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

Nagore I Marín-Ramos; Niyati Jhaveri; Thu Zan Thein; Rochelle A Fayngor; Thomas C Chen; Florence M Hofman

doi:10.1016/j.canlet.2018.10.034

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

Cancer Lett. 2019 Feb 1:442:170-180. doi: 10.1016/j.canlet.2018.10.034. Epub 2018 Oct 28.

Authors

Nagore I Marín-Ramos¹, Niyati Jhaveri¹, Thu Zan Thein¹, Rochelle A Fayngor¹, Thomas C Chen², Florence M Hofman³

Affiliations

¹ Department of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
² Department of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA; Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
³ Department of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA; Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA. Electronic address: hofman@usc.edu.

PMID: 30392789
DOI: 10.1016/j.canlet.2018.10.034

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.

Keywords: EndMT; Glioma stem cells (GSC); Notch; Smad; TGF-β.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Brain Neoplasms / blood supply*
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Movement / drug effects
Coculture Techniques
Dacarbazine / analogs & derivatives*
Dacarbazine / pharmacology
Endothelial Cells / drug effects*
Endothelial Cells / metabolism
Endothelial Cells / pathology
Epithelial-Mesenchymal Transition / drug effects*
Glioblastoma / blood supply*
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Glioblastoma / pathology
Humans
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Mice, Nude
Neoplasm Invasiveness
Neovascularization, Pathologic*
Receptors, Notch / metabolism
Signal Transduction / drug effects
Transforming Growth Factor beta / metabolism
Xenograft Model Antitumor Assays

Substances

NEO212
Receptors, Notch
Transforming Growth Factor beta
Dacarbazine
MMP2 protein, human
Matrix Metalloproteinase 2
MMP9 protein, human
Matrix Metalloproteinase 9