB C; Protein Aggregates; Stroke; Trifluoperazine
PubMed: 33561476
DOI: 10.1016/j.bbamem.2021.183573 -
Molecular Pain Apr 2012Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p.,...
BACKGROUND
Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca(2+)/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca(2+) influx, in the oxaliplatin-induced mechanical allodynia in rats.
RESULTS
An increase of CaMKII phosphorylation was found in the spinal cord (L(4-6)) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.
CONCLUSIONS
These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.
Topics: Animals; Antipsychotic Agents; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Hyperalgesia; Male; Organoplatinum Compounds; Oxaliplatin; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Trifluoperazine
PubMed: 22510452
DOI: 10.1186/1744-8069-8-26 -
Journal of Molecular Medicine (Berlin,... May 2019Sepsis is a disease responsible for the death of almost all critical patients. Once infected by virus or bacteria, patients can die due to systemic inflammation within a...
Sepsis is a disease responsible for the death of almost all critical patients. Once infected by virus or bacteria, patients can die due to systemic inflammation within a short period of time. Cytokine storm plays an essential role in causing organ dysfunction and septic shock. Thus, inhibition of cytokine secretion is considered very important in sepsis therapy. In this study, we found that TFP, an antipsychotic drug mainly used to treat schizophrenia by suppressing dopamine secretion, inhibited cytokine release from activated immune cells both in vitro and in vivo. Trifluoperazine (TFP) decreased the levels of pro-inflammatory cytokines without altering their transcription level. In LPS-induced endotoxemia and cecal content injection (CCI) models, TFP intraperitoneal administration improved survival rate. Thus, TFP was considered to inhibit the secretion of proteins through a mechanism similar to that of W7, a calmodulin inhibitor. Finally, we confirmed that TFP treatment relieved organ damage by estimating the concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and blood urea nitrogen (BUN) in the serum. Our findings were regarded as a new discovery of the function of TFP in treating sepsis patients. KEY MESSAGES: • TFP inhibits LPS-induced activation of DCs by suppressing pro-inflammatory cytokine. • Treatment of TFP increases survival of LPS-induced endotoxemia and CCI sepsis models. • TFP exerted a protective effect against tissue or organ damage in animal models.
Topics: Animals; Anti-Inflammatory Agents; Antipsychotic Agents; Cells, Cultured; Cytokines; Drug Repositioning; Female; Lipopolysaccharides; Mice, Inbred C57BL; Sepsis; Trifluoperazine
PubMed: 30848296
DOI: 10.1007/s00109-019-01762-4 -
FEBS Open Bio Oct 2020Multiple myeloma (MM) is the second most common hematologic malignancy of immunoglobulin-secreting plasma cells. Recent modern combination therapies have improved...
Multiple myeloma (MM) is the second most common hematologic malignancy of immunoglobulin-secreting plasma cells. Recent modern combination therapies have improved survival rates, but many patients develop resistance to novel drugs, leading to relapse. Trifluoperazine (TFP), a typical antipsychotic drug, has been reported to exert antitumor effects by targeting various pathways. Thus far, the role of TFP in MM has not been elucidated. In the current study, we demonstrated that TFP inhibited cell growth and autophagy activity but induced apoptosis of U266 and RPMI 8226 MM cells. Furthermore, cotreatment of these cell lines with TFP and rapamycin, a potent autophagy inducer, reduced cell apoptosis compared with TFP treatment alone. We also found that TFP inhibited nuclear protein 1 (NUPR1) expression. In the presence of TFP, cells stably overexpressing NUPR1 showed a higher viability than cells treated with the nonspecific control. Autophagy suppression and apoptosis induction caused by TFP were also reversed in MM cells upon NUPR1 overexpression. Overall, our results indicate that in the context of MM, TFP targets NUPR1, inhibiting cell growth and inducing apoptosis by autophagy inhibition. Our results could contribute toward efforts for the development of more effective therapies for MM to be tested in future clinical trials.
Topics: Apoptosis; Autophagy; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle; Cell Line, Tumor; Cell Proliferation; China; Humans; Multiple Myeloma; Neoplasm Proteins; Sirolimus; Trifluoperazine
PubMed: 32810364
DOI: 10.1002/2211-5463.12960 -
Cellular Physiology and Biochemistry :... 2017The high potency antipsychotic drug trifluoperazine (10-[3-(4-methyl-1-piperazinyl)-propyl]-2-(trifluoromethyl)-(10)H-phenothiazine dihydrochloride; TFP) may either...
BACKGROUND AND PURPOSE
The high potency antipsychotic drug trifluoperazine (10-[3-(4-methyl-1-piperazinyl)-propyl]-2-(trifluoromethyl)-(10)H-phenothiazine dihydrochloride; TFP) may either counteract or promote suicidal cell death or apoptosis. Similar to apoptosis, erythrocytes may enter eryptosis, characterized by phosphatidylserine exposure at the cell surface and cell shrinkage. Eryptosis can be stimulated by an increase in cytoplasmic Ca2+ concentration ([Ca2+]i) and inhibited by nitric oxide (NO). We explored whether TFP treatment of erythrocytes induces phosphatidylserine exposure, cell shrinkage, and calcium influx, whether it impairs S-nitrosylation and whether these effects are inhibited by NO.
METHODS
Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, and protein nitrosylation from fluorescence switch of the Bodipy-TMR/Sypro Ruby signal.
RESULTS
Exposure of human erythrocytes to TFP significantly enhanced the percentage of annexin-V-binding cells, raised [Ca2+]i, and decreased S-nitrosylation. The effect of TFP on annexin-V-binding was not affected by removal of extracellular Ca2+ alone, but was significantly inhibited by pre-treatment with sodium nitroprusside (SNP), an effect significantly augmented by additional removal of extracellular Ca2+. A 3 hours treatment with 0.1 µM Ca2+ ionophore ionomycin triggered annexin-V-binding and cell shrinkage, effects fully reversed by removal of extracellular Ca2+.
CONCLUSIONS
TFP induces eryptosis and decreases protein S-nitrosylation, effects blunted by nitroprusside. The effect of nitroprusside is attenuated in the presence of extracellular Ca2+.
Topics: Action Potentials; Calcium; Cell Size; Eryptosis; Erythrocyte Membrane; Erythrocytes; Hemolysis; Humans; Ionomycin; Microscopy, Fluorescence; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Patch-Clamp Techniques; Phosphatidylserines; Protein Processing, Post-Translational; Trifluoperazine
PubMed: 28793283
DOI: 10.1159/000479838 -
Methods and Findings in Experimental... Dec 2000The influence of the calcium channel blockers (CCBs) nifedipine, verapamil and diltiazem, and the calmodulin antagonist trifluoperazine on the antinociceptive activity...
The influence of the calcium channel blockers (CCBs) nifedipine, verapamil and diltiazem, and the calmodulin antagonist trifluoperazine on the antinociceptive activity of acetaminophen was studied in male albino mice. The nociceptive response was determined by the acetic acid writhing test. Nifedipine (50 or 20 mg/kg), verapamil (20 mg/kg), diltiazem (70 mg/kg) and trifluoperazine (3 mg/kg) were administered orally alone or 1 h before acetaminophen (100 mg/kg). Nifedipine (50 mg/kg), verapamil, diltiazem and trifluoperazine administered alone demonstrated significant antinociceptive effects compared to controls. Nifedipine, verapamil, diltiazem and trifluoperazine applied 1 h before acetaminophen potentiated its antinociceptive activity, which was strongest in mice injected with verapamil and nifedipine (20 mg/kg). It was established that 1 h after nifedipine (50 mg/kg) treatment, cytochrome P450 content, NADPH cytochrome c reductase and ethylmorphine-N-demethylase (EMND) activities were increased in the liver microsomes. Verapamil, diltiazem and trifluoperazine did not change the drug metabolizing enzymes studied. It is assumed that their effect on acetaminophen analgesia is not associated with the changes in acetaminophen oxidative metabolism in the liver.
Topics: Acetaminophen; Analgesics; Analgesics, Non-Narcotic; Animals; Calcium Channel Blockers; Cell Fractionation; Diltiazem; Dopamine Antagonists; Drug Synergism; Liver; Male; Mice; Nifedipine; Pain Measurement; Trifluoperazine; Verapamil
PubMed: 11346895
DOI: 10.1358/mf.2000.22.10.802291 -
Biological & Pharmaceutical Bulletin 2016Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) and Aurantii Fructus Immaturus. The present study aims to investigate the...
Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) and Aurantii Fructus Immaturus. The present study aims to investigate the inhibition potential of HET and NGR derivatives towards one of the most important phase II drug-metabolizing enzymes-uridine diphosphate (UDP)-glucuronosyltransferases (UGTs). We used trifluoperazine as a probe substrate to test UGT1A4 activity, and recombinant UGT-catalyzed 4-methylumbelliferone glucuronidation was used as a probe reaction for other UGT isoforms. Data show that HET and NGR displayed broad-spectrum inhibition against human UGTs. Besides, HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC and K values lower than 10 µM), and the inhibitory effects of NGR against three major UGTs, including UGT1A1, 1A3 and 2B7. In a combination of inhibition parameters (K) and in vivo concentration of HET and NGR, the potential in vivo inhibition magnitude was predicted. Based on the reported maximum plasma concentration of HET and NGR in vivo, these findings indicate the potential herb-drug interactions (HDI) between HET or NGR and the drugs mainly undergoing UGT1A3 or UGT2B7 catalyzed metabolic elimination. Considering the variety of citrus that contains HET and NGR, so caution should be applied when taking drugs that utilize UGTs for metabolism and clearance with citrus fruits.
Topics: Animals; Cell Line; Citrus; Flavanones; Glucuronosyltransferase; Herb-Drug Interactions; Hesperidin; Humans; Hymecromone; Insecta; Recombinant Proteins; Trifluoperazine
PubMed: 27904048
DOI: 10.1248/bpb.b16-00581 -
The Biochemical Journal Jun 1981The possible involvement of calmodulin in insulin release was evaluated by studying the effects on intact islets of trifluoperazine and pimozide, two antipsychotic...
The possible involvement of calmodulin in insulin release was evaluated by studying the effects on intact islets of trifluoperazine and pimozide, two antipsychotic agents known to bind strongly to calmodulin in cell-free systems. Trifluoperazine (10-100mum) produced a dose- and time-dependent inhibition of the two phases of glucose-stimulated insulin release. The effect was not reversible by simple washing of the drug, but could be prevented by cytochalasin B or theophylline. Trifluoperazine also inhibited the release induced by glyceraldehyde, oxoisocaproate, tolbutamide or barium, but not that stimulated by 10mm-theophylline or 1mm-3-isobutyl-1-methylxanthine. Pimozide (0.5-10mum) also produced a dose-dependent inhibition of insulin release triggered by glucose, leucine or barium, but did not affect the release induced by methylxanthines. Glucose utilization by islet cells was not modified by trifluoperazine (25mum), which slightly increased cyclic AMP concentration in islets incubated without glucose. The drug did not prevent the increase in cyclic AMP concentration observed after 10min of glucose stimulation, but suppressed it after 60min. Basal or glucose-stimulated Ca(2+) influx (5min) was unaffected by 25mum-trifluoperazine, whereas Ca(2+)net uptake (60min) was inhibited by 20%. Glucose-stimulated Ca(2+) uptake was almost unaffected by pimozide. In a Ca(2+)-free medium, trifluoperazine decreased Ca(2+) efflux from the islets and did not prevent the further decrease by glucose; in the presence of Ca(2+), the drug again decreased Ca(2+) efflux and inhibited the stimulation normally produced by glucose. In the absence of glucose, trifluoperazine lowered the rate of Rb(+) efflux from the islets, decreased Rb(+) influx (10min), but did not affect Rb(+) net uptake (60min). It did not interfere with the ability of glucose to decrease Rb(+) efflux rate further and to increase Rb(+) net uptake. The results show thus that trifluoperazine does not alter the initial key events of the stimulus-secretion coupling. Its inhibition of insulin release suggests a role of calmodulin at late stages of the secretory process.
Topics: Animals; Calcium; Calcium-Binding Proteins; Calmodulin; Cyclic AMP; Depression, Chemical; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Male; Pimozide; Rats; Rats, Inbred Strains; Rubidium; Trifluoperazine
PubMed: 6274321
DOI: 10.1042/bj1960771