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

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Abstract

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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Blood-brain barrier structure and function and the challenges for CNS drug delivery.

N. Abbott (2013)

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the 'neurovascular unit' (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.

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The role and mechanisms of action of microRNAs in cancer drug resistance

Wengong Si, Jiaying Shen, Huilin Zheng … (2019)

MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.

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Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

Fei Tang, Anika Hartz, Björn Bauer (2017)

Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

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Author and article information

Contributors

Yangmei Xie: URI : http://loop.frontiersin.org/people/335967/overview

Ming Wang: URI : http://loop.frontiersin.org/people/865236/overview

Yiye Shao: URI : http://loop.frontiersin.org/people/302374/overview

Xiaolin Deng: URI : http://loop.frontiersin.org/people/558352/overview

Yinghui Chen: URI : http://loop.frontiersin.org/people/264908/overview

Journal

Journal ID (nlm-ta): Front Neurosci

Journal ID (iso-abbrev): Front Neurosci

Journal ID (publisher-id): Front. Neurosci.

Title: Frontiers in Neuroscience

Publisher: Frontiers Media S.A.

ISSN (Print): 1662-4548

ISSN (Electronic): 1662-453X

Publication date (Electronic): 17 December 2019

Publication date Collection: 2019

Volume: 13

Electronic Location Identifier: 1358

Affiliations

[1] ¹Department of Neurology, Jinshan Hospital, Fudan University , Shanghai, China

[2] ²Department of Neurology, Huashan Hospital North, Fudan University , Shanghai, China

Author notes

Edited by: Divya Vohora, Jamia Hamdard University, India

Reviewed by: Jian Qu, Central South University, China; Faheem Hyder Pottoo, Imam Abdulrahman Bin Faisal University, Saudi Arabia

*Correspondence: Yinghui Chen, yinghuichen@ 123456fudan.edu.cn

This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

Article

DOI: 10.3389/fnins.2019.01358

PMC ID: 6928106

SO-VID: 9b85b482-f32a-4589-9585-1d5e877e0aec

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 18 July 2019

Date accepted : 02 December 2019

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Figures: 5, Tables: 0, Equations: 0, References: 40, Pages: 10, Words: 0

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

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Most cited references 32

Blood-brain barrier structure and function and the challenges for CNS drug delivery.

The role and mechanisms of action of microRNAs in cancer drug resistance

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

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