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Journal of Translational Medicine Mar 2023Breast cancer is the second leading cause of death among women after lung cancer. Despite the improvement in prevention and in therapy, breast cancer still remains a...
BACKGROUND
Breast cancer is the second leading cause of death among women after lung cancer. Despite the improvement in prevention and in therapy, breast cancer still remains a threat, both for pre- and postmenopausal women, due to the development of drug resistance. To counteract that, novel agents regulating gene expression have been studied in both hematologic and solid tumors. The Histone Deacetylase (HDAC) inhibitor Valproic Acid (VA), used for epilepsy and other neuropsychiatric diseases, has been demonstrated a strong antitumoral and cytostatic activity. In this study, we tested the effects of Valproic Acid on the signaling pathways involved in breast cancer cells viability, apoptosis and in Reactive Oxygen Species (ROS) production using ER-α positive MCF-7 and triple negative MDA-MB-231 cells.
METHODS
Cell proliferation assay was performed by MTT Cell cycle, ROS levels and apoptosis were analyzed by flow cytometry, protein levels were detected by Western Blotting.
RESULTS
Cell treatment with Valproic Acid reduced cell proliferation and induced G0/G1 cell cycle arrest in MCF-7 and G2/M block in MDA-MB-231 cells. In addition, in both cells the drug enhanced the generation of ROS by the mitochondria. In MCF-7 treated cells, it has been observed a reduction in mitochondrial membrane potential, a down regulation of the anti-apoptotic marker Bcl-2 and an increase of Bax and Bad, leading to release of cytochrome C and PARP cleavage. Less consistent effects are recorded in MDA-MB-231 cells, in which the greater production of ROS, compared to MCF-7cells, involves an inflammatory response (activation of p-STAT3, increased levels of COX2).
CONCLUSIONS
Our results have demonstrated that in MCF-7 cells the Valproic Acid is a suitable drug to arrest cell growth, to address apoptosis and mitochondrial perturbations, all factors that are important in determining cell fate and health. In a triple negative MDA-MB 231 cells, valproate directs the cells towards the inflammatory response with a sustained expression of antioxidant enzymes. Overall, the not always unequivocal data between the two cellular phenotypes indicate that further studies are needed to better define the use of the drug, also in combination with other chemotherapy, in the treatment of breast tumors.
Topics: Female; Humans; Valproic Acid; MCF-7 Cells; Reactive Oxygen Species; Cell Cycle; Cell Proliferation; Histone Deacetylase Inhibitors
PubMed: 36864445
DOI: 10.1186/s12967-023-04015-8 -
Archives of Toxicology Feb 2021Since teratogenicity testing in mammals is a particular challenge from an animal welfare perspective, there is a great need for the development of alternative test...
Since teratogenicity testing in mammals is a particular challenge from an animal welfare perspective, there is a great need for the development of alternative test systems. In this context, the zebrafish (Danio rerio) embryo has received increasing attention as a non-protected embryonic vertebrate in vivo model. The predictive power of zebrafish embryos for general vertebrate teratogenicity strongly depends on the correlation between fish and mammals with respect to both overall general toxicity and more specific endpoints indicative of certain modes-of-action. The present study was designed to analyze the correlation between (1) effects of valproic acid and nine of its analogues in zebrafish embryos and (2) their known neurodevelopmental effects in mice. To this end, zebrafish embryos exposed for 120 h in an extended version of the acute fish embryo toxicity test (FET; OECD TG 236) were analyzed with respect to an extended list of sublethal endpoints. Particular care was given to endpoints putatively related to neurodevelopmental toxicity, namely jitter/tremor, deformation of sensory organs (eyes) and craniofacial deformation, which might correlate to neural tube defects caused by valproic acid in mammals. A standard evaluation of lethal (LC according to OECD TG 236) and sublethal toxicity (EC) merely indicated that four out of ten compounds tested in zebrafish correlate with positive results in mouse in vivo studies. A detailed assessment of more specific effects, however, namely, jitter/tremor, small eyes and craniofacial deformation, resulted in a correspondence of 75% with in vivo mouse data. A refinement of endpoint analysis from an integration of all observations into one LC or EC data (as foreseen by current ecotoxicology-driven OECD guidelines) to a differential evaluation of endpoints specific of selected modes-of-action thus increases significantly the predictive power of the zebrafish embryo model for mammalian teratogenicity. However, for some of the endpoints observed, e.g., scoliosis, lordosis, pectoral fin deformation and lack of movement, further experiments are required for the identification of underlying modes-of-action and an unambiguous interpretation of their predictive power for mammalian toxicity.
Topics: Animals; Ecotoxicology; Embryo, Nonmammalian; Lethal Dose 50; Mice; Models, Biological; Morphogenesis; Neurodevelopmental Disorders; Neurotoxins; Toxicity Tests, Acute; Valproic Acid; Zebrafish
PubMed: 33111190
DOI: 10.1007/s00204-020-02928-7 -
CNS Drugs Jan 2016Valproic acid is a versatile antiepileptic drug that is often used in the acute care setting. Intravenous valproic acid lends itself well to a continuous infusion as it...
INTRODUCTION
Valproic acid is a versatile antiepileptic drug that is often used in the acute care setting. Intravenous valproic acid lends itself well to a continuous infusion as it exhibits a relatively short half-life. We evaluated the pharmacokinetics and clinical efficacy of continuous infusion valproic acid in hospitalized patients with migraine and seizures.
METHODS
A retrospective cohort study was performed utilizing information from the medical records of patients receiving an intravenous continuous infusion of valproic acid. Patients were included if they were aged 1 month to 85 years and they received a continuous infusion of valproic acid. Therapeutic response, common adverse effects, and the pharmacokinetic profile of valproic acid were evaluated.
RESULTS
Continuous infusion valproic acid led to a concentration within the desired range (50-100 μg/ml) in 83.4% of patients, a rate that was higher in pediatric patients. The clinical response rate was also higher in pediatric patients with seizures or migraines and appeared to be better when the concentration was >75 μg/ml. Analysis of safety parameters suggests similar safety considerations to valproic acid when administered via intermittent infusion.
CONCLUSIONS
Continuous infusion valproic acid appears to be a safe, effective, and predictable manner by which to administer valproic acid to pediatric and adult patients admitted to the hospital.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Child, Preschool; Cohort Studies; Data Interpretation, Statistical; Female; Humans; Infant; Infusions, Intravenous; Male; Medical Records; Middle Aged; Migraine Disorders; Retrospective Studies; Seizures; Treatment Outcome; Valproic Acid; Young Adult
PubMed: 26715390
DOI: 10.1007/s40263-015-0304-5 -
Journal of Cellular Biochemistry Apr 2019Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activities. Valproic acid (VPA) is a recently emerged antineoplastic histone...
BACKGROUND
Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activities. Valproic acid (VPA) is a recently emerged antineoplastic histone deacetylase inhibitor. The aim of the present study is to investigate the synergistic role of oridonin and VPA to inhibit the growth and metastasis of human leukemia cells.
METHODS
The effect of oridonin and VPA on proliferation was evaluated by the MTT assay. Cell migration and invasion were evaluated by transwell and scratch assays, respectively. In addition, cell apoptosis was examined by flow cytometry. The inhibitive effects of oridonin and VPA in vivo were determined by using xenografted nude mice.
RESULTS
The results demonstrated that oridonin in combination with VPA synergistically inhibited the proliferation of HL-60 cells, and induced obvious caspase-dependent apoptosis through activation of the intrinsic apoptosis pathway, which is involved in the downregulation of Bcl-2/Bax ratio. Furthermore, the combination treatment in vivo remarkably reduced the xenograft tumor size and triggered tumor cell apoptosis.
CONCLUSION
Our results suggested that the novel combination of oridonin plus VPA exerted synergistic antiproliferative and apoptosis-inducing effects on human myeloid leukemia cells, and may serve as a potentially promising antileukemia strategy.
Topics: Apoptosis; Diterpenes, Kaurane; Drug Synergism; HL-60 Cells; Humans; Leukemia; Signal Transduction; Valproic Acid
PubMed: 30320906
DOI: 10.1002/jcb.27845 -
The Journal of Trauma and Acute Care... Aug 2022Valproic acid (VPA) has been extensively used for treatment of anxiety and seizure. Recent studies have shown that VPA has cellular protective effects in preclinical...
BACKGROUND
Valproic acid (VPA) has been extensively used for treatment of anxiety and seizure. Recent studies have shown that VPA has cellular protective effects in preclinical models following severe hemorrhage. This study investigated the effects of VPA on coagulation and survival in pigs after traumatic hemorrhage and hypotensive resuscitation.
METHODS
Following baseline measurements, femur fracture was performed in 20 anesthetized and instrumented pigs (41 ± 2 kg), followed by hemorrhage of 55% of the estimated blood volume and a 10-minute shock period. Pigs were then resuscitated for 30 minutes with normal saline (NS) alone (NS group, n = 10, 4 mL/kg) or VPA solution (VPA group, n = 10, 90 mg/kg, 2 mL/kg of 45 mg VPA/mL, plus 2 mL NS/kg). All pigs were then monitored for 2 hours or until death. Hemodynamics were recorded, and blood samples were taken for blood and coagulation analysis (Rotem) at baseline, after hemorrhage, resuscitation, and 2 hours or death.
RESULTS
Femur fracture and hemorrhage caused similar reductions in mean arterial pressure and cardiac output, and increase in heart rate in both groups. Resuscitation with NS or VPA did not return these measurements to baseline. No differences were observed in hematocrit, pH, lactate, base excess, or total protein between the groups. Compared with NS, resuscitation with VPA decreased platelet counts and prolonged activated partial thromboplastin time, with no differences in fibrinogen levels, prothrombin time, or any of the Rotem measurements between the two groups. Neither survival rates (NS, 7 of 10 pigs; VPA, 7 of 10 pigs) nor survival times after resuscitation (NS, 97 ± 40 minutes; VPA, 98 ± 43 minutes) differed between the groups.
CONCLUSION
Following traumatic hemorrhage and hypotensive resuscitation in pigs, VPA provides no benefit toward improving coagulation function or survival times.
Topics: Animals; Blood Coagulation; Disease Models, Animal; Hemorrhage; Resuscitation; Shock, Hemorrhagic; Swine; Valproic Acid
PubMed: 35583983
DOI: 10.1097/TA.0000000000003705 -
Methods in Molecular Biology (Clifton,... 2023Systemic administration of histone deacetylase inhibitors (HDACi), like valproic acid (VPA), is often associated with rapid drug metabolization and untargeted tissue...
Systemic administration of histone deacetylase inhibitors (HDACi), like valproic acid (VPA), is often associated with rapid drug metabolization and untargeted tissue distribution. This requires high-dose application that can lead to unintended side effects. Hence, drug carrier systems such as nanoparticles (NPs) are developed to circumvent these disadvantages by enhancing serum half-life as well as organ specificity.This chapter gives a summary of the biological characterization of HDACi-coupled NPs in vitro, including investigation of cellular uptake, biocompatibility, as well as intracellular drug release and activity. Suitable methods, opportunities, and challenges will be discussed to provide general guidelines for the analysis of HDACi drug carrier systems with a special focus on recently developed cellulose-based VPA-coupled NPs.
Topics: Histone Deacetylase Inhibitors; Valproic Acid; Nanoparticles; Drug Carriers; Cellulose
PubMed: 36255622
DOI: 10.1007/978-1-0716-2788-4_9 -
Future Medicinal Chemistry May 2023New hybrid compounds were synthesized by linking the valproic acid (VPA) structure with other anticonvulsant/anti-inflammatory scaffolds. The chemistry involved the...
New hybrid compounds were synthesized by linking the valproic acid (VPA) structure with other anticonvulsant/anti-inflammatory scaffolds. The chemistry involved the incorporation of the linker oxymethyl ester into VPA, followed by reaction with the second scaffold. The antiseizure effects were investigated by the maximal electroshock seizure test, and the most active compound was additionally evaluated in the 6 Hz test and pentylenetetrazol test in mice. The compounds showed protection against seizures. The hybrid structure with the butylparaben scaffold exhibited an ED of 8.265 mg/kg (0.0236 mmol/Kg) in the maximal electroshock seizure test and 50.00 mg/kg (0.147 mmol/kg) in the 6 Hz test. The antiseizure activity of the synthesized compounds highlighted the potential of hybrid structures to treat multifactorial diseases such as epilepsy.
Topics: Mice; Animals; Valproic Acid; Anticonvulsants; Epilepsy; Seizures; Pentylenetetrazole; Disease Models, Animal; Dose-Response Relationship, Drug
PubMed: 37227752
DOI: 10.4155/fmc-2022-0222 -
Toxicological Sciences : An Official... Feb 2023The purpose of this study was to use chemical similarity evaluations, transcriptional profiling, in vitro toxicokinetic data, and physiologically based pharmacokinetic...
The purpose of this study was to use chemical similarity evaluations, transcriptional profiling, in vitro toxicokinetic data, and physiologically based pharmacokinetic (PBPK) models to support read-across for a series of branched carboxylic acids using valproic acid (VPA), a known developmental toxicant, as a comparator. The chemicals included 2-propylpentanoic acid (VPA), 2-ethylbutanoic acid, 2-ethylhexanoic acid (EHA), 2-methylnonanoic acid, 2-hexyldecanoic acid, 2-propylnonanoic acid (PNA), dipentyl acetic acid or 2-pentylheptanoic acid, octanoic acid (a straight chain alkyl acid), and 2-ethylhexanol. Transcriptomics was evaluated in 4 cell types (A549, HepG2, MCF7, and iCell cardiomyocytes) 6 h after exposure to 3 concentrations of the compounds, using the L1000 platform. The transcriptional profiling data indicate that 2- or 3-carbon alkyl substituents at the alpha position of the carboxylic acid (EHA and PNA) elicit a transcriptional profile similar to the one elicited by VPA. The transcriptional profile is different for the other chemicals tested, which provides support for limiting read-across from VPA to much shorter and longer acids. Molecular docking models for histone deacetylases, the putative target of VPA, provide a possible mechanistic explanation for the activity cliff elucidated by transcriptomics. In vitro toxicokinetic data were utilized in a PBPK model to estimate internal dosimetry. The PBPK modeling data show that as the branched chain increases, predicted plasma Cmax decreases. This work demonstrates how transcriptomics and other mode of action-based methods can improve read-across.
Topics: Carboxylic Acids; Molecular Docking Simulation; Transcriptome; Valproic Acid; Structure-Activity Relationship
PubMed: 36583546
DOI: 10.1093/toxsci/kfac139 -
European Journal of Clinical... Aug 2020Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However,... (Meta-Analysis)
Meta-Analysis
PURPOSE
Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA.
METHODS
The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6).
RESULTS
In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01).
CONCLUSION
This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.
Topics: Anticonvulsants; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2C9; Epilepsy; Humans; Valproic Acid
PubMed: 32385545
DOI: 10.1007/s00228-020-02872-6 -
International Journal of Molecular... Aug 2023Eosinophils function in rapid innate immune responses and allergic reactions. Recent research has raised the possibility that the histone deacetylase inhibitor valproic...
Eosinophils function in rapid innate immune responses and allergic reactions. Recent research has raised the possibility that the histone deacetylase inhibitor valproic acid (VPA) may be a promising therapeutic agent for treatment of allergic responses and certain cancers. However, its effects on eosinophils remain unclear. Utilizing the EoL-1 human eosinophil cell line as a model, we investigated the effects of VPA on oxidative stress- and autophagy-mediated immune responses. We found that VPA induced reactive oxidative species (ROS) generation and eosinophil activation without affecting cell viability. Moreover, VPA treatment suppressed the negative regulator of antioxidant transcription factor Nrf2, which is known to activate antioxidant defense. Interestingly, VPA was able to increase autophagic markers, as well as NLRP3 and NLRC4 mRNA activation, in Eol-1 cells in a dose-dependent manner. Collectively, our results indicate that VPA could increase the severity of allergic responses, and if so, it clearly would not be a suitable drug for the treatment of allergic reactions. However, VPA does have the potential to induce autophagy and to regulate the inflammatory responses via inflammasome-driven caspase-1 deactivation in a dose-dependent manner.
Topics: Humans; Valproic Acid; Antioxidants; Oxidative Stress; Inflammation; Autophagy; Hypersensitivity
PubMed: 37686250
DOI: 10.3390/ijms241713446