Yeo Eun-Jin, Chun Yang-Sook, Cho Young-Suk, Kim Jinho, Lee June-Chul, Kim Myung-Suk, Park Jong-Wan
Department of Pharmacology, BK21 Human Life Sciences, Seoul National University College of Medicine, Seoul, Korea.
J Natl Cancer Inst. 2003 Apr 2;95(7):516-25. doi: 10.1093/jnci/95.7.516.
Hypoxia-inducible factor 1 alpha (HIF-1alpha), a component of HIF-1, is expressed in human tumors and renders cells able to survive and grow under hypoxic (low-oxygen) conditions. YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, an agent developed for circulatory disorders that inhibits platelet aggregation and vascular contraction, inhibits HIF-1 activity in vitro. We tested whether YC-1 inhibits HIF-1 and tumor growth in vivo.
Hep3B hepatoma, NCI-H87 stomach carcinoma, Caki-1 renal carcinoma, SiHa cervical carcinoma, and SK-N-MC neuroblastoma cells were grown as xenografts in immunodeficient mice (69 mice total). After the tumors were 100-150 mm(3), mice received daily intraperitoneal injections of vehicle or YC-1 (30 microg/g) for 2 weeks. HIF-1 alpha protein levels and vascularity in tumors were assessed by immunohistochemistry, and the expression of HIF-1-inducible genes (vascular endothelial growth factor, aldolase, and enolase) was assessed by reverse transcription-polymerase chain reaction. All statistical tests were two-sided.
Compared with tumors from vehicle-treated mice, tumors from YC-1-treated mice were statistically significantly smaller (P<.01 for all comparisons), expressed lower levels of HIF-1 alpha (P<.01 for all comparisons), were less vascularized (P<.01 for all comparisons), and expressed lower levels of HIF-1-inducible genes, regardless of tumor type.
The inhibition of HIF-1 alpha activity in tumors from YC-1-treated mice is associated with blocked angiogenesis and an inhibition of tumor growth. YC-1 has the potential to become the first antiangiogenic anticancer agent to target HIF-1 alpha.
缺氧诱导因子1α(HIF-1α)是HIF-1的一个组成部分,在人类肿瘤中表达,并使细胞能够在缺氧(低氧)条件下存活和生长。YC-1,即3-(5'-羟甲基-2'-呋喃基)-1-苄基吲唑,是一种用于治疗循环系统疾病的药物,可抑制血小板聚集和血管收缩,在体外能抑制HIF-1活性。我们测试了YC-1在体内是否能抑制HIF-1和肿瘤生长。
将Hep3B肝癌细胞、NCI-H87胃癌细胞、Caki-1肾癌细胞、SiHa宫颈癌细胞和SK-N-MC神经母细胞瘤细胞作为异种移植物接种到免疫缺陷小鼠体内(共69只小鼠)。待肿瘤体积达到100 - 150立方毫米后,小鼠每天接受腹腔注射溶剂或YC-1(30微克/克),持续2周。通过免疫组织化学评估肿瘤中HIF-1α蛋白水平和血管生成情况,并通过逆转录聚合酶链反应评估HIF-1诱导基因(血管内皮生长因子、醛缩酶和烯醇化酶)的表达。所有统计检验均为双侧检验。
与溶剂处理组小鼠的肿瘤相比,YC-1处理组小鼠的肿瘤在统计学上显著更小(所有比较P <.01),HIF-1α表达水平更低(所有比较P <.01),血管生成更少(所有比较P <.01),且HIF-1诱导基因表达水平更低,无论肿瘤类型如何。
YC-1处理组小鼠肿瘤中HIF-1α活性的抑制与血管生成受阻和肿瘤生长抑制相关。YC-1有可能成为首个靶向HIF-1α的抗血管生成抗癌药物。