Hypoxia and
hypoxia inducible factor-1alpha (HIF-1alpha) play a critical role in
glioblastoma (GBM) which is characterized by highly aggressive and widespread cell invasion into adjacent normal brain tissue. The purpose of this study was to investigate the effect of the novel
aminothiazole com-pound
SNS-032 in
glioblastoma cell invasion under hypoxic condition.
SNS-032 is a potent and selective inhibitor of
cyclin-dependent kinases 2, 7 and 9 and inhibits both cell cycle and transcription. We analyzed the effect of
SNS-032 (0.5 microM) on HIF-1alpha expression and its major trans-regulating factors including COX-2,
VEGF, MMP-2 and uPAR that are involved in cellular invasion in tumor hypoxia. Our observations demonstrate
SNS-032: i) inhibited
hypoxia-induced U87MG cell invasion and among all the other inhibitors tested,
SNS-032 is the most effective, ii) blocked HIF-1alpha mediated transcription of COX-2,
MMP-2,
VEGF and uPAR expression in U87MG cells in response to
hypoxia, iii) blocked HIF-1alpha expression by a
proteasome independent pathway. The effects were similar to those observed with HIF-1alpha
siRNA which prevented cellular invasion by blocking HIF-1alpha expression and its downstream effectors. Taken together, our data suggest that
SNS-032 prevents
hypoxia-mediated U87MG cell invasion by blocking the expression of HIF-1alpha and its trans-regulating factors. Our results present an opportunity in controlling highly invasive
tumors such as
glioblastoma using this novel class of compounds.