SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression

M. Aktar Ali, Aimee Reis, Liang Hao Ding, Michael D. Story, Amyn A. Habib, Ansuman Chattopadhyay, Debabrata Saha

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Hypoxia and hypoxia inducible factor-1α (HIF-1α) 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 compound 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 μM) on HIF-1α 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-1α mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1α expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1α siRNA which prevented cellular invasion by blocking HIF-1α 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-1α and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.

Original languageEnglish (US)
Pages (from-to)1051-1060
Number of pages10
JournalInternational Journal of Oncology
Volume34
Issue number4
DOIs
StatePublished - 2009

Fingerprint

Hypoxia-Inducible Factor 1
Glioblastoma
Matrix Metalloproteinases
Vascular Endothelial Growth Factor A
Cyclin-Dependent Kinase 9
Cyclin-Dependent Kinase 2
Proteasome Endopeptidase Complex
N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
Hypoxia
Small Interfering RNA
Cell Cycle
Brain

Keywords

  • CDK
  • Cell invasion
  • Glioblastoma
  • HIF-1α
  • Hypoxia
  • MMPs
  • SNS-032
  • VEGF
  • VEGK

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression. / Ali, M. Aktar; Reis, Aimee; Ding, Liang Hao; Story, Michael D.; Habib, Amyn A.; Chattopadhyay, Ansuman; Saha, Debabrata.

In: International Journal of Oncology, Vol. 34, No. 4, 2009, p. 1051-1060.

Research output: Contribution to journalArticle

@article{364d89a1eb6642a1975556c1f2c8b1c0,
title = "SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression",
abstract = "Hypoxia and hypoxia inducible factor-1α (HIF-1α) 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 compound 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 μM) on HIF-1α 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-1α mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1α expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1α siRNA which prevented cellular invasion by blocking HIF-1α 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-1α and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.",
keywords = "CDK, Cell invasion, Glioblastoma, HIF-1α, Hypoxia, MMPs, SNS-032, VEGF, VEGK",
author = "Ali, {M. Aktar} and Aimee Reis and Ding, {Liang Hao} and Story, {Michael D.} and Habib, {Amyn A.} and Ansuman Chattopadhyay and Debabrata Saha",
year = "2009",
doi = "10.3892/ijo_00000231",
language = "English (US)",
volume = "34",
pages = "1051--1060",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "Spandidos Publications",
number = "4",

}

TY - JOUR

T1 - SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression

AU - Ali, M. Aktar

AU - Reis, Aimee

AU - Ding, Liang Hao

AU - Story, Michael D.

AU - Habib, Amyn A.

AU - Chattopadhyay, Ansuman

AU - Saha, Debabrata

PY - 2009

Y1 - 2009

N2 - Hypoxia and hypoxia inducible factor-1α (HIF-1α) 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 compound 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 μM) on HIF-1α 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-1α mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1α expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1α siRNA which prevented cellular invasion by blocking HIF-1α 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-1α and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.

AB - Hypoxia and hypoxia inducible factor-1α (HIF-1α) 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 compound 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 μM) on HIF-1α 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-1α mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1α expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1α siRNA which prevented cellular invasion by blocking HIF-1α 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-1α and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.

KW - CDK

KW - Cell invasion

KW - Glioblastoma

KW - HIF-1α

KW - Hypoxia

KW - MMPs

KW - SNS-032

KW - VEGF

KW - VEGK

UR - http://www.scopus.com/inward/record.url?scp=67649446851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649446851&partnerID=8YFLogxK

U2 - 10.3892/ijo_00000231

DO - 10.3892/ijo_00000231

M3 - Article

VL - 34

SP - 1051

EP - 1060

JO - International Journal of Oncology

JF - International Journal of Oncology

SN - 1019-6439

IS - 4

ER -