Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-\u03baB/MDR1 pathway

Kenji Shono,Izumi Yamaguchi,Keiko Kitazato,Hideyuki Saya,Yuri Fujiwara,Yoshihiro Uto,Kazuhito Matsuzaki,Yoshifumi Mizobuchi,Kohei Nakajima,Oltea Sampetrean,Yasushi Takagi,Toshitaka Fujihara

doi:10.1038/s41598-021-93896-0

Abstract

Glioblastoma (GBM) has high mortality rates because of extreme therapeutic resistance. During surgical resection for GBM, 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is conventionally applied to distinguish GBM. However, surgical intervention is insufficient for high invasive GBM. Sonodynamic therapy (SDT) combined with low-intensity ultrasonication (US) and PpIX, as a sonosensitizer, is an emerging and promising approach, although its efficacy is limited. Based on our previous study that down-regulation of multidrug resistant protein (MDR1) in GBM augmented the anti-tumor effects of chemotherapy, we hypothesized that elevation of cellular PpIX levels by down-regulation of MDR1 enhances anti-tumor effects by SDT. In high invasive progeny cells from mouse glioma stem cells (GSCs) and a GSC-bearing mouse glioma model, we assessed the anti-tumor effects of SDT with a COX-2 inhibitor, celecoxib. Down-regulation of MDR1 by celecoxib increased cellular PpIX levels, as well as valspodar, an MDR1 inhibitor, and augmented anti-tumor effects of SDT. MDR1 down-regulation via the Akt/NF-κB pathway by celecoxib was confirmed, using an NF-κB inhibitor, CAPÉ. Thus, elevation of cellar PpIX by down-regulation of MDR1 via the Akt/NF-κB pathway may be crucial to potentiate the efficacy of SDT in a site-directed manner and provide a promising new therapeutic strategy for GBM.

Highlights

Glioblastoma (GBM) is the most common primary malignant brain tumor and has high recurrence and mortality rates[1,2]
We reported that a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib exerted anti-tumor effects associated with the down-regulation of Akt/NF-κB pathways in mouse glioma stem cells (GSCs) and GSCs-bearing glioma m odel[18,19]
We initially show that combination of Sonodynamic therapy (SDT) and celecoxib to down-regulate MDR1 augmented the anti-tumor effects in GSCs and the mouse GSC-bearing malignant glioma model indicating invasive and therapeutic resistance

Summary

Introduction

Glioblastoma (GBM) is the most common primary malignant brain tumor and has high recurrence and mortality rates[1,2]. We reported that a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib exerted anti-tumor effects associated with the down-regulation of Akt/NF-κB pathways in mouse glioma stem cells (GSCs) and GSCs-bearing glioma m odel[18,19] Based on these findings, we hypothesized that down-regulation of MDR1 by celecoxib via Akt/NF-κB pathways may promote the uptake of 5-ALA into GBM, thereby elevating cellular PpIX levels and enhance the anti-tumor effects of SDT. This study shows that elevation of cellular PpIX through celecoxib-mediated MDR1 down-regulation potentiates anti-tumor effects of SDT in a mouse GSC-bearing malignant glioma model which is highly invasive and similar to GBM in many r espects[20,21]

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Conclusion