Expression of P-gp in Glioblastoma: What we can Learn from Brain Development

Abstract

P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial expression of P-gp, and the subcellular localization of the transporter at the luminal endothelial cell (EC) plasma membrane are early hallmarks of blood-brain barrier (BBB) differentiation and suggest a functional BBB activity that may complement the placental barrier function and the expression of P-gp at the blood-placental interface. In early fetal ages, P-gp has also been immunolocalized on radial glia cells (RGCs), located in the proliferative ventricular zone (VZ) of the dorsal telencephalon and now considered to be neural progenitor cells (NPCs). RG-like NPCs have been found in many regions of the developing brain and have been suggested to give rise to neural stem cells (NSCs) of adult subventricular (SVZ) neurogenic niches. The P-gp immunosignal, associated with RG-like NPCs during cortical histogenesis, progressively decreases in parallel with the last waves of neuroblast migrations, while ‘outer’ RGCs and the deriving astrocytes do not stain for the efflux transporter. These data suggest that in human glioblastoma (GBM), P-gp expressed by ECs may be a negligible component of tumor MDR. Instead, tumor perivascular astrocytes may dedifferentiate and resume a progenitor-like P-gp activity, becoming MDR cells and contribute, together with perivascular P-gpexpressing glioma stem-like cells (GSCs), to the MDR profile of GBM vessels. In conclusion, the analysis of Pgp immunolocalization during brain development may contribute to identify the multiple cellular sources in the GBM vessels that may be involved in P-gp-mediated chemoresistance and can be responsible for GBM therapy failure and tumor recurrence.

Development and Validation of a Long-Term 3D Glioblastoma Cell Culture in Alginate Microfibers as a Novel Bio-Mimicking Model System for Preclinical Drug Testing

“…Among them, P-glycoprotein (ABCB1) is the most studied, and its role in the blood-brain-barrier is well-established [33]. Its increased expression and role in glioblastoma resistance have been reported [13,30,33,34] as well as its direct interaction with TMZ [35]. Our results demonstrated that besides MGMT, ABCB1 expression also increases in 3D glioblastoma cell culture more profoundly than in 2D.…”

“…In addition, the ATP-binding cassette (ABC) transporter superfamily plays an important role in glioblastoma resistance to chemotherapy [31,32]. Among them, P-glycoprotein (ABCB1) is the most studied, and its role in the blood-brain-barrier is well-established [33]. Its increased expression and role in glioblastoma resistance have been reported [13,30,33,34] as well as its direct interaction with TMZ [35].…”

Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-κB/MDR1 pathway

“…P-Glycoprotein, referred to as multidrug resistance receptor (MDR1), is a transmembrane glycoprotein functioning as an efflux pump and conferring multidrug resistance in brain tumors 15 , 16 . We have previously reported high expression of MDR1 in GBM and demonstrated that down-regulation of MDR1 via Akt/NF-κB pathways upon transfection of the Ad-DKK3 gene augmented the anti-tumor effects of temozolomide in GBM cells and in a GBM-xenograft model 17 .…”

Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NFkB/MDR1 pathway

“…14 P-Glycoprotein, referred to as multidrug resistance receptor (MDR1), is a transmembrane glycoprotein functioning as an e ux pump and conferring multidrug resistance in brain tumors. 15,16 Elsewhere, we reported high expression of MDR1 in GBM and demonstrated that down-regulation of MDR1 via Akt/NF-kB pathways upon transfection of the Ad-DKK3 gene augmented the anti-tumor effects of temozolomide in GBM cells and in a GBM-xenograft model. 17 We also reported that a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib exerted anti-tumor effects associated with the down-regulation of Akt/NF-kB pathways in mouse glioma stem cells (GSCs) and GSCs-bearing glioma model.…”