Valproate activates ERK signaling pathway in primary human hepatocytes

Bitman, Michal; Vrzal, Radim; Dvořák, Zdeněk; Pávek, Petr

doi:10.5507/bp.2012.038

Cited by 5 publications

(6 citation statements)

References 46 publications

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“…Melatonin is effective in preventing the ischemic brain injury‐induced down‐regulation of Raf‐1, MEK1/2 and ERK1/2 phosphorylation , suggesting that the activation of Raf/MEK/ERK cascade can be mediated by Melatonin. In human hepatocytes, the ERK pathway can be activated by VPA exposure . Given that both melatonin and VPA have been reported to prevent tumor growth and progression in animal models of cancer , it would be interesting to determine the combinatorial effects in vivo in our future studies.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

et al. 2017

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Effective drug combinations have the potential to strengthen therapeutic efficacy and combat drug resistance. Both melatonin and valproic acid ( VPA ) exhibit antitumor activities in various cancer cells. The aim of this study was to evaluate the cell death pathways initiated by anticancer combinatorial effects of melatonin and VPA in bladder cancer cells. The results demonstrated that the combination of melatonin and VPA leads to significant synergistic growth inhibition of UC 3 bladder cancer cells. Gene expression studies revealed that cotreatment with melatonin and VPA triggered the up‐regulation of certain genes related to apoptosis ( TNFRSF 10A and TNFRSF 10B), autophagy ( BECN , ATG 3 and ATG 5) and necrosis ( MLKL , PARP ‐1 and RIPK 1). The combinatorial treatment increased the expression of endoplasmic reticulum ( ER )‐stress‐related genes ATF 6, IRE 1, EDEM 1 and ER dj4. Cotreatment with melatonin and VPA enhanced the expression of E‐cadherin, and decreased the expression of N ‐cadherin, Fibronectin, Snail and Slug. Furthermore, the Wnt pathway and Raf/ MEK / ERK pathway were activated by combinatorial treatment. However, the effects on the expression of certain genes were not further enhanced in cells following combinatorial treatment in comparison to individual treatment of melatonin or VPA . In summary, these findings provided evidence that cotreatment with melatonin and VPA exerted increased cytotoxicity by regulating cell death pathways in UC 3 bladder cancer cells, but the clinical significance of combinatorial treatment still needs to be further exploited.

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Section: Discussionmentioning

confidence: 99%

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

et al. 2017

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“…In contrast to the CNS, a paucity of information has been available to link VPA with ERK-activity in the liver. Thus, by far, only one in vitro study reported that VPA activates ERK phosphorylation in primary human hepatocytes, a response that was mimicked by HDAC inhibitor, trichostatin-A ( Bitman et al, 2014 ), implying that HDAC inhibition is a primary stimulus for ERK in human hepatocytes. However, this this study has not looked at role of oxidative stress or VPA metabolites, possibly due to limited biologic windows within a cell culture setup.…”

Section: Discussionmentioning

confidence: 99%

Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis

El‐Mowafy

Mohamed

Pye

et al. 2016

Heliyon

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Background/AimHepatic injury is a hallmark adverse reaction to Valproate (VPA), a common used drug in the management of numerous CNS disorders, including epilepsy. DHA has a myriad of health benefits, including renal- and hepato-protective effects. Unfortunately, however, the underpinnings of such liver-pertinent VPA- and DHA-actions remain largely undefined. Accordingly, this study attempted to unveil the cellular and molecular triggers whereby VPA evokes, while DHA abates, hepatotoxicity.MethodsWe evaluated activity and/or expression of cellular markers of oxidative stress, inflammation, and apoptosis in rat liver, following treatment with VPA (500 mg/kg/day) with and without concurrent treatment with DHA (250 mg/kg/day) for two weeks.Results and conclusionVPA promoted hepatic oxidative stress as evidenced by enhancing activity/expression of NADPH-oxidase and its subunits, a ROS-generator, and by accumulation of lipid-peroxides. Moreover, VPA enhanced hepatic phosphorylation/activation of mitogen-activated protein kinase (MAPK), and expression of cyclooxygenase-2(COX-2), as proinflammatory signals. Besides, VPA promoted hepatocellular apoptosis, as attested by enhanced expression of cleaved caspase-9 and increased number of TUNEL-positive hepatocytes. Lastly, VPA upregulated levels of hypoxia-inducible factor-1-alpha (HIF-1α), a multifaceted modulator of hepatocytic biology, and activity of its downstream antioxidant enzyme heme-oxygenase-1(HO-1). These changes were significantly blunted by co-administration of DHA. Our findings demonstrate that VPA activated NADPH-oxidase and HIF-1α to induce oxidative-stress and hypoxia as initiators of hepatic injury. These changes were further aggravated by up-regulation of inflammatory (MAPK and COX-2) and apoptotic cascades, but could be partly lessened by HO-1 activation. Concurrent administration of DHA mitigated all VPA-induced anomalies.

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“…Another study reported that CYP1A1 can be active in catalyzing the formation of ROS The previous reports have suggested that Nrf2-dependent transcription may be facilitated by the MAPK pathway such as ERK, JNK, and p38 (Eggler et al, 2008;Zhai et al, 2013), which were activated by VPA (Einat et al, 2003;Xie et al, 2010;Yamauchi et al, 2010). However, Bitman et al (2014) reported that the effect of VPA on MAPK pathways are different for different cell lines. Thus, we studied the phosphorylation of the ERK, JNK, and p38 pathways by VPA in Caco-2 cells.…”

Section: Discussionmentioning

confidence: 97%

“…However, Bitman et al. (2014) reported that the effect of VPA on MAPK pathways are different for different cell lines. Thus, we studied the phosphorylation of the ERK, JNK, and p38 pathways by VPA in Caco‐2 cells.…”

Section: Discussionmentioning

confidence: 99%

Changes in uridine 5′‐diphospho‐glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid

Sakakibara

Kojima

Asai

et al. 2022

Biopharm & Drug Disp

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Valproic acid (VPA) is well‐known as a histone deacetylase (HDAC) inhibitor. It has been reported that HDAC inhibitors enhance basal and aryl hydrocarbon receptor (AhR) ligand‐induced aryl hydrocarbon receptor‐responsive gene expression. Other studies suggested that HDAC inhibition might significantly activate the NF‐E2‐related factor‐2 (Nrf2). Moreover, VPA activates mitogen‐activated protein kinases (MAPKs). MAPK pathways regulate Nrf2 transactivation domain activity. Uridine 5′‐diphospho‐glucuronosyltransferase (UGT) 1A6 is one of the important isoforms to affect drug pharmacokinetics. UGT1A6 gene is regulated transcriptionally by AhR and Nrf2. The present study aimed to investigate whether UGT1A6 expression was changed by VPA and to elucidate the mechanism of the alteration. Following VPA treatment for 72 h in Caco‐2 cells, UGT1A6 mRNA was increased by 7.9‐fold. Moreover, UGT1A6 mRNA was increased by other HDAC inhibitors, suggesting that HDAC inhibition caused the UGT1A6 mRNA induction. AhR and Nrf2 proteins in the nucleus of Caco‐2 cells were increased by 1.5‐ and 1.7‐fold, respectively, following the VPA treatment. However, VPA treatment did not activate the extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal kinase (JNK) pathways in Caco‐2 cells. In conclusion, we observed that VPA induced UGT1A6 mRNA expression via AhR and Nrf2 pathways, but not via the ERK or JNK pathways.

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Valproate activates ERK signaling pathway in primary human hepatocytes

Cited by 5 publications

References 46 publications

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis

Changes in uridine 5′‐diphospho‐glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid

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