SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1alpha expression.
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.
Ali
M Aktar
MA
Department of Radiation Oncology, Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9187, USA.
Reis
Aimee
A
Ding
Liang-Hao
LH
Story
Michael D
MD
Habib
Amyn A
AA
Chattopadhyay
Ansuman
A
Saha
Debabrata
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007797:Laminin / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D010080:Oxazoles / Q000494:pharmacology*; D011509:Proteoglycans / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D017931:DNA Primers; D004338:Drug Combinations; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D011509:Proteoglycans; D034741:RNA, Small Interfering; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen