A natural small molecule harmine inhibits angiogenesis and suppresses tumour growth through activation of p53 in endothelial cells.
A natural small molecule harmine inhibits angiogenesis and suppresses tumour growth through activation of p53 in endothelial cells.
复制标题
天然小分子骆驼蓬碱通过激活内皮细胞中的 p53 抑制血管生成并抑制肿瘤生长
DOI：
10.1371/journal.pone.0052162
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yi Z
中科院分区：
文献类型：
--
作者：
Dai F;Chen Y;Song Y;Huang L;Zhai D;Dong Y;Lai L;Zhang T;Li D;Pang X;Liu M;Yi Z
p53的激活有效地抑制肿瘤生长和转移所必需的肿瘤血管生成。通过小分子重新激活p53已经成为癌症治疗的一种有前途的新策略。已经使用各种方法发现了激活p53通路的几类小分子。在这里，我们确定了骆驼蓬碱（β-咔啉生物碱）作为一种新的p53信号转导激活剂，参与抑制血管生成和肿瘤生长。去氢骆驼蓬碱诱导p53磷酸化并破坏p53-MDM 2相互作用。去氢骆驼蓬碱也阻止了放线菌酮存在下p53的降解，并激活了p53的核积累，随后增加了其在内皮细胞中的转录活性。此外，去氢骆驼蓬碱不仅诱导内皮细胞周期阻滞和凋亡，而且还抑制内皮细胞迁移和管形成以及诱导新生血管在小鼠角膜微袋测定。最后，骆驼蓬碱通过减少肿瘤血管生成来抑制肿瘤生长，如异种移植肿瘤模型所示。我们的研究结果表明，骆驼蓬碱抑制肿瘤生长的一种新的机制和生物活性，激活p53信号通路和阻断血管内皮细胞的血管生成。
Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells.
登录
查看更多内容
针对P53-MDM2相互作用以治疗癌症。
影响因子：
8.8
作者：
Klein, C;Vassilev, LT
通讯作者：
Vassilev, LT
DOI：
10.1016/s1499-3872(11)60102-1
发表时间：
2011-12-01
影响因子：
3.3
作者：
Cao, Ming-Rong;Li, Qiang;Jiang, Jian-Wei
通讯作者：
Jiang, Jian-Wei
影响因子：
5.3
作者：
LEESMILLER, SP;SAKAGUCHI, K;ANDERSON, CW
通讯作者：
ANDERSON, CW
DOI：
10.1007/s00432-007-0270-5
发表时间：
2008-02-01
影响因子：
3.6
作者：
Montero, Elvira;Abreu, Carmen;Tonino, Paola
通讯作者：
Tonino, Paola
影响因子：
11.2
作者：
Cho SG;Yi Z;Pang X;Yi T;Wang Y;Luo J;Wu Z;Li D;Liu M
通讯作者：
Liu M