C118P, a novel microtubule inhibitor with anti-angiogenic and vascular disrupting activities, exerts anti-tumor effects against hepatocellular carcinoma.
C118P, a novel microtubule inhibitor with anti-angiogenic and vascular disrupting activities, exerts anti-tumor effects against hepatocellular carcinoma.
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C118P 是一种新型微管抑制剂，具有抗血管生成和血管破坏活性，对肝细胞癌具有抗肿瘤作用。
DOI：
10.1016/j.bcp.2021.114641
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发表时间：
2021-05
影响因子：
5.8
通讯作者：
Qian Zhang
中科院分区：
文献类型：
--
作者：
Shihui Wei;Liwen Zhao;Zhiling Zhou;Xian Zhang;Mei Yang;Zhengguang Liao;Luwei Han;Yanhong Su;Meixiao Zhan;Zhiqiang Wang;Li Sun;Danyu Du;Jingwei Jiang;Shengtao Yuan;Qian Zhang
肝细胞癌是一种血管丰富的实体瘤，是世界范围内最主要的癌症死亡原因。针对肿瘤血管的微管结合剂已被研究并应用于临床。C118P是一种新合成的CA4类似物，具有更好的水溶性和更长的半衰期。目前的研究主要考察了C118P及其活性代谢物C118的药理作用。在这里，我们首先通过体外实验证实C118具有微管解聚活性，并通过分子对接发现它与微管蛋白的秋水仙素结合部位相匹配。此外，我们还发现C118P和C118改变了人脐静脉内皮细胞的微管动力学和细胞骨架。因此，我们通过管状形成实验和鸡绒毛膜尿囊膜血管生成实验观察到C118P和C118抑制血管生成并破坏已建立的血管网络。此外，我们的数据显示，C118P和C118对多种癌细胞，包括肝癌细胞株，都表现出明显的抑制增殖作用。此外，通过流式细胞仪和免疫印迹分析发现，C118P诱导肝癌细胞株BEL7402和SMMC7721发生G2/M期细胞周期停滞和凋亡。最后，我们证实了C118P通过靶向肿瘤血管和诱导SMMC7721移植瘤小鼠模型中的细胞凋亡来抑制肝癌的生长。综上所述，我们的研究表明，C118P作为一种强有力的微管稳定剂，通过诱导细胞周期停滞和细胞凋亡以及靶向肿瘤血管而发挥其抗肝癌的多种药理作用。因此，C118P可能是治疗肝癌的一种有前途的候选药物。
Hepatocellular carcinoma (HCC), a hypervascular solid tumor, is the most leading cause of cancer mortality worldwide. Microtubule binding agents targeting tumor vasculature have been investigated and employed clinically. C118P is a newly synthesized analog of CA4 with improved water solubility and extended half-life. The current studies investigated the pharmacological effects of C118P and its active metabolite C118. Here, we first confirmed by in vitro assays that C118 exerts microtubule depolymerization activity and by molecular docking revealed that it fits to the colchicine binding site of tubulin. In addition, we found that C118P and C118 altered microtubule dynamics and cytoskeleton in human umbilical vein endothelial cells. Accordingly, we observed that C118P and C118 inhibited angiogenesis and disrupted established vascular networks using tube formation assays and chick chorioallantoic membrane angiogenesis assays. In addition, our data showed that C118P and C118 exhibited board anti-proliferative effect on various cancer cells, including HCC cell lines, in MTT assays or Sulforhodamine B assays. Moreover, we found that C118P induced G2/M phase cell cycle arrest and apoptosis in HCC cell lines BEL7402 and SMMC7721 using flow cytometry analysis and immunoblotting assays. Finally, we confirmed that C118P suppressed HCC growth via targeting tumor vasculature and inducing apoptosis in the SMMC7721 xenograft mouse model. In conclusion, our studies revealed that C118P, as a potent microtubule destabilizing agent, exerts its multiple pharmacological effects against HCC by inducing cell cycle arrest and apoptosis, as well as targeting tumor vasculature. Thus, C118P might be a promising drug candidate for liver cancer treatment.
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内皮蛋白酶作为肿瘤血管生成的调节剂和潜在治疗靶点。
DOI：
10.1007/s00018-016-2347-2
发表时间：
2017-02
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Song K;Wu H;Rahman HN;Dong Y;Wen A;Brophy ML;Wong S;Kwak S;Bielenberg DR;Chen H
通讯作者：
Chen H
影响因子：
9.2
作者：
C. Waterman-Storer;E. Salmon
通讯作者：
C. Waterman-Storer;E. Salmon
影响因子：
4.7
作者：
Jackson, SJT;Singletary, KW
通讯作者：
Singletary, KW
影响因子：
13.5
作者：
Bruix, J;Llovet, JM
通讯作者：
Llovet, JM
影响因子：
3.6
作者：
Liu K;Zhang X;Xu W;Chen J;Yu J;Gamble JR;McCaughan GW
通讯作者：
McCaughan GW