MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

Xie, Yangmei; Shao, Yiye; Deng, Xiaolin; Wang, Ming; Chen, Yinghui

doi:10.3389/fnins.2018.00602

Cited by 34 publications

(26 citation statements)

References 33 publications

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“…The establishment of the PHT-resistant cell line was described in our previous study (Xie et al, 2018). In the present study, it was observed that the expression of P-gp was significantly elevated in HBMEC/PHT cells as determined by IF staining (Figure 1A).…”

Section: The Expression Of Kcnq1ot1 Is Upregulated In Pht-resistant Hsupporting

confidence: 77%

Long Non-coding RNA KCNQ1OT1 Contributes to Antiepileptic Drug Resistance Through the miR-138-5p/ABCB1 Axis in vitro

et al. 2019

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Compelling evidence has verified that long non-coding RNAs (lncRNAs) play a critical role on drug resistance in various diseases, especially cancer. However, the role of lncRNAs underlying multidrug resistance in epilepsy remains to be clarified. In the present study, we investigated the potential regulatory mechanism of the lncRNA KCNQ1OT1 in regulating antiepileptic drug (AED) resistance in human brain microvascular endothelial cells (HBMECs). The results revealed that expression of P-glycoprotein (P-gp) and KCNQ1OT1 was significantly elevated in phenytoin-resistant HBMECs (HBMEC/PHT). Meanwhile, the activity of nuclear factor-kappa B (NF-κB) was increased in HBMECs/PHT cells. Microarray analysis indicated that miR-138-5p was downregulated in HBMEC/PHT cells. Interestingly, bioinformatics prediction tools indicated miR-138-5p could directly target the transcripts of KCNQ1OT1 and NF-κB p65, and these results were confirmed by luciferase assays. Moreover, KCNQ1OT1 downregulation or miR-138-5p upregulation in vitro could inhibit P-gp expression and suppress NF-κB signaling pathway activation. Additionally, knockdown of KCNQ1OT1 or overexpression of miR-138-5p could increase the accumulation of rhodamine 123 (Rh123) and AEDs in HBMEC/PHT cells. Collectively, our results suggested that KCNQ1OT1 contributes to AED resistance through the miR-138-5p/NF-κB/ABCB1 axis in HBMEC/PHT cells, and these results provide a promising therapeutic target for the treatment of medically intractable epilepsy.

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Section: The Expression Of Kcnq1ot1 Is Upregulated In Pht-resistant Hsupporting

confidence: 77%

Long Non-coding RNA KCNQ1OT1 Contributes to Antiepileptic Drug Resistance Through the miR-138-5p/ABCB1 Axis in vitro

et al. 2019

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“…Specific mechanisms of drug resistance mediated by miRNAs are under ongoing investigation. Accumulating evidence, however, shows that the ATP-binding cassette (ABC) transporter family of proteins that activate drug resistance are regulated by miRNAs (Guo et al., 2018; Xie et al., 2018). The ABC family includes P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRP), and breast cancer resistance proteins (BCRP), all of which can pump out drugs to create additional biological energy through ATP hydrolysis (Choi, 2005; Paskeviciute and Petrikaite, 2019).…”

Section: Drug Resistance and Mirnasmentioning

confidence: 99%

The Potential for microRNA Therapeutics and Clinical Research

Hanna¹,

Hossain²,

2019

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As FDA-approved small RNA drugs start to enter clinical medicine, ongoing studies for the microRNA (miRNA) class of small RNAs expand its preclinical and clinical research applications. A growing number of reports suggest a significant utility of miRNAs as biomarkers for pathogenic conditions, modulators of drug resistance, and/or as drugs for medical intervention in almost all human health conditions. The pleiotropic nature of this class of nonprotein-coding RNAs makes them particularly attractive drug targets for diseases with a multifactorial origin and no current effective treatments. As candidate miRNAs begin to proceed toward initiation and completion of potential phase 3 and 4 trials in the future, the landscape of both diagnostic and interventional medicine will arguably continue to evolve. In this mini-review, we discuss miRNA drug discovery development and their current status in clinical trials.

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“…Other mRNAs, including miR-298, mediate the downregulation of Pgp [ 50 ]. Recently, it was shown that miR-298 reverses multidrug resistance to ASDs by downregulating Pgp expression in the BBB, using human BCECs [ 51 ].…”

Section: Regulation Of Pgp At the Bbb: Conventional Mechanismsmentioning

confidence: 99%

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

Löscher

Gericke

2020

Pharmaceutics

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The blood–brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.

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MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

Cited by 34 publications

References 33 publications

Long Non-coding RNA KCNQ1OT1 Contributes to Antiepileptic Drug Resistance Through the miR-138-5p/ABCB1 Axis in vitro

Long Non-coding RNA KCNQ1OT1 Contributes to Antiepileptic Drug Resistance Through the miR-138-5p/ABCB1 Axis in vitro

The Potential for microRNA Therapeutics and Clinical Research

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

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