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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 -
Neurotherapeutics : the Journal of the... Jan 2007The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become... (Review)
Review
The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become second-generation VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.
Topics: Animals; Anticonvulsants; Brain; Clinical Trials as Topic; Epilepsy; Humans; Structure-Activity Relationship; Valproic Acid
PubMed: 17199028
DOI: 10.1016/j.nurt.2006.11.007 -
Journal of Traditional Chinese Medicine... Apr 2023To investigate the efficacy and mechanisms of Dingxian pill combined with valproic acid (VPA) on pentylenetetrazol-induced chronical epilepsy in rats.
OBJECIVE
To investigate the efficacy and mechanisms of Dingxian pill combined with valproic acid (VPA) on pentylenetetrazol-induced chronical epilepsy in rats.
METHODS
A rat model of epilepsy was established by administering pentylenetetrazol (PTZ) water solution (35 mg/kg). Rats were divided into 4 groups, among which three groups were treated with different drugs once a day for 28 d including Dingxian pill (2.4 g/kg), VPA (0.2 g/kg), or a combination of Dingxian pill (2.4 g/kg) and VPA (0.2 g/kg) respectively, and the control group was given the same volume of saline. Rats in different groups were compared based on animal behavior, electroencephalograms, Morris water maze, immunohistochemistry, transcriptomics and real-time polymerase chain reaction.
RSULTS
The combination therapy of Dingxian pill and VPA inhibited PTZ-induced seizure-like behavior and reduced seizure grades more significantly than VPA alone. Compared with the control group, the learning and memory ability of chronic PTZ-induced epileptic rats was improved in all the drug treatment groups, especially in the group that received both Dingxian pill and VPA. Similar to the results of MWM tests, expression of the neuroexcitability marker gene c-Fos was reduced after Dingxian pill and/or VPA treatment, and the effect was most pronounced in the combined treatment group. Transcriptomic analysis revealed that gene expression in the rodent hippocampus, which is involved in epilepsy, was upregulated by combined treatment with Dingxian pill and VPA, compared with VPA treatment alone.
CONCLUSION
Our results not only highlight the anti-epileptic effects of combined Dingxian pill and VPA treatment, but also shed light on the underlying molecular mechanisms and provide a way to apply Traditional Chinese Medicine in the treatment of epilepsy.
Topics: Rats; Animals; Valproic Acid; Pentylenetetrazole; Epilepsy; Anticonvulsants; Seizures
PubMed: 36994516
DOI: 10.19852/j.cnki.jtcm.20220928.002 -
Brain Research Bulletin Dec 2022This study aimed to explore the effect of concomitant use of Furosemide (FRS) and Valproic acid (VPA), demonstrating anti-inflammation efficacy, on epilepsy, and its...
OBJECTIVES
This study aimed to explore the effect of concomitant use of Furosemide (FRS) and Valproic acid (VPA), demonstrating anti-inflammation efficacy, on epilepsy, and its underlying mechanism.
METHODS
Twenty-five adult male Wistar rats were divided into five groups including, Group 1: (Normal) rats received no drugs, Group 2: (E): rats were administered with a single dose of kainic acid (stereotaxic surgery), Group 3: (E + VPA): rats received Valproic acid (200 mg/kg/day/orally), Group 4: (E + FRS): rats received a single dose of Furosemide (100 mg/kg/I.P.) 30 min before epilepsy induction, Group 5: (E + VPA (200 mg/Kg)+FRS (100 mg/Kg, combination treatment). The treatment group received VPA for 14 days. We assessed seizures based on modified Racine΄s scores and conducted the electroencephalographic (EEG) recording. NLRP1 and NLRP3 mRNA levels, Apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), absence in melanoma2 (AIM2) protein expression levels, and apoptosis rate of the brain cells were analyzed utilizing real-time PCR, immunohistochemistry, and tunnel assay, respectively.
RESULTS
The results revealed that FRS and VPA treatment, alone or in combination, improved behavioral outcome and reduced seizure intensity in epileptic rats. The combination therapy significantly decreased the apoptosis rate NLRP1 and NLRP3 gene as well as ASC and AIM2 protein expression levels.
CONCLUSION
Combination therapy protected the brain against neuronal damages in rats, and decreased the severity of epilepsy in K.A. induced rats. Reducing inflammation and apoptosis and improving the performance of behavioral testing in the K.A. induced epilepsy model increased the likelihood of success of combination therapy compared with VPA and FRS treatment alone.
Topics: Animals; Male; Rats; Brain; Disease Models, Animal; DNA-Binding Proteins; Epilepsy; Furosemide; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Rats, Wistar; RNA, Messenger; Valproic Acid
PubMed: 36209957
DOI: 10.1016/j.brainresbull.2022.10.002 -
Anais Da Academia Brasileira de Ciencias 2021Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA,...
Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA, glutamate, glutamine, aspartate, taurine, and glycine in brain tissue and plasma of rats prenatally exposed to valproic acid (VPA), a well-characterized experimental model of autism. Pregnant rats were injected with VPA (600mg/Kg) during the twelfth-embryonic-day. Control rats were injected with saline. On the fourteen-postnatal-day, rats from both groups (males and females) were anesthetized, euthanized by decapitation and their brain dissected out. The frontal cortex, hippocampus, amygdala, brain stem and cerebellum were dissected and homogenized. Homogenates were centrifuged and supernatants were used to quantify amino acid concentrations by HPLC coupled with fluorometric detection. Blood samples were obtained by a cardiac puncture; plasma was separated and deproteinized to quantify amino acid concentration by HPLC. We found that, in VPA rats, glutamate and glutamine concentrations were increased in hippocampus and glycine concentration was increased in cortex. We did not find changes in other regions or in plasma amino acid concentration in the VPA group with respect to control group. Our results suggest that VPA exposure in utero may impair inhibitory and excitatory amino acid transmission in the infant brain.
Topics: Amino Acids; Animals; Autism Spectrum Disorder; Brain; Female; Male; Plasma; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Valproic Acid
PubMed: 33729379
DOI: 10.1590/0001-3765202120190861 -
Annals of Palliative Medicine May 2021Several case reports and retrospective studies have indicated that carbapenems decrease the plasma concentration of valproic acid (VPA). This retrospective study...
BACKGROUND
Several case reports and retrospective studies have indicated that carbapenems decrease the plasma concentration of valproic acid (VPA). This retrospective study examines the effect of carbapenems on VPA levels, and explores whether the drug-drug interaction can influence the liver function of patients.
METHODS
The data of 141 patients were collected from the Department of Neurosurgery at Shanxi Bethune Hospital from January 2018 to December 2019. We compared the VPA levels between the VPA monotherapy group and VPA + carbapenem group to evaluate the influence of carbapenem antibiotics on the plasma concentration of VPA. We also compared the liver injury rate of the VPA monotherapy group, VPA + meropenem group, and VPA + imipenem group to evaluate the influence of concomitant use of VPA with carbapenem antibiotics on liver function.
RESULTS
The VPA serum concentration in the VPA + meropenem group was 22.32±21.77 µg/mL, which was markedly lower than that in the VPA monotherapy group (i.e., without carbapenems) (65.17±21.49 µg/mL) (P<0.01). The rate of liver injury was significantly different between the VPA monotherapy, VPA + meropenem, and VPA + imipenem groups (χ2=30.13, P<0.01). Further comparisons showed that the liver injury rate of the VPA + meropenem group (35.42%) was higher than that of the VPA + imipenem (3.7%) and VPA monotherapy (1.52%) groups (P<0.01). Although no significant differences in liver injury rate were observed between the VPA + imipenem (3.7%) and VPA monotherapy (1.52%) groups, the alanine aminotransferase (ALT) value of the VPA + imipenem group after co-administration (65.22±48.01 U/L) was notably higher than before (40.48±24.97 U/L) (P<0.01).
CONCLUSIONS
In this study, the interaction between VPA and carbapenems resulted in decreased plasma concentrations of VPA as well as possible liver injury. Clinicians should be aware of this potential interaction, and closely monitor VPA concentrations and liver function. Different carbapenems combined with VPA showed different effects on both VPA concentration and liver function, indicating that the mechanisms of these two effects might be related.
Topics: Carbapenems; Humans; Liver; Pharmaceutical Preparations; Retrospective Studies; Valproic Acid
PubMed: 34107696
DOI: 10.21037/apm-21-795 -
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 -
Epilepsia 1999Clinical use of the antiepileptic drug (AED) lamotrigine (LTG) has dramatically increased since its introduction in Europe in 1991 and in the United States in 1994. This... (Review)
Review
Clinical use of the antiepileptic drug (AED) lamotrigine (LTG) has dramatically increased since its introduction in Europe in 1991 and in the United States in 1994. This article surveys the English-language literature of LTG published before 1998. This literature is concerned with the molecular mechanisms of LTG's antiepileptic action, evaluation of its clinical antiepileptic efficacy, adverse experiences associated with its clinical use, and current guidelines for its initiation. LTG's efficacy has been extensively confirmed in multiple postmarketing studies, and its applications are broad. The most serious adverse experiences have involved skin rash. Valproic acid affects LTG metabolism, and a specific set of guidelines for the concurrent use of valproic acid and LTG has been developed. Unique issues are also associated with its pediatric use. LTG has a significant place in clinical management of a wide range of epilepsy syndromes, and the scope of its use is expanding. Accumulating clinical data enable the clinician to maximize its efficacy and minimize adverse experiences. Guidelines for its pediatric use must be followed diligently.
Topics: Adolescent; Adult; Animals; Anticonvulsants; Child; Clinical Trials as Topic; Diplopia; Dizziness; Drug Administration Schedule; Drug Eruptions; Drug Interactions; Drug Prescriptions; Drug Therapy, Combination; Epilepsy; Headache; Humans; Lamotrigine; Practice Guidelines as Topic; Product Surveillance, Postmarketing; Treatment Outcome; Triazines; Valproic Acid
PubMed: 10530692
DOI: 10.1111/j.1528-1157.1999.tb00917.x -
The American Journal of Psychiatry Jan 2021
Topics: Forensic Psychiatry; Humans; Internship and Residency; Standard of Care; Valproic Acid
PubMed: 33384011
DOI: 10.1176/appi.ajp.2020.20030350 -
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