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Analytical Chemistry Oct 2023The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of...
The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of tumor-specific systems is highly desirable. In this work, a general design of tumor stimulus-activatable pretheranostic agents was put forward via a series of structures-tunable triphenylamine derivatives (, , and ) with phenothiazine, benzothiazine, and thiomorpholine as identifying groups of hypochlorite (HClO), respectively. Notably, the sulfur atom in phenothiazine of was more easily oxidized to sulfoxide groups by HClO, transforming into an electron acceptor to form an excellent push-pull electronic system, which was beneficial to a large redshift of absorbance and emission wavelengths. Based on this, resorted to a key of overexpressed HClO in the tumor to open "three locks", viz, NIR fluorescence, photothermal, and photoacoustic signals for multimodal diagnostic and treatment of the tumor. This study provided an elegant design to adopt tumor stimulus-triggerable pretheranostic for improving theranostic accuracy and efficiency, which was regarded as a promising candidate for precision medicine.
Topics: Humans; Neoplasms; Antineoplastic Agents; Phenothiazines; Theranostic Nanomedicine; Phototherapy; Nanoparticles
PubMed: 37824749
DOI: 10.1021/acs.analchem.3c02777 -
Neuroscience and Biobehavioral Reviews Oct 2022Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first... (Review)
Review
Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first phenothiazine antipsychotic, chlorpromazine, was found to inhibit cancer. During the years of elucidating the pharmacology of the phenothiazines, reserpine, an antipsychotic with a long historical background, was likewise discovered to have anti-cancer properties. Research on the effects of antipsychotics on cancer continued slowly until the 21st century when efforts to repurpose antipsychotics for cancer treatment accelerated. This review examines the history of these developments, and identifies which antipsychotics might treat cancer, and which cancers might be treated by antipsychotics. The review also describes the molecular mechanisms through which antipsychotics may inhibit cancer. Although the overlap of molecular pathways between schizophrenia and cancer have been known or suspected for many years, no comprehensive review of the subject has appeared in the psychiatric literature to assess the significance of these similarities. This review fills that gap and discusses what, if any, significance the similarities have regarding the etiology of schizophrenia.
Topics: Antipsychotic Agents; Chlorpromazine; Humans; Methylene Blue; Neoplasms; Phenothiazines; Reserpine; Schizophrenia
PubMed: 35970416
DOI: 10.1016/j.neubiorev.2022.104809 -
Veterinary Anaesthesia and Analgesia Mar 2021To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
OBJECTIVE
To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
STUDY DESIGN
Prospective, experimental study.
ANIMALS
Healthy, adult, mixed-breed dogs (two male and four female) weighing 16.8 ± 5.1 kg (mean ± standard deviation).
METHODS
Dogs were anesthetized with propofol (7 mg kg) intravenously (IV) and isoflurane. Thermodilution and arterial catheters were placed for hemodynamic monitoring and arterial blood sampling for blood gas analysis. Baseline measurements were performed with stable expired concentration of isoflurane (Fe'Iso) at 1.8%. Each dog was then administered four incremental acepromazine injections (10, 15, 25 and 50 μg kg) IV, and measurements were repeated 20 minutes after each acepromazine injection with Fe'Iso decreased to 1.2%. The four acepromazine injections resulted in cumulative doses of 10, 25, 50 and 100 μg kg (time points ACP, ACP, ACP and ACP, respectively).
RESULTS
Compared with baseline, cardiac index (CI) increased significantly by 34%, whereas systemic vascular resistance index (SVRI) decreased by 25% at ACP and ACP. Arterial oxygen content (CaO) was significantly lower than baseline after all acepromazine injections (maximum decreases of 11%) and was lower at ACP and ACP than at ACP. No significant change was found in heart rate, stroke index, oxygen delivery index and systolic, mean and diastolic blood pressures. Hypotension (mean arterial pressure < 60 mmHg) was observed in one dog at baseline, ACP, ACP and ACP, and in two dogs at ACP.
CONCLUSIONS AND CLINICAL RELEVANCE
Compared with isoflurane alone, anesthesia with acepromazine-isoflurane resulted in increased CI and decreased SVRI and CaO values. These effects were dose-related, being more pronounced at ACP and ACP. Under the conditions of this study, acepromazine administration did not change blood pressure.
Topics: Acepromazine; Animals; Blood Pressure; Cross-Over Studies; Dogs; Female; Heart Rate; Hemodynamics; Isoflurane; Male; Prospective Studies
PubMed: 33388251
DOI: 10.1016/j.vaa.2020.11.003 -
Cell Death & Disease Dec 2023Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the...
Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified the neuroleptic drug chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as one of the major targets of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug's ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared less responsive to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and thus malignancy in GBM cells, while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in a recent multicenter Phase II clinical trial.
Topics: Humans; Glioblastoma; Chlorpromazine; Pyruvate Kinase; Cell Line, Tumor; Energy Metabolism
PubMed: 38092755
DOI: 10.1038/s41419-023-06353-3 -
Chemosphere Aug 2021Wastewater treatment is the most serious problem in this upcoming era. A harmful effluent like organic dyes, heavy metals, acids from industries mixed in wastewater is...
Wastewater treatment is the most serious problem in this upcoming era. A harmful effluent like organic dyes, heavy metals, acids from industries mixed in wastewater is deteriorating the environment. To get rid of these poisonous materials and to recycle wastewater for domestic purposes, there are many steps which included photocatalytic dye degradation. PVP assisted Mn-CdS nanoparticles was prepared by novel hydrothermal technique. The characteristic behavior of pure and PVP (1% and 2%) assisted Mn-CdS samples were studied by further analysis. The structural, optical, vibrational, morphological, chemical composition behavior of synthesized pristine and surfactant induced Mn-CdS nanoparticles were analyzed. UV-Vis spectra revealed the optical behavior of the prepared pure and PVP (1% and 2%) assisted Mn-CdS samples. The bandgap obtained was 2.2, 2.06 and 1.99 eV for pure Mn-CdS, 1% PVP-Mn-CdS and 2% PVP- Mn-CdS. The narrow bandgap is one of the advantage of the material. Mn-CdS, 1% PVP-(Mn-CdS) and 2% PVP- (Mn-CdS) morphology were further investigated by Scanning Electron Microscopic studies (SEM). The surfactant (PVP) was added to enhance the morphology development and decrease agglomeration on the surface and the SEM images revealed a clear evidence for enhancement of morphology in all three samples. 2% PVP-(Mn-CdS) sample showed a good development in morphology when compared with other two samples and the best sample showed formation of nanorods below the surface of nanoparticles. Further, Mn-CdS, 1% PVP-(Mn-CdS) and 2% PVP- (Mn-CdS) was indulged to investigate the cationic degradation. The photocatalytic activities of three samples were carried out with loading different amount of the catalysts and 30 mg catalyst 2% PVP- (Mn-CdS) loaded dye solution showed a considerable degradation of methylene blue dye. The 30 mg catalyst (2% PVP-Mn-CdS) showed 98% efficiency under visible light irradiation for about 2 h. The best candidate, 30 mg catalyst (2% PVP-Mn-CdS) investigated for its reusability. The catalyst showed almost 98% of efficiency up to three cycles which confirmed the level of potential of the sample. 2% PVP-(Mn-CdS) sample would be promising candidate in wastewater treatment. It can be further utilized for removing dyes from wastewater in wastewater remediation process.
Topics: Catalysis; Coloring Agents; Light; Methylene Blue; Nanoparticles
PubMed: 33780675
DOI: 10.1016/j.chemosphere.2021.130346 -
Journal of B.U.ON. : Official Journal... 2020In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular... (Review)
Review
In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment - i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.
Topics: Dopamine Antagonists; Glioblastoma; Humans; Perphenazine
PubMed: 33099901
DOI: No ID Found -
Journal of Enzyme Inhibition and... Dec 2023Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming...
Antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants potently activate pharmacologically relevant human carbonic anhydrase isoforms II and VII.
Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming increasingly important in the biomedical field since enhancing CA activity may have beneficial effects at neurological level. Here, we investigate selected antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants (TCAs) as potential activators of human CAs I, II, IV, and VII. Our findings indicate that these compounds are more effective at activating hCA II and VII compared to hCA I and IV. Overall, hCA VII was the most efficiently activated isoform, particularly by phenothiazines and TCAs. This is especially relevant since hCA VII is the most abundant isoform in the central nervous system (CNS) and is implicated in neuronal signalling and bicarbonate balance regulation. This study offers additional insights into the pharmacological profiles of clinically employed drugs and sets the ground for the development of novel optimised CAAs.
Topics: Humans; Antipsychotic Agents; Antidepressive Agents, Tricyclic; Carbonic Anhydrases; Protein Isoforms; Phenothiazines; Histamine Antagonists; Carbonic Anhydrase Inhibitors; Structure-Activity Relationship; Molecular Structure
PubMed: 36912265
DOI: 10.1080/14756366.2023.2188147 -
Journal of Chromatography. A Aug 2023In this study, a simple, rapid, and ultrasensitive technique was developed to identify five pairs of phenothiazine drugs by using ultrasound-enhanced and...
Ultrasensitive determination of 10 phenothiazine derivatives and their enantiomers in biological fluids by capillary electrophoresis with contactless conductivity detection.
In this study, a simple, rapid, and ultrasensitive technique was developed to identify five pairs of phenothiazine drugs by using ultrasound-enhanced and surfactant-assisted dispersive liquid-liquid microextraction (UESA-DLLME), field-amplified sample injection with capillary electrophoresis (FASI-CE), and capacitively coupled capacitively coupled contactless conductivity detection (CD). During the CE separation process, UESA-DLLME was used for sample clean-up and offline concentration, and FASI-CE was used for the online concentration of phenothiazine enantiomers. At baseline, the five pairs of phenothiazine enantiomer drugs required 18 min for separation. UESA-DLLME was then used to extract 0.01 mM Tween 80 at pH 10 from a sample solution (extraction solvent, 100 mL of dichloromethane). Subsequently, FASI was used to stack the sample solution (buffer, 30 mM 2-(N-morpholino)ethanesulfonic acid/aspartic acid, additive 4 mM hydroxypropyl-γ-cyclodextrin, pH 2.5), and CD was used for signal detection (amplitude, 2 Vpp; frequency, 400 kHz). The results indicated that the linear range for quantifying all analyte enantiomers was 1.0-150 nM, with a coefficient of determination exceeding 0.99. In addition, the relative standard deviations in the migration time and peak areas for the 10 analytes were less than 3.2% and 7.2%, respectively. The proposed system has a limit of detection (LOD) for the 10 analytes at a signal-to-noise ratio of 3, ranging from 0.24 to 0.28 nM. The sensitivity enhancement, which compares the LOD (limit of detection in the normal method) to LOD (limit of detection achieved using the proposed UESA-DLLME-FASI-CE-CD method), varies between approximately 1200 and 2000 for the 10 analytes. Analysis of the 10 separated analytes spiked in urine and serum samples revealed recovery rates of 88%-106% and 89%-105%, respectively. Therefore, this highly sensitive advanced technique was successfully used to analyze phenothiazine enantiomers in urine and serum samples.
Topics: Phenothiazines; Solvents; Limit of Detection; Antipsychotic Agents; Electrophoresis, Capillary; Electric Conductivity
PubMed: 37487301
DOI: 10.1016/j.chroma.2023.464212 -
International Journal of Oncology Aug 2019Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet‑derived growth...
Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet‑derived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern‑matching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine‑class drugs). Western blot analysis demonstrated that all four drugs had ETV1‑downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellular‑signal‑regulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.
Topics: Antineoplastic Agents; Antiprotozoal Agents; Apoptosis; Biomarkers, Tumor; Connectome; DNA-Binding Proteins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Phenothiazines; Prognosis; Signal Transduction; Transcription Factors
PubMed: 31268158
DOI: 10.3892/ijo.2019.4829 -
Antiviral Research Dec 2023Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle...
Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (M) and papain-like protease (PL), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 M and PL protease activity was identified. In silico docking studies also predicted the binding of the phenothiazine urea to the active sites of structurally similar M and PL proteases from distantly related alphacoronavirus, HCoV-229 E (229 E), and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cellulo. It was further demonstrated that the compound inhibited 229 E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles, and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative readily inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.
Topics: Humans; Peptide Hydrolases; SARS-CoV-2; Papain; Viral Proteases; Phenothiazines; Protease Inhibitors; Antiviral Agents
PubMed: 38008194
DOI: 10.1016/j.antiviral.2023.105758