The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway.
The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway.
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DOI：
10.3892/ijo.2015.2946
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发表时间：
2015
影响因子：
5.2
通讯作者：
Chen YC
中科院分区：
文献类型：
--
作者：
Chen J;Chen AY;Huang H;Ye X;Rollyson WD;Perry HE;Brown KC;Rojanasakul Y;Rankin GO;Dasgupta P;Chen YC
尽管卵巢癌很重要，但在过去的五十年里，其死亡率一直没有变化，这就要求在这种恶性肿瘤的预防和治疗方面有所改进。由于没有已知的致癌物，目前还无法进行有针对性的预防，而且通过筛选生物标志物对这种恶性肿瘤进行早期检测的努力也失败了。抑制血管生成，也称为血管预防，是一种有前景的限制实体肿瘤（包括卵巢癌）生长的策略。川陈皮素是一种从柑橘属植物中分离出来的多甲氧基黄酮类化合物，已被证明能抑制多种人类癌症的生长。然而，没有关于川陈皮素对人类卵巢癌影响的报道。本报告显示，川陈皮素在体外能显著降低卵巢癌细胞的活力。然而，在浓度低于40μM时，川陈皮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）模型中也观察到了川陈皮素的抗肿瘤活性。川陈皮素的抗肿瘤活性是由于其抑制血管生成的能力。我们还研究了川陈皮素抑制血管生成的分子机制。我们观察到川陈皮素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，川陈皮素通过下调Akt抑制HIF - 1α的产生。这种HIF - 1α水平的降低是川陈皮素诱导的VEGF抑制的原因。我们的数据表明，川陈皮素可能是一种有前景的抗血管生成药物，与卵巢癌的治疗相关。
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.
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影响因子：
4.8
作者：
Gonzalez-Perez RR;Xu Y;Guo S;Watters A;Zhou W;Leibovich SJ
通讯作者：
Leibovich SJ
影响因子：
11.5
作者：
Adhami, Vaqar Mustafa;Malik, Arshi;Mukhtar, Hasan
通讯作者：
Mukhtar, Hasan
影响因子：
3.8
作者：
Bosetti, Cristina;Rossi, Marta;LaVecchia, Carlo
通讯作者：
LaVecchia, Carlo
影响因子：
2
作者：
Bast, RC;Xu, FJ;Mills, GB
通讯作者：
Mills, GB
影响因子：
4.8
作者：
Cain, K;Langlais, C;Cohen, GM
通讯作者：
Cohen, GM