NEO212, a conjugate of temozolomide and perillyl alcohol, blocks the endothelial-to-mesenchymal transition in tumor-associated brain endothelial cells in glioblastoma

Abstract

As the endothelial-to-mesenchymal transition (EndMT) supports the pro-angiogenic and invasive characteristics of glioblastoma multiforme (GBM), blocking this process would be a promising approach to inhibit tumor progression and recurrence. Here, we demonstrate that glioma stem cells (GSC) induce EndMT in brain endothelial cells (BEC). TGF-β signaling is necessary, but not sufficient to induce this EndMT process. Cell-to-cell contact and the contribution of Notch signaling are also required. NEO212, a conjugate of temozolomide and perillyl alcohol, blocks EndMT induction and reverts the mesenchymal phenotype of tumor-associated BEC (TuBEC) by blocking TGF-β and Notch pathways. Consequently, NEO212 reduces the invasiveness and pro-angiogenic properties associated with TuBEC, without affecting control BEC. Intracranial co-implantation of BEC and GSC in athymic mice showed that EndMT occurs in vivo, and can be blocked by NEO212, supporting the potential clinical value of NEO212 for the treatment of GBM.