Multi-drug resistance P-glycoprotein (P-gp/MDR1) is one of the most clinically relevant ABC transporters, highly enriched at the blood-brain barrier (BBB) with a broad substrate spectrum including therapeutic drugs and metabolic waste products. Altered P-gp transport function has been implicated in multi-drug resistance and in the pathogenesis and progression of neurological diseases. Recent studies have shown that P-gp expression is modulated by micro-RNAs in peripheral organs. Particularly, miR-27a-3p has been shown to play a critical role in the regulation of P-gp in multi-drug resistant cancer cells. In brain disorders, altered levels of miR-27a-3p were reported in several diseases associated with alterations in P-gp expression at the BBB. However, effect of altered miR-27a-3p expression on P-gp expression at the BBB remains to be determined. In this study, we investigated the role of miR-27a-3p in the regulation of P-gp expression and activity at the brain endothelium. Levels of miR-27a-3p were modulated by mimic and inhibitor transfection in an in-vitro model of human brain endothelial hCMEC/D3 cells. Effect of miR-27a-3p modulation on P-gp expression and activity was examined and the underlying regulatory mechanisms explored. Our results showed that transfection of hCMEC/D3 cells with miR-27a-3p mimic induces expression and activity of P-gp while miR-27a-3p inhibition exerted opposite effects. Mechanistic studies revealed that miR-27a-3p regulates P-gp by mediating Glycogen Synthase Kinase 3 Beta (GSK3ß) inhibition and activating Wnt/ß-catenin signaling. These findings shed light on miR-27a-3p/GSK3ß/ß-catenin as a novel axis that could be exploited to modulate P-gp efflux activity at the brain endothelium and help improving CNS diseases treatment or brain protection.
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http://dx.doi.org/10.1016/j.xphs.2021.10.021 | DOI Listing |
Technol Cancer Res Treat
January 2025
Cell Therapy Center, The University of Jordan, Amman, Jordan.
Background: Doxorubicin (DOX) is a potent chemotherapeutic agent for breast cancer, but its effectiveness is often diminished by resistance mechanisms, particularly through p-glycoprotein (P-gp) mediated drug efflux. Clarithromycin (CAM), a macrolide antibiotic, inhibits multiple metabolic pathways including CYP3A and P-gp, potentially countering DOX resistance.
Objective: This study aimed to evaluate the potentiation of DOX and its effectiveness against the MCF-7 breast cancer cell line by encapsulating both DOX and CAM in PEGylated liposomes.
Eur J Pharm Sci
January 2025
Preclinical Sciences & Translational Safety, Janssen R&D, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address:
The purpose of this study was to evaluate EpiColon, a novel human organotypic 3D colon microtissue prototype, developed to assess colonic drug disposition, with a particular focus on permeability ranking, and compare its performance to Caco-2 monolayers. EpiColon was characterized for barrier function using transepithelial electrical resistance (TEER), morphology via histology and immunohistochemistry, and functionality through drug transport studies measuring apparent permeability (P). Cutoff thresholds for the permeability of FITC-dextran 4 kDa (FD4), FITC-dextran 10 kDa (FD10S), and [C]mannitol were established to monitor microtissue integrity.
View Article and Find Full Text PDFBioorg Chem
January 2025
Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India. Electronic address:
Histone deacetylases (HDACs) play a critical role in chromatin remodelling and modulating the activity of various histone proteins. Aberrant HDAC functions has been related to the progression of breast cancer (BC), making HDAC inhibitors (HDACi) promising small-molecule therapeutics for its treatment. Hydroxamic acid (HA) is a significant pharmacophore due to its strong metal-chelating ability, HDAC inhibition properties, MMP inhibition abilities, and more.
View Article and Find Full Text PDFJ Chromatogr B Analyt Technol Biomed Life Sci
January 2025
Université Clermont Auvergne, Institut Universitaire de Technologie, UMR INSERM-UCA, U1240, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), 5 Avenue Blaise Pascal, 63000 Clermont-Ferrand, France.
A method using high-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) was developed and validated to quantify the innovative tool LightSpot®-FL-1, a selective permeability-glycoprotein (P-gp)-targeted fluorescent conjugate used to measure P-gp expression in cell samples. Quantifying P-gp is a major challenge in oncology as its overexpression in many cancer cells results in Multidrug Resistance (MDR) associated with chemotherapy failure. To develop the method reported herein, both sample preparation and analysis parameters were investigated.
View Article and Find Full Text PDFInt J Mol Sci
January 2025
Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health Sciences (NIH), Research Triangle Park, Durham, NC 27709, USA.
Acquired resistance to chemotherapeutic drugs is the primary cause of treatment failure in the clinic. While multiple factors contribute to this resistance, increased expression of ABC transporters-such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins-play significant roles in the development of resistance to various chemotherapeutics. We found that Erastin, a ferroptosis inducer, was significantly cytotoxic to NCI/ADR-RES, a P-gp-expressing human ovarian cancer cell line.
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