The simultaneous effect of valproic acid and gamma radiation on telomerase activity and bax and Bcl-2 protein levels in MCF-7 breast cancer cell line

Background: Breast cancer is one of the most prevalent types of cancer. Factors such as ionizing radiation and chemotherapeutic agents can trigger apoptosis and cancer cell death. An anticonvulsant drug named Valproic acid is a histone deacetylase inhibitor that shows promising anti-tumor effects in a variety of cancers. Telomerase is a ribonucleoprotein enzyme that activated in cancer cells and lead to telomeres shortening inhibition and triggering the apoptosis. Objectives: The purpose of this research was to investigate the simultaneously effect of Valproic acid and gamma radiation on telomerase activity and bax and Bcl-2 protein level in MCF-7 breast cancer cell line. Materials and Methods: MCF-7 cells was treated with different dose of Valproic acid (0, 2, 8 and 16 mM/l) and single dose of gamma radiation (4 Gy/min. (cell toxicity was determined using neutral uptake test. Telomerase activity was determined using TRAP assay (PCR-ELISA) method. Bax and Bcl-2 protein level was determined by ELISA method, as well. Results: Combination of Valproic acid and gamma radiation increased significantly cell toxicity in a time and dose dependent manner compared with control (P < 0.0001). The ratio of Bax/Bcl-2 was increased in a dose dependent manner at 48 and 72 hour treatment (P < 0.0001). There was a decrease in Telomerase activity after 24, 48 and 72 hours treatment in a dose dependent manner (P < 0.0001). Conclusions: The increasing cell toxicity, apoptosis-inducing effects and decreasing telomerase activity may play an important role in the Valproic acid and radiation mechanism. The current survey suggested that it is likely beneficial to combine Valproic acid and gamma radiation to treat breast cancer. © 2015, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences

The Protective Role of Folic Acid and Vitamin E Against Toxical Effects of Valproic Acid on Liver Tissue During Period of Gestation

Valproic acid is an anticonvulsan drug used in epilepsy. Thehistopathological changes of valproic acid on liver and the protective effectof vitamin E and also folic acid were observed. 24 adult female Wistar Albinorats were used. The first control, the second valproic acid group that wasgiven 300 mg/kg on 8.9. and 10. days of gestation, the third valproic acid+vitamin E group. Vitamin E was given 250mg/kg via nasogastric intubationbefore one hour administration of valproic acid on 8.9.10.days of gestation.The fourth valproic acid+ folic acid group; via valproic acid, folic acid wasgiven 400 microgram ordinarily in drinking water per day. In the liversections of valproic acid group, perivenullar dilatation, swelling of Kuppfercells, microvesicular steatosis and degeneration were observed. In the secondgroup there was moderate degeneration in hepatocytes,necrotic areas insome places, mononuclear cell infiltration. In valproic acid +vitamin E groupnormal-like appearance of the structure of Remark cell lines were observed.Under these source of results, we viewed antioxidants decreased thehepatotoxicity on liver tissue by using folic acid and vitamin E

Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line

The biochemical mechanisms mediating the rapid distribution of valproic acid across placenta are not precisely known. We have characterized valproic acid transport by the human trophoblast using the human choriocarcinoma cell line, BeWo. The uptake of [14C]valproic acid by BeWo cells was found to be saturable and blocked by pre-exposure to the metabolic inhibitors, sodium azide and 2,4-dinitrophenol. Valproic acid uptake by the BeWo cells was also inhibited by the protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) but not anion exhange inhibitor. Selected monocarboxylic acids inhibited the uptake of [14C]valproic acid by BeWo cells, whereas dicarboxylic acids did not alter the uptake process. Analysis of Lineweaver-Burk plots of valproic acid uptake in the presence of benzoic acid, a marker for the monocarboxylic acid transporter, revealed a competitive process for uptake. In transcellular transport experiments, the permeation of [14C]valproic acid from the apical-to-basal side of the monolayers was signficantly greater than the permeation from basal-to-apical side. Additionally, the permeation of [14C]valproic acid from apical-to-basal side was inhibited by monocarboxylic acids and not dicarboxylic acids. The results provide biochemical evidence of a proton-dependent, saturable, and asymmetric transport system, presumed to be a monocarboxylic acid transporter, for valproic acid in a human trophoblast model

Chard extract increased gastric sialic acid and ameliorated oxidative stress in valproic acid-administered rats

Valproic acid, one of the most used drugs for epilepsy patients, has some known side effects. Chard extract has many pharmacological activities. The study aims to evaluate whether valproic acid might interfere with oxidative metabolism in gastric tissue and whether chard ameliorates these effects. The Sprague Dawley rats were divided into four groups (n=8); control, chard-given control, valproic acid, and chard-given valproic acid. The aqueous extracts of chard leaves were given 1 h before the administration of valproic acid for 7 days. On the 8th day, the animals were sacrificed under anesthesia and gastric tissues were homogenized. When compared to the control group, valproic acid significantly increased malondialdehyde and catalase activity, while superoxide dis- mutase activity decreased. Chard administration increased glutathione and, sialic acid levels and decreased malondialdehyde levels and superoxide dismutase activity in the valproic acid group. Based on these findings, since chard increased gastric sialic acid levels, we may suggest that chard may protect gastric mucosa may be through its antioxidant effects

The effect of valproic acid on rat ovarium and the protective role of vitamin E and folic acid: An ultrastructural study

This study was undertaken to investigate the effect of valproic acid and protective effects of vitamin E and folic acid on rat ovary ultrastructural changes. Twenty-four Wistar rats were used. Animals were divided into four groups. The first group of rats was used as control. The second group was injected valproic acid. The third group was injected valproic acid + folic acid and the fourth group was given valproic acid + vitamin E. At the end of the study, ovarium tissues were taken under anesthesia. Tissues were prepared and examined by transmission electron microscopy. Microscopically, the groups are cited as follows: Control group (in which the ovarium tissue was normal), valproic acid group (which showed increase in lipid content plus mitochondrial crystalysis seen in folliculer and theca interna cells of rat ovarium), valproic acid + folic acid group (in which the theca interna and granulosa cells of rat ovarium had normal appearance) and valproic acid + vitamin E group (where all the organelles of theca interna and granulosa cells of rat ovarium were observed to be normal). Vitamin E and folic acid have protective effects against valproic acid-induced tissue damage in rat ovaries.Keywords: Valproic acid, vitamin E, folic acid, ovarium, ratAfrican Journal of Biotechnology Vol. 9(34), pp. 5616-5622, 23 August, 201

Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report

Valproic Acid is a commonly used psychiatric drug primarily used as a mood stabilizer. Mild hyperammonemia is a Valproic Acid common adverse effect. This report presents an example of treated hyperammonemia on Valproic acid therapy managed with L-carnitine administration in BD patients characterized by sudden vulnerability

Valproic acid induced pancreatitis: a case report

Valproic acid is a commonly used antiepileptic drug. Apart from its common side effect there is definite association between valproic acid therapy and acute pancreatitis. Since 1979, many cases of acute pancreatitis induced by valproic acid have been published in medical literature. Here we are reporting a case of valproic acid induced acute pancreatitis in a 27 years old boy. The treatment is supportive, re-challenge is hazardous and should be avoided

Valproic Acid-Associated Acute Pancreatitis: Systematic Literature Review.

Long-term medication with valproic acid has been associated with acute pancreatitis. The purpose of this report is to gain insight into the features of this pancreatitis. A preregistered literature search (CRD42023438294) was performed on the National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar. Patients with alcohol abuse disorder, gallstone disease, hypertriglyceridemia or hypercalcemia, patients with acute valproic acid intoxication, and patients with a pre-existing pancreatitis were excluded. For the final analysis, we retained 73 reports published between 1979 and 2023, which described 125 subjects (83 children and 42 adults predominantly affected by an epilepsy) with an acute pancreatitis related to valproic acid. The diagnosis was made 11 (3.0-24) months (median and interquartile range) after starting valproic acid. One hundred and five cases (84%) recovered and twenty (16%) died. Sex, age, dosage or circulating level of valproic acid, latency time, prevalence of intellectual disability, and antiepileptic co-medication were similar in cases with and without a lethal outcome. Nineteen subjects were rechallenged with valproic acid after recovery: sixteen (84%) cases developed a further episode of pancreatitis. In conclusion, pancreatitis associated with valproic acid presents at any time during treatment and has a high fatality rate

Brain derived neurotrophic factor expression and DNA methylation in response to subchronic valproic acid and/or aldosterone treatment

Aim To test the hypothesis that valproic acid treatment positively affects brain-derived neurotrophic factor (BDNF) expression and DNA methylation in the hippocampus and brain cortex of rats simultaneously treated with aldosterone. Methods Male Sprague-Dawley rats (N = 40) were treated for two weeks with valproic acid (100 mg/1 kg body weight/d) in drinking water and aldosterone (2 μg/100 g body weight/d) or placebo via subcutaneous osmotic minipumps. Results Treatment with valproic acid did not modify BDNF gene expression in the hippocampus but reduced BDNF mRNA levels in the brain cortex. Valproic acid treatment marginally enhanced global DNA methylation in the frontal cortex. BDNF expression negatively correlated with DNA methylation in the hippocampus of valproic acidtreated rats. An unexpected finding was that aldosterone treatment significantly decreased global DNA methylation in the hippocampus. Conclusion The effect of valproic acid on BDNF expression in the brain may depend on the extent of pathological changes present at the time of treatment onset. The observed negative correlation between BDNF expression and DNA methylation in the hippocampus of valproic acid- treated rats encourages further studies

VALPROIC ACID PROTECTS KIDNEYS FROM CISPLATIN

Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application