Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions

Rajarshi Sengupta, Amy Barone, Jayne Marasa, Sara Taylor, Erin Jackson, Nicole M. Warrington, Shyam Rao, Albert H. Kim, Jeffrey R. Leonard, David Piwnica-Worms, Joshua B. Rubin

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth.

Original languageEnglish (US)
Pages (from-to)18282-18292
Number of pages11
JournalOncotarget
Volume6
Issue number21
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Co-culture
  • GBM
  • High throughput screen
  • Iridin
  • Perivascular niche

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions'. Together they form a unique fingerprint.

  • Cite this

    Sengupta, R., Barone, A., Marasa, J., Taylor, S., Jackson, E., Warrington, N. M., Rao, S., Kim, A. H., Leonard, J. R., Piwnica-Worms, D., & Rubin, J. B. (2015). Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions. Oncotarget, 6(21), 18282-18292. https://doi.org/10.18632/oncotarget.4957