The novel CXCR4 antagonist, PRX177561, reduces tumor cell proliferation and accelerates cancer stem cell differentiation in glioblastoma preclinical models

Abstract

Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell-derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell-derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential.

Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

“…Chia et al (2018) showed that, whilst CSF-1 played a role in macrophage recruitment, signalling to Cxcr4 was absolutely required for the recruitment of macrophages to the Akt-transformed brain in zebrafish tumour initiation, and that PNC-derived Cxcl12 was the major ligand for this interaction [142]. Cxcr4 signalling has been shown to promote progression of many cancers in mammals including glioblastoma, through both cancer cell autonomous signalling and leukocyte interactions [106,[176][177][178][179][180][181]. However, the pro-tumour effect of Cxcr4 signalling at the preneoplastic stage was macrophage specific [142].…”

Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways

“…This protein reduces the frequency of aldehyde dehydrogenase positivity among the cancerous cells which are the indicators of CSC function [52]. This data suggests that THTMP could not promote the dormancy of CSCs, in contrast, we could observe that the CXC chemokine receptor 4 signaling (CXCR4) is modulated by THTMP, which confirms its role in the wake-up therapeutic strategy in targeting CSCs [53,54].…”

Cancer stem cells and differentiation therapy

“…A novel antagonist of CXCR4, a receptor for CXCL12 that increases in tumors, induced CSC differentiation and reduced tumor cell growth in a preclinical glioblastoma multiforme (GBM) model. 157 …”