Acacetin inhibits in vitro and in vivo angiogenesis and downregulates Stat signaling and VEGF expression.
Acacetin inhibits in vitro and in vivo angiogenesis and downregulates Stat signaling and VEGF expression.
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DOI：
10.1158/1940-6207.capr-13-0209
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Singh RP
中科院分区：
文献类型：
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作者：
Bhat TA;Nambiar D;Tailor D;Pal A;Agarwal R;Singh RP
血管生成是肿瘤控制的有效靶点。植物黄酮类化合物刺槐素的抗血管生成作用及其机制尚不清楚。在本研究中，acacetin抑制正常条件下人脐静脉内皮细胞（HUVEC）的生长和存活（高达92%，p<0.001），抑制基质上毛细血管样管的形成（高达98%，p<0.001），以及vegf诱导和肿瘤细胞条件下的中等刺激生长条件。它导致预形成的毛细血管网络收缩和解体（高达91%，p<0.001）。HUVEC的迁移和侵袭被抑制68% ~ 100% （p<0.001）。Acacetin抑制HUVEC中Stat-1 （Tyr701）和Stat-3 （Tyr705）磷酸化，下调促血管生成因子VEGF、eNOS、iNOS、MMP-2和bFGF。它还抑制pStat-3 （Tyr705）的核定位。Acacetin对大鼠主动脉环和受精卵绒毛膜-尿囊膜（CAM）毛细血管的萌发和形成有明显的抑制作用（约71%，p<0.001）。此外，它还抑制了植入瑞士白化小鼠的基质桥塞的血管生成。阿卡辛还能抑制癌细胞中酪氨酸的Stat-1和Stat-3磷酸化以及VEGF的表达。综上所述，acacetin在体外、离体和体内均能抑制Stat信号，抑制血管生成，因此可能是抑制肿瘤血管生成和生长的潜在药物。
Angiogenesis is an effective target in cancer control. The anti-angiogenic efficacy and associated mechanisms of acacetin, a plant flavone, is poorly known. In the present study, acacetin inhibited growth and survival (upto 92%, p<0.001), and capillary-like tube formation on matrigel (upto 98%, p<0.001) by human umbilical vein endothelial cells (HUVEC) in regular condition, as well as VEGF-induced and tumor cells conditioned medium-stimulated growth conditions. It caused retraction and disintegration of preformed capillary networks (upto 91%, p<0.001). HUVEC migration and invasion were suppressed by 68-100% (p<0.001). Acacetin inhibited Stat-1 (Tyr701) and Stat-3 (Tyr705) phosphorylation, and down-regulated pro-angiogenic factors including VEGF, eNOS, iNOS, MMP-2 and bFGF in HUVEC. It also suppressed nuclear localization of pStat-3 (Tyr705). Acacetin strongly inhibited capillary sprouting and networking from rat aortic rings and fertilized chicken egg chorioallantoic membrane (CAM) (~71%, p<0.001). Furthermore, it suppressed angiogenesis in matrigel plugs implanted in Swiss albino mice. Acacetin also inhibited tyrosine phosphorylation of Stat-1 and Stat-3, and expression of VEGF in cancer cells. Overall, acacetin inhibits Stat signaling and suppresses angiogenesis in vitro, ex vivo and in vivo, and therefore, it could be a potential agent to inhibit tumor angiogenesis and growth.