(-)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis.
(-)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis.
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DOI：
10.1158/1535-7163.mct-10-0936
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发表时间：
2011-05
影响因子：
5.7
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Pang X;Wu Y;Wu Y;Lu B;Chen J;Wang J;Yi Z;Qu W;Liu M
（−）-棉酚是一种天然的BH 3模拟物和小分子Bcl-2抑制剂，在正在进行的人类癌症II期临床试验中显示出希望。然而，（-）-棉酚是否在肿瘤血管生成中发挥功能性作用尚未直接阐明。在这项研究中，我们证明了（−）-棉酚剂量依赖性地抑制人前列腺癌细胞（PC-3和DU 145）和体外培养的人脐静脉内皮细胞（HUVECs）中血管内皮生长因子（VEGF）、Bcl-2和Bcl-xL的表达。值得注意的是，15 mg/kg/d剂量的（−）-棉酚显著抑制了小鼠中人前列腺肿瘤PC-3异种移植物的生长。（-）-棉酚在体内的这种抑制作用在很大程度上依赖于抑制实体瘤中的血管生成，其中VEGF表达和微血管密度显著降低。此外，（−）-棉酚抑制VEGF诱导的HUVECs和人微血管内皮细胞的趋化运动和微管生成，并抑制大鼠离体主动脉环的微血管出芽。当研究其机制时，我们发现（-）-棉酚在内皮细胞中阻断VEGF受体2激酶的激活，其半最大抑制浓度为2.38 μmol/L。因此，VEGF触发的关键细胞内促血管生成分子的磷酸化，如Src家族激酶、粘着斑激酶、细胞外信号相关激酶和AKT激酶，都被治疗抑制。综上所述，本研究表明，（-）-棉酚通过调节VEGF信号通路有效地抑制人前列腺肿瘤的生长，这进一步验证了其在临床实践中的巨大潜力。
(−)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (−)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we demonstrated that (−)-gossypol dose-dependently inhibited the expression of vascular endothelial growth factor (VEGF), Bcl-2 and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and human primary cultured umbilical vein endothelial cells (HUVECs) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (−)-gossypol at dosage of 15 mg/kg/d. This inhibitory action of (−)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (−)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells, and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (−)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, VEGF-triggered phosphorylation of key intracellular proangiogenic molecules, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase and AKT kinase, were all suppressed by the treatment. Taken together, the present study demonstrates that (−)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice.