HMG-CoA reductase inhibition causes increased necrosis and apoptosis in an in vivo mouse glioblastoma multiforme model.
BACKGROUND
Statins are thought to have tumorolytic properties, reducing angiogenesis by inhibiting pro-angiogenic factors and inducing apoptosis of mural pericytes within the tumor vascular tree.


METHODS
An orthotopic mouse glioblastoma (GL-26) model was used to investigate the effect of simvastatin on glioblastoma vasculature in vivo. GL-26 cells were implanted into the striatum of C5LKa mice treated with either control, low- or high-dose simvastatin. Brains were analyzed for necrotic volume, apoptosis, morphology and pericytic cells within the vascular tree.


RESULTS
Low-dose simvastatin increased necrosis and apoptosis compared to both control and high-dose simvastatin groups. High-dose simvastatin increased vessel caliber by reducing pericytic cells along the tumor vessel wall compared to both control and low-dose simvastatin groups.


CONCLUSIONS
Simvastatin has a dual effect on tumorigenesis. At high doses, it may worsen instead of 'normalizing' tumor angio-architecture, albeit low doses affect tumor cell survival by promoting necrosis and apoptosis.
Bababeygy
Simon R
SR
Department of Neurosurgery, Stanford University Medical Center, 1201 Welch Road, P310, Stanford, CA 94305-5327, USA.
Polevaya
Nika V
NV
Youssef
Sawsan
S
Sun
Amy
A
Xiong
Anming
A
Prugpichailers
Tiffany
T
Veeravagu
Anand
A
Hou
Lewis C
LC
Steinman
Lawrence
L
Tse
Victor
V
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009374:Neoplasms, Experimental; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*
D000214:Acyl Coenzyme A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D019821:Simvastatin