Chen Jianchu, Chen Allen Y, Huang Haizhi, Ye Xingqian, Rollyson William D, Perry Haley E, Brown Kathleen C, Rojanasakul Yon, Rankin Gary O, Dasgupta Piyali, Chen Yi Charlie
College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China.
Department of Pharmaceutical Science, West Virginia University, Morgantown, WV 26506, USA.
Int J Oncol. 2015;46(6):2629-38. doi: 10.3892/ijo.2015.2946. Epub 2015 Apr 1.
Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving the effect on nobiletin on human ovarian cancer. The present report shows that nobiletin potently decreases the viability of ovarian cancer cells in vitro. However, nobiletin does not affect the viability of normal ovarian epithelial cells at <40 µM. The antitumor activity of nobiletin was also observed in athymic mouse models and in chicken chorioallantoic membrane (CAM) models. The anti-neoplastic activity of nobiletin was due to its ability to inhibit angiogenesis. We also studied the molecular mechanisms by which nobiletin suppresses angiogenesis. We observed that nobiletin inhibits secretion of the key angiogenesis mediators, Akt, HIF-1α, NF-κB and vascular epithelial growth factor (VEGF) by ovarian cancer cells. Transient transfection experiments showed that nobiletin inhibits production of HIF-1α by downregulation of Akt. Such decreased levels of HIF-1α were responsible for nobiletin-induced suppression of VEGF. Our data suggest that nobiletin may be a promising anti-angiogenic agent relevant for therapy of ovarian cancers.
尽管卵巢癌很重要，但在过去五十年里其死亡率一直未变，这就需要改进对这种恶性肿瘤的预防和治疗。由于尚无已知致癌物，目前无法进行针对性预防，而且通过筛查生物标志物来早期检测这种恶性肿瘤的努力也失败了。抑制血管生成，也称为血管预防，是限制包括卵巢癌在内的实体瘤生长的一种有前景的策略。诺必藜素是从天然植物中分离出的一种多甲氧基黄酮类化合物，已被证明能抑制多种类型的人类癌症生长。然而，尚无关于诺必藜素对人类卵巢癌影响的报道。本报告表明，诺必藜素在体外能有效降低卵巢癌细胞的活力。然而，在浓度低于40微摩尔时，诺必藜素不影响正常卵巢上皮细胞的活力。在无胸腺小鼠模型和鸡胚绒毛尿囊膜（CAM）模型中也观察到了诺必藜素的抗肿瘤活性。诺必藜素的抗肿瘤活性归因于其抑制血管生成的能力。我们还研究了诺必藜素抑制血管生成的分子机制。我们观察到，诺必藜素能抑制卵巢癌细胞分泌关键的血管生成介质Akt、HIF-1α、NF-κB和血管内皮生长因子（VEGF）。瞬时转染实验表明，诺必藜素通过下调Akt来抑制HIF-1α的产生。HIF-1α水平的降低导致了诺必藜素诱导的VEGF抑制。我们的数据表明，诺必藜素可能是一种有前景的抗血管生成药物，可用于卵巢癌的治疗。
