Downregulation of the CCL2/CCR2 and CXCL10/CXCR3 axes contributes to antitumor effects in a mouse model of malignant glioma

Abstract

Glioblastoma multiforme involves glioma stem cells (GSCs) that are resistant to various therapeutic approaches. Here, we studied the importance of paracrine signaling in the glioma microenvironment by focusing on the celecoxib-mediated role of chemokines C–C motif ligand 2 (CCL2), C-X-C ligand 10 (CXCL10), and their receptors, CCR2 and CXCR3, in GSCs and a GSC-bearing malignant glioma model. C57BL/6 mice were injected with orthotopic GSCs intracranially and divided into groups administered either 10 or 30 mg/kg celecoxib, or saline to examine the antitumor effects associated with chemokine expression. In GSCs, we analyzed cell viability and expression of chemokines and their receptors in the presence/absence of celecoxib. In the malignant glioma model, celecoxib exhibited antitumor effects in a dose dependent manner and decreased protein and mRNA levels of Ccl2 and CxcL10 and Cxcr3 but not of Ccr2. CCL2 and CXCL10 co-localized with Nestin+ stem cells, CD16+ or CD163+ macrophages and Iba-1+ microglia. In GSCs, celecoxib inhibited Ccl2 and Cxcr3 expression in a nuclear factor-kappa B-dependent manner but not Ccr2 and CxcL10. Moreover, Ccl2 silencing resulted in decreased GSC viability. These results suggest that celecoxib-mediated regulation of the CCL2/CCR2 and CXCL10/ CXCR3 axes may partially contribute to glioma-specific antitumor effects.

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

“…In addition, MDR1 expression is associated with several cellular signaling pathways and protein kinases, chaperons, ubiquitin-related enzymes, and transcription factors. 31 As the COX-2 inhibitor induced apoptosis by inhibiting the AKT pathway in lowgrade glioma cells in a previous study, 18 we observed MDR1 down-regulation through the Akt/NF-kB pathway upon celecoxib treatment. Furthermore, we observed the down-regulation of MDR1 by a NF-kB inhibitor, CAPE.…”

“…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. 18,19 Based on these ndings, we hypothesized that down-regulation of MDR1 by celecoxib via Akt/NF-kB pathways may promote the uptake of 5-ALA into GBM, thereby elevating cellular PpIX levels and enhance the anti-tumor effects of SDT.…”

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

“…First, we confirmed that SDT monotherapy exerted anti-tumor effects in GSCs and GSCs-bearing glioma model; however, it displayed transient and limited efficacy. Since we have demonstrated the anti-tumor effects by a COX2 inhibitor, celecoxib 18 , 19 , we assessed the efficacy of SDT combined with pre-treatment by celecoxib. Expectedly, the pre-treatment by celecoxib decreased the expression of MDR-1 and elevated the cellular PpIX levels induced by 5-ALA, resulting in the enhanced anti-tumor effects of the combination therapy in the GSC-bearing glioma model.…”

“…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 . We also 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 model 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.…”

Calycosin(CA) Inhibits Proliferation, Migration and Invasion by Suppression of CXCL10 Signaling Pathway in Glioma

“…A recent immunohistochemical study found that CXCL10 was overexpressed in GBM [26]. Kenji Shono et al revealed that CXCL10 exerts anti-tumor impact in a mouse model of malignant glioma [27]. CXCL10 appears to be critical regulator of GBM growth and progression.…”