Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions.
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.
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
Rajarshi
R
Sengupta
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
Amy
A
Barone
High Throughput Screening Core, Washington University School of Medicine, St. Louis, Missouri, USA.
Jayne
J
Marasa
Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Sara
S
Taylor
Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Erin
E
Jackson
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
Nicole M
NM
Warrington
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
Shyam
S
Rao
Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Albert H
AH
Kim
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Jeffrey R
JR
Leonard
Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
David
D
Piwnica-Worms
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Joshua B
JB
Rubin
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D011479:Protamines / Q000302:isolation & purification / Q000494:pharmacology; D000077185:Resveratrol; D054852:Small Molecule Libraries / Q000302:isolation & purification / Q000494:pharmacology*; D013150:Spirostans / Q000302:isolation & purification / Q000494:pharmacology; D013267:Stilbenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D010936:Plant Extracts; D011479:Protamines; D054852:Small Molecule Libraries; D013150:Spirostans; D013267:Stilbenes; C001472:iridine; C046297:sarsasapogenin; D000077185:Resveratrol
GBM; Iridin; co-culture; high throughput screen; perivascular niche