Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Ther. 2010 Jan;18(1):188-97. doi: 10.1038/mt.2009.219. Epub 2009 Sep 15.
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.
缺氧诱导因子-1（HIF-1）通过上调其靶基因在肿瘤促进中发挥关键作用，这些靶基因参与能量代谢、血管生成、细胞存活、侵袭、转移和耐药性。HIF-1alpha 亚基受 O2 依赖性羟化、泛素化和降解调节，已被确定为癌症治疗的重要分子靶标。我们合理设计了富含 G 的寡脱氧核苷酸（ODN）作为人类癌症治疗的 HIF-1alpha 抑制剂。先导化合物 JG243 和 JG244 形成分子内平行 G-四联体结构，选择性靶向 HIF-1alpha，并降低 HIF-1alpha 和 HIF-2alpha 的水平（IC50 < 2 μmol/l），还抑制 HIF-1 调节蛋白[血管内皮生长因子（VEGF）、Bcl-2 和 Bcl-XL]的表达，但不破坏 p300、Stat3 或 p53 的表达。JG-ODN 诱导 HIF-1alpha 和 HIF-2alpha 的蛋白酶体降解，这依赖于脯氨酰-4-羟化酶-2 的羟化酶活性。JG243 和 JG244 显著抑制前列腺、乳腺和胰腺肿瘤异种移植物的生长。肿瘤组织的 Western blot 显示，JG-ODN 显著降低 HIF-1alpha 和 HIF-2alpha 水平并阻断 VEGF 的表达。JG-ODN 是通过抑制 HIF-1 抑制肿瘤生长的新型抗癌药物。
