Increased MDR1 Transporter Expression in Human Brain Endothelial Cells Through Enhanced Histone Acetylation and Activation of Aryl Hydrocarbon Receptor Signaling

You, Dahea; Wen, Xiaozhong; Gorczyca, Ludwik; Morris, Ayeshia; Richardson, Jason R.; Aleksunes, Lauren M.

doi:10.1007/s12035-019-1565-7

Cited by 21 publications

(32 citation statements)

References 61 publications

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“…Also, in different lung cancer cell lines, 3mM sodium butyrate significantly increased both mRNA and protein levels of MDR1 (Zhao et al, 2018). Similar to TSA and SAHA, VPA (0.3mM to 5mM) was able to modulate MDR1 expression and/or function in hCMEC/D3 brain endothelial cells (Noack et al, 2016;You et al, 2019b). However, 0.25mM sodium butyrate, which was the highest nontoxic concentration in hCMEC/D3 cells, did not significantly alter the mRNA or protein expression of MDR1 in those cells.…”

Section: Short Chain Fatty Acidsmentioning

confidence: 86%

“…MDR1 intercellular transfer has been implicated in the acquisition of multidrug resistance in tumor cells (Levchenko et al, 2005). By contrast, a recent study demonstrated the protein expression of MDR1 in hCMEC/D3 cells was significant increased after 24 h of treatment with 0.25M TSA, which was noted as the highest non-toxic concentration (You et al, 2019b).…”

Section: Hydroxamic Acidsmentioning

confidence: 87%

“…Time-dependent reversal of MDR1 induction was also seen in human brain microvascular endothelial (hCMEC/D3) cells, an in vitro model of the human BBB, which is a highly regulated structure in the body. In hCMEC/D3 cells, TSA caused approximately two-fold increase in MDR1 mRNA at 12 h, which was largely attenuated by 24 h (You et al, 2019b). Gomez-Martinez et al, 2007;Balaguer et al, 2012;Toth et al, 2012).…”

Section: Hydroxamic Acidsmentioning

confidence: 98%

“…Likewise, MDR1 mRNA in hCMEC/D3 cells was shown to be significantly increased as early as 6 h following exposure to 10M SAHA, and then returned to the baseline level by 24 h. In the same cells, the level of MDR1 protein, which has a longer half-life than MDR1 mRNA, remained elevated until 36 h after SAHA treatment. Such protein up-regulation translated into enhanced functional activity of MDR1, as indicated by reduced intracellular accumulation of Rhodamine 123, a fluorescent MDR1 substrate (You et al, 2019b).…”

Section: Hydroxamic Acidsmentioning

confidence: 99%

“…Apicidin increased the mRNA and/or protein expression of MDR1 in DLD-1 human colon cancer cells, hCMEC/D3 human microvascular endothelial cells, as well as HeLa and SiHa cervical cancer cells at concentrations ranging from 0.1M to 3M Kim et al, 2009;You et al, 2019b). In hCMEC/D3 cells, apicidin even led to an enhanced functionality of the MDR1 transporter, as measured by the extent of accumulation of Rhodamine 123, a MDR1 substrate (You et al, 2019b). However, apicicidin did not alter MDR1 levels in KB cells or A172 and U87 glioblastoma cells, displaying selectivity in transporter regulation Kim et al, 2009;Kim et al, 2011).…”

Section: Cyclic Peptidesmentioning

confidence: 99%

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Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

2020

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Section: Short Chain Fatty Acidsmentioning

confidence: 86%

Section: Hydroxamic Acidsmentioning

confidence: 87%

Section: Hydroxamic Acidsmentioning

confidence: 98%

Section: Hydroxamic Acidsmentioning

confidence: 99%

Section: Cyclic Peptidesmentioning

confidence: 99%

See 3 more Smart Citations

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

2020

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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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Drug‐resistant epilepsy: Drug target hypothesis and beyond the receptors

Fonseca-Barriendos¹,

Frías‐Soria²,

Pérez-Pérez³

et al. 2021

Epilepsia Open

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Epilepsy is a common chronic neurological disorder that affects more than 50 million people worldwide. 1 Antiseizure drug that serves as the first line of treatment is used to control seizures. However, one-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE) because they fail to achieve control of seizures despite the appropriate treatment schemes used (in monotherapy or various combinations). 2 According to the target hypothesis that explains the drug-resistance phenotype in epilepsy, failure to control epileptic activity by antiseizure medication (ASM) results in losing therapeutic efficacy as a consequence of alterations in the structure and/or function of their targets 3 (Figure 1). In this regard, adopting different therapeutic targets in patients with DRE is crucial, which include alterations in voltage-gated sodium channels (VGSCs) and γ-aminobutyric acid (GABA) receptors.Some studies confirm that resected brain tissue obtained from patients with drug-resistant temporal lobe epilepsy (DR-TLE) who have undergone surgery show reduced sensitivity to carbamazepine, a drug that inhibits VGSC. 4,5 Experimental models have not yet reproduced this condition in DRE. However, studies in models of acute seizures and epilepsy have demonstrated induced alterations in VGSC similar to those detected in brain tissue of patients with the DRE. [6][7][8]

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Increased MDR1 Transporter Expression in Human Brain Endothelial Cells Through Enhanced Histone Acetylation and Activation of Aryl Hydrocarbon Receptor Signaling

Cited by 21 publications

References 61 publications

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

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

Drug‐resistant epilepsy: Drug target hypothesis and beyond the receptors

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