The Experts below are selected from a list of 1902 Experts worldwide ranked by ideXlab platform
Leonard Amaral - One of the best experts on this subject based on the ideXlab platform.
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Thioridazine alters the cell envelope permeability of mycobacterium tuberculosis
Journal of Proteome Research, 2016Co-Authors: Jeroen De Keijzer, Leonard Amaral, Dick Van Soolingen, Arnout Mulder, Petra E W De Haas, Evy M Heerkens, Peter A Van VeelenAbstract:The increasing occurrence of multidrug resistant tuberculosis exerts a major burden on treatment of this infectious disease. Thioridazine, previously used as a neuroleptic, is active against extensively drug resistant tuberculosis when added to other second- and third-line antibiotics. By quantitatively studying the proteome of Thioridazine-treated Mycobacterium tuberculosis, we discovered the differential abundance of several proteins that are involved in the maintenance of the cell-envelope permeability barrier. By assessing the accumulation of fluorescent dyes in mycobacterial cells over time, we demonstrate that long-term drug exposure of M. tuberculosis indeed increased the cell-envelope permeability. The results of the current study demonstrate that Thioridazine induced an increase in cell-envelope permeability and thereby the enhanced uptake of compounds. These results serve as a novel explanation to the previously reported synergistic effects between Thioridazine and other antituberculosis drugs. ...
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Thioridazine Alters the Cell-Envelope Permeability of Mycobacterium tuberculosis
2016Co-Authors: Jeroen De Keijzer, Leonard Amaral, Dick Van Soolingen, Arnout Mulder, Evy M Heerkens, Petra E. W. De Haas, Peter A Van VeelenAbstract:The increasing occurrence of multidrug resistant tuberculosis exerts a major burden on treatment of this infectious disease. Thioridazine, previously used as a neuroleptic, is active against extensively drug resistant tuberculosis when added to other second- and third-line antibiotics. By quantitatively studying the proteome of Thioridazine-treated Mycobacterium tuberculosis, we discovered the differential abundance of several proteins that are involved in the maintenance of the cell-envelope permeability barrier. By assessing the accumulation of fluorescent dyes in mycobacterial cells over time, we demonstrate that long-term drug exposure of M. tuberculosis indeed increased the cell-envelope permeability. The results of the current study demonstrate that Thioridazine induced an increase in cell-envelope permeability and thereby the enhanced uptake of compounds. These results serve as a novel explanation to the previously reported synergistic effects between Thioridazine and other antituberculosis drugs. This new insight in the working mechanism of this antituberculosis compound could open novel perspectives of future drug-administration regimens in combinational therapy
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effect of Thioridazine stereoisomers on the drug accumulation of mouse lymphoma and human prostate cancer cell lines in vitro
in Vivo, 2013Co-Authors: Akos Csonka, Oliver Hendricks, Jette E Kristiansen, Jorn B Christensen, Leonard Amaral, Gabriella Spengler, Ana Martins, Imre OcsovszkiAbstract:Background: Cancer cells become refractory to chemotherapy as a consequence of their overexpression of multidrug transporters. Materials and Methods: The anticancer and multidrug resistance (MDR) reversal effects of the racemic form and the two enantiomers of thoridazine were investigated on a mouse T-lymphoma cell line over- expressing the ATP-binding cassette, subfamily-B (MDR/TAP), member 1 (ABCB1) transporter (also known as P-glycoprotein) and on human PC3 prostate cancer cell line by 3-(4.5-dimethylthiazolyl-2)-2.5-diphenyl tetrazolium bromide (MTT) assay. The modulation of ABCB1 transporter activity was studied by rhodamine123 accumulation, the apoptosis-inducing effect was investigated using fluorescein isothiocyanate (FITC)-labeled annexin V and propidium iodide. Results: The Thioridazine racemic and (+) and (-) enantiomers were similarly effective. Drug accumulation by MDR mouse T-lymphoma cells was moderately modified in the presence of Thioridazine derivatives. Thioridazine induced apoptosis of the MDR cancer cell line, but there was no significant apoptotic effect on the PC3 cell line. Conclusion: Apparently, the chirality of Thioridazine has no importance in the inhibition of MDR phenotype of cancer cells.
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potential therapy of multidrug resistant and extremely drug resistant tuberculosis with Thioridazine
in Vivo, 2012Co-Authors: Leonard Amaral, Joseph MolnarAbstract:Multidrug-resistant tuberculosis (MDRTB) infections that continue to increase in frequency globally have progressed to become extremely drug-resistant tuberculosis (XDRTB). The therapeutic problems associated with MDRTB pale in comparison to those for XDRTB where mortality is high. This mini-review highlights the evidence that supports the use of the phenothiazine neuroleptic Thioridazine for the therapy of XDRTB. Although Thioridazine does produce some serious side-effects, the poor prognosis associated with an XDRTB infection of a patient that presents with AIDS merits that the use of Thioridazine for therapy of XDRTB is seriously considered. A recommended protocol is presented.
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the antipsychotic Thioridazine shows promising therapeutic activity in a mouse model of multidrug resistant tuberculosis
PLOS ONE, 2010Co-Authors: Dick Van Soolingen, Leonard Amaral, Jakko Van Ingen, Rogelio Hernandezpando, Hector Fabio Bermudez Orozco, Diana Aguilar, Cecile Magisescurra, Martin J BoereeAbstract:Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobial drugs. Within this pharmacological class we selected Thioridazine, which is most efficacious and least toxic, when used as an antipsychotic drug. We tested Thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (-4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when Thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01). Thioridazine may represent an effective compound for treatment of susceptible and multidrug-resistant tuberculosis. The phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs.
Jette E Kristiansen - One of the best experts on this subject based on the ideXlab platform.
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phenothiazines as a solution for multidrug resistant tuberculosis from the origin to present
International Microbiology, 2015Co-Authors: Jette E Kristiansen, Somasish Ghosh Dastidar, Shauroseni Palchoudhuri, Oliver Hendricks, Jorn B ChristensenAbstract:Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. The phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds. Several phenothiazines awakened the interest among scientists to determine their antimycobacterial activity. Chlorpromazine, trifluoperazine, methdilazine and Thioridazine were found to have distinct antitubercular action. Thioridazine took the lead as researchers repeatedly claimed its potentiality. Although Thioridazine is known for its central nervous system and cardiotoxic side-effects, extensive and repeated in vitro and in vivo studies by several research groups revealed that a very small dose of Thioridazine is required to kill tubercle bacilli inside macrophages in the lungs, where the bacteria try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (–) Thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down Thioridazine and its (–) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease. [Int Microbiol 2015; 18(1):1-12]Keywords: Mycobacterium tuberculosis · phenotiazines · Thioridazine · tuberculosis
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differential effects of Thioridazine enantiomers on action potential duration in rabbit papillary muscle
European Journal of Pharmacology, 2015Co-Authors: Ask Schou Jensen, Jette E Kristiansen, Jorn B Christensen, Cristian Pablo Pennisi, Cristian Sevcencu, Johannes J StruijkAbstract:The antipsychotic drug Thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both Thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-Thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated Thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-Thioridazine, (-)-Thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (ΔΔ-APD90) was evaluated. Increasing concentrations of (+)-Thioridazine and the racemate caused significant dose-dependent ΔΔ-APD90 prolongation, while (-)-Thioridazine did not. At 0.5 and 2Hz pacing, (+)-Thioridazine caused 19.5% and 20.1% ΔΔ-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-Thioridazine caused 1.5% and 1.1%. The effect of (-)-Thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P<0.01 in all cases), and there was no significant difference between (-)-Thioridazine and control. The results of this study indicate that the APD prolonging effect of Thioridazine is primarily due to the (+)-Thioridazine enantiomer. If these results are valid in humans, (-)-Thioridazine may be a safer drug for treatment of multidrug-resistant tuberculosis and other microbes.
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differential effects of Thioridazine enantiomers on action potential duration in rabbit papillary muscle
European Journal of Pharmacology, 2015Co-Authors: Ask Schou Jensen, Jette E Kristiansen, Jorn B Christensen, Cristian Pablo Pennisi, Cristian Sevcencu, Johannes J StruijkAbstract:Abstract The antipsychotic drug Thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both Thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-Thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated Thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-Thioridazine, (−)-Thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (ΔΔ-APD 90 ) was evaluated. Increasing concentrations of (+)-Thioridazine and the racemate caused significant dose-dependent ΔΔ-APD 90 prolongation, while (−)-Thioridazine did not. At 0.5 and 2 Hz pacing, (+)-Thioridazine caused 19.5% and 20.1% ΔΔ-APD 90 prolongation, the racemate caused 8.0% and 12.9%, and (−)-Thioridazine caused 1.5% and 1.1%. The effect of (−)-Thioridazine on APD 90 was significantly less than that of the other drugs at both pacing rates ( P
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effect of Thioridazine stereoisomers on the drug accumulation of mouse lymphoma and human prostate cancer cell lines in vitro
in Vivo, 2013Co-Authors: Akos Csonka, Oliver Hendricks, Jette E Kristiansen, Jorn B Christensen, Leonard Amaral, Gabriella Spengler, Ana Martins, Imre OcsovszkiAbstract:Background: Cancer cells become refractory to chemotherapy as a consequence of their overexpression of multidrug transporters. Materials and Methods: The anticancer and multidrug resistance (MDR) reversal effects of the racemic form and the two enantiomers of thoridazine were investigated on a mouse T-lymphoma cell line over- expressing the ATP-binding cassette, subfamily-B (MDR/TAP), member 1 (ABCB1) transporter (also known as P-glycoprotein) and on human PC3 prostate cancer cell line by 3-(4.5-dimethylthiazolyl-2)-2.5-diphenyl tetrazolium bromide (MTT) assay. The modulation of ABCB1 transporter activity was studied by rhodamine123 accumulation, the apoptosis-inducing effect was investigated using fluorescein isothiocyanate (FITC)-labeled annexin V and propidium iodide. Results: The Thioridazine racemic and (+) and (-) enantiomers were similarly effective. Drug accumulation by MDR mouse T-lymphoma cells was moderately modified in the presence of Thioridazine derivatives. Thioridazine induced apoptosis of the MDR cancer cell line, but there was no significant apoptotic effect on the PC3 cell line. Conclusion: Apparently, the chirality of Thioridazine has no importance in the inhibition of MDR phenotype of cancer cells.
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a comparative analysis of in vitro and in vivo efficacies of the enantiomers of Thioridazine and its racemate
PLOS ONE, 2013Co-Authors: Jorn B Christensen, Somasish Ghosh Dastidar, Oliver Hendricks, Shawati Chaki, Sayanti Mukherjee, Ayan Das, Tapan Kumar Pal, Jette E KristiansenAbstract:A long list of chemotherapeutical drugs used in the treatment of the peripheral and the central nervous systems possess anti-microbial activity. Some of these neurotropic compounds are chiral, with the one stereo isomeric form exaggerating reduced neurotropism. This is the case for the levorotatory form of Thioridazine. The phenothiazine Thioridazine is an interesting compound, characterized by exhibiting a significant growth inhibiting activity on a wide array of micro-organisms. Thioridazine is characterized by another challenging feature, because the compound is concentrated in certain human tissue cells. The present study describes a comparative study of the two enantiomers as well as the racemic form of Thioridazine. The study exploits the stereochemical aspect and the in vitro and in vivo potential of these compounds, with a focus on the effects on gram negative organism Salmonella enterica serover Typhimurium. In summary, the results of this study yielded a significant antibacterial activity of all forms of Thioridazine, indicating the levorotatory (-)-form to be superior in terms of both its in vitro and in vivo efficacies.
Taeg Kyu Kwon - One of the best experts on this subject based on the ideXlab platform.
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nox4 mediated ros production induces apoptotic cell death via down regulation of c flip and mcl 1 expression in combined treatment with Thioridazine and curcumin
Redox biology, 2017Co-Authors: Seung Un Seo, Kyoungjin Min, Tae Hwan Kim, Dongeun Kim, Taeg Kyu KwonAbstract:Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, Thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with Thioridazine and curcumin induces apoptosis. Combined treatment with Thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with Thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, Thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus Thioridazine-treated cells. Combined treatment with curcumin and Thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in Thioridazine and curcumin-treated cells. Therefore, we demonstrated that Thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis.
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Thioridazine enhances sensitivity to carboplatin in human head and neck cancer cells through downregulation of c-FLIP and Mcl-1 expression
Cell Death & Disease, 2017Co-Authors: Jong-wook Park, Yung Hyun Choi, Young Sam Keum, Jin Won Hyun, Hyun Ho Park, Taeg Kyu KwonAbstract:Carboplatin is a less toxic analog of cisplatin, but carboplatin also has side effects, including bone marrow suppression. Therefore, to improve the capacity of the anticancer activity of carboplatin, we investigated whether combined treatment with carboplatin and Thioridazine, which has antipsychotic and anticancer activities, has a synergistic effect on apoptosis. Combined treatment with carboplatin and Thioridazine markedly induced caspase-mediated apoptosis in head and neck squamous cell carcinoma (AMC-HN4) cells. Combined treatment with carboplatin and Thioridazine induced downregulation of Mcl-1 and c-FLIP expression. Ectopic expression of Mcl-1 and c-FLIP inhibited carboplatin plus Thioridazine-induced apoptosis. We found that augmentation of proteasome activity had a critical role in downregulation of Mcl-1 and c-FLIP expression at the post-translational level in carboplatin plus Thioridazine-treated cells. Furthermore, carboplatin plus Thioridazine induced upregulation of the expression of proteasome subunit alpha 5 (PSMA5) through mitochondrial reactive oxygen species (ROS)-dependent nuclear factor E2-related factor 2 (Nrf2) activation. In addition, combined treatment with carboplatin and Thioridazine markedly induced apoptosis in human breast carcinoma (MDA-MB231) and glioma (U87MG) cells, but not in human normal mesangial cells and normal human umbilical vein cells (EA.hy926). Collectively, our study demonstrates that combined treatment with carboplatin and Thioridazine induces apoptosis through proteasomal degradation of Mcl-1 and c-FLIP by upregulation of Nrf2-dependent PSMA5 expression.
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antipsychotic agent Thioridazine sensitizes renal carcinoma caki cells to trail induced apoptosis through reactive oxygen species mediated inhibition of akt signaling and downregulation of mcl 1 and c flip l
Cell Death and Disease, 2014Co-Authors: Kyoungjin Min, Bo Ram Seo, Yong Chul Bae, Young Hyun Yoo, Taeg Kyu KwonAbstract:Thioridazine has been known as an antipsychotic agent, but it also has anticancer activity. However, the effect of Thioridazine on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization has not yet been studied. Here, we investigated the ability of Thioridazine to sensitize TRAIL-mediated apoptosis. Combined treatment with Thioridazine and TRAIL markedly induced apoptosis in various human carcinoma cells, including renal carcinoma (Caki, ACHN, and A498), breast carcinoma (MDA-MB231), and glioma (U251MG) cells, but not in normal mouse kidney cells (TMCK-1) and human normal mesangial cells. We found that Thioridazine downregulated c-FLIP(L) and Mcl-1 expression at the post-translational level via an increase in proteasome activity. The overexpression of c-FLIP(L) and Mcl-1 overcame Thioridazine plus TRAIL-induced apoptosis. We further observed that Thioridazine inhibited the Akt signaling pathway. In contrast, although other phosphatidylinositol-3-kinase/Akt inhibitors (LY294002 and wortmannin) sensitized TRAIL-mediated apoptosis, c-FLIP(L) and Mcl-1 expressions were not altered. Furthermore, Thioridazine increased the production of reactive oxygen species (ROS) in Caki cells, and ROS scavengers (N-acetylcysteine, glutathione ethyl ester, and trolox) inhibited Thioridazine plus TRAIL-induced apoptosis, as well as Akt inhibition and the downregulation of c-FLIP(L) and Mcl-1. Collectively, our study demonstrates that Thioridazine enhances TRAIL-mediated apoptosis via the ROS-mediated inhibition of Akt signaling and the downregulation of c-FLIP(L) and Mcl-1 at the post-translational level.
Claudia Busonero - One of the best experts on this subject based on the ideXlab platform.
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in silico screening for erα down modulators identifies Thioridazine as an anti proliferative agent in primary 4oh tamoxifen resistant and y537s erα expressing breast cancer cells
Cellular Oncology, 2018Co-Authors: Claudia Busonero, Stefano Leone, Fabrizio Bianchi, Filippo Acconcia, Fabrizio Bianchi, Filippo AcconciaAbstract:Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (ICI 182,780; ICI). Unfortunately, a high fraction of ET treated women relapses and becomes resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using modulation of the intracellular ERα content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells. We screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and Thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells. We found that mitoxantrone and Thioridazine induced ERα downmodulation and prevented MCF-7 BC cell proliferation. Interestingly, while mitoxantrone was found to be toxic for normal breast epithelial cells, Thioridazine showed a preferential activity towards BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα expressing BC cells. We suggest that modulation of the intracellular ERα concentration in BC cells can be exploited in in silico screens to identify anti-BC drugs and uncover a re-purposing opportunity for Thioridazine in the treatment of primary and metastatic ET resistant BCs.
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in silico screening for erα downmodulators identifies Thioridazine as an anti proliferative agent in primary 4oh tamoxifen resistant and y537s erα expressing breast cancer cells
bioRxiv, 2018Co-Authors: Claudia Busonero, Stefano Leone, Fabrizio Bianchi, Filippo AcconciaAbstract:Abstract Purpose Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI). Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ERα intracellular content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells. Methods We screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and Thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells. Results Mitoxantrone and Thioridazine induced ERα downmodulation and prevented MCF-7 cell proliferation. Interestingly, while mitoxantrone was toxic for normal breast cells, Thioridazine showed preferential activity toward BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells. Conclusions We suggest that the modulation of the ERα intracellular concentration in BC cells can also be robustly exploited in in silico screenings to identify anti-BC drugs and further demonstrate a re-purposing opportunity for Thioridazine in primary and metastatic ET-resistant BC treatment.
Marja Liisa Dahl - One of the best experts on this subject based on the ideXlab platform.
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Thioridazine steady state plasma concentrations are influenced by tobacco smoking and cyp2d6 but not by the cyp2c9 genotype
European Journal of Clinical Pharmacology, 2003Co-Authors: Roland Berecz, Alfredo De La Rubia, Pedro M Fernandezsalguero, Pedro Dorado, Marja Liisa DahlAbstract:Background Approximately 7% of Caucasians have genetically impaired activity of the cytochrome P450 enzyme CYP2D6 and are classified as poor metabolizers (PM). The disposition of Thioridazine has been related to the CYP2D6 phenotype. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and tobacco smoking on steady-state Thioridazine plasma levels.
