title: G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth.
abstract: Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in tumor promotion by upregulating its target genes, which are involved in energy metabolism, angiogenesis, cell survival, invasion, metastasis, and drug resistance. The HIF-1alpha subunit, which is regulated by O2-dependent hydroxylation, ubiquitination, and degradation, has been identified as an important molecular target for cancer therapy. We have rationally designed G-rich oligodeoxynucleotides (ODNs) as inhibitors of HIF-1alpha for human cancer therapy. The lead compounds, JG243 and JG244, which form an intramolecular parallel G-quartet structure, selectively target HIF-1alpha and decreased levels of both HIF-1alpha and HIF-2alpha (IC50 < 2 micromol/l) and also inhibited the expression of HIF-1-regulated proteins [vascular endothelial growth factor (VEGF), Bcl-2, and Bcl-XL], but did not disrupt the expression of p300, Stat3, or p53. JG-ODNs induced proteasomal degradation of HIF-1alpha and HIF-2alpha that was dependent on the hydroxylase activity of prolyl-4-hydroxylase-2. JG243 and JG244 dramatically suppressed the growth of prostate, breast, and pancreatic tumor xenografts. Western blots from tumor tissues showed that JG-ODNs significantly decreased HIF-1alpha and HIF-2alpha levels and blocked the expression of VEGF. The JG-ODNs are novel anticancer agents that suppress tumor growth by inhibiting HIF-1.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guan
authors.forename: Kavitha Ramasamy
authors.initials: KR
authors.lastname: Reddy
authors.forename: Qiqing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Yifei
authors.initials: Y
authors.lastname: Li
authors.forename: KangAe
authors.initials: K
authors.lastname: Lee
authors.forename: Priya
authors.initials: P
authors.lastname: Weerasinghe
authors.forename: Josef
authors.initials: J
authors.lastname: Prchal
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Naijie
authors.initials: N
authors.lastname: Jing
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D009841:Oligonucleotides / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009841:Oligonucleotides; D000099162:Endothelial PAS Domain-Containing Protein 1; C568499:ODN JG244