HUMULONE, A POTENT COX-2 INHIBITOR FROM BEER HOP, INHIBITS ANGIOGENESIS

血管生成是指形成新的供氧和营养的毛细血管，对实体肿瘤的持续生长和转移是必不可少的。有效的血管生成抑制剂抑制肿瘤血管生成可能是肿瘤治疗的一条有效途径。近年来，环氧合酶(COX)尤其是COX-2被认为与肿瘤的生长、转移和血管生成有关。为了找到一种新的有效的血管生成抑制剂，我们将先前的发现集中在葫芦酮，一种来自啤酒啤酒花(Humulus lupulus L.)是一种有效的骨吸收抑制剂，可以抑制环氧合酶-2的催化活性，更有效地抑制环氧合酶-2基因的转录。我们首先利用鸡胚绒毛尿囊膜(CAM)和血管内皮细胞和肿瘤细胞观察了绿草隆对血管生成的影响。虎杖草酮以剂量依赖的方式显著抑制CAM体内血管生成。虎杖草酮可有效抑制碱性成纤维细胞生长因子、血管内皮生长因子和血清刺激内皮细胞的增殖。它还能抑制血管内皮细胞和肿瘤细胞的血管生成和血管生成因子(VEGF)的产生。接下来，我们研究了从葫芦酮中合成或纯化的化合物对CAM血管生成的影响。在所测试的化合物中，虎杖草酮是最有效的血管生成抑制剂。因此，我们合成了大量的草甘草酮，并在小鼠体内进行了检测。在小鼠背部气囊实验中，虎杖草酮可抑制肿瘤诱导的血管生成，并可通过腹腔给药抑制肿瘤细胞的自发肺转移。基于这些结果，虎杖草酮是一种有效的血管生成抑制剂，可能成为治疗实体瘤、类风湿性关节炎和糖尿病视网膜病变等多种血管生成疾病的新的有力工具。

Angiogenesis, the formation of new capillary blood vessels for supplying oxygen and nutrients, is essential for their continuous growth and metastasis of solid tumors. The inhibition of tumor angiogenesis by potent angiogenic inhibitors may be a useful approach for cancer therapy. Recently, cyclooxygenase (COX), particularly COX-2, was postulated to be involved in tumor growth, metastasis and angiogenesis. To find a new potent angiogenic inhibitor, we focused our previous finding that humulone, a bitter acid from beer hop (Humulus lupulus L.) was a potent inhibitor of bone resorption and inhibited catalytic activity of cyclooxygenase-2 and more potently the transcription of COX-2 gene.We first examined the effect of humulone on angiogenesis, using chick embryo chorioallantoic membranes (CAM) and vascular endothelial and tumor cells. Humulone significantly prevented in vivo angiogenesis in CAM in a dose dependent manner. Humulone potently inhibited the proliferation of endothelial cells stimulated by bFGF, VEGF and serum. It also suppressed in vitro angiogenesis of vascular endothelial tube formation and production of angiogenic factor (VEGF) in endothelial and tumor cells. We next examined the effects of the synthesized or purified compounds derived from humulone on angiogenesis in CAM. Among the compounds tested, humulone was the most potent angiogenesis inhibitor. Therefore, we synthesized large volume of humulone and examined in vivo assays in mice. Humulone inhibited tumor-induced angiogenesis in mouse dorsal air sac assay and also suppressed spontaneous lung metastasis of tumor cells by intraperitoneal administration. On the bases of these results, humulone is a potent angiogenesis inhibitor, and may be a novel powerful tool for the therapy in various angiogenic diseases involving solid tumor, rheumatoid arthritis and diabetic retinopathy.