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G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth

Yongli Guan1, Kavitha Ramasamy Reddy, Qiqing Zhu

  • 1Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|September 17, 2009
PubMed

Insights

Novel G-rich oligodeoxynucleotides (ODNs) target and degrade Hypoxia-inducible factor-1 alpha (HIF-1alpha), inhibiting tumor growth. These compounds show promise as anticancer agents by suppressing key cancer-promoting genes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hypoxia-inducible factor-1 (HIF-1) promotes tumor progression through target genes involved in metabolism, angiogenesis, survival, invasion, metastasis, and drug resistance.
  • The HIF-1alpha subunit is a critical molecular target for cancer therapy due to its oxygen-dependent regulation and degradation.
  • Existing therapies face challenges in effectively targeting HIF-1alpha pathways in various cancers.

Purpose of the Study:

  • To design and evaluate G-rich oligodeoxynucleotides (ODNs) as novel inhibitors of HIF-1alpha for human cancer therapy.
  • To investigate the mechanism of action of these ODN inhibitors, including their specificity and impact on HIF-1 regulated pathways.
  • To assess the therapeutic efficacy of lead ODN compounds in preclinical cancer models.

Main Methods:

  • Rational design of G-rich oligodeoxynucleotides (ODNs) forming intramolecular G-quartet structures.
  • In vitro assessment of ODN compounds (JG243, JG244) for HIF-1alpha and HIF-2alpha inhibition and impact on downstream proteins (VEGF, Bcl-2, Bcl-XL, p300, Stat3, p53).
  • In vivo studies using prostate, breast, and pancreatic tumor xenografts to evaluate tumor growth suppression and molecular changes.

Main Results:

  • Lead compounds JG243 and JG244 selectively targeted and decreased HIF-1alpha and HIF-2alpha levels (IC50 < 2 micromol/l).
  • JG-ODNs inhibited expression of HIF-1 regulated proteins including vascular endothelial growth factor (VEGF), Bcl-2, and Bcl-XL, without affecting p300, Stat3, or p53.
  • ODN-induced degradation of HIF-1alpha and HIF-2alpha was dependent on prolyl-4-hydroxylase-2 activity, and JG243/JG244 significantly suppressed tumor xenograft growth.

Conclusions:

  • G-rich oligodeoxynucleotides (ODNs) represent a novel class of anticancer agents targeting HIF-1alpha.
  • These ODNs effectively suppress tumor growth by inducing proteasomal degradation of HIF-1alpha and HIF-2alpha.
  • The findings support the therapeutic potential of JG-ODNs for treating various human cancers driven by HIF-1 signaling.

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