Mao Jie, Wang Duowei, Wang Zhuo, Tian Wei, Li Xianjing, Duan Jingjing, Wang Yun, Yang Hongbao, You Linjun, Cheng Yan, Bian Jinsong, Chen Zhen, Yang Yong
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Cancer Lett. 2016 Sep 28;380(1):134-43. doi: 10.1016/j.canlet.2016.06.020. Epub 2016 Jun 24.
Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CA1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3β activation, Wnt/β-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3β-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMs). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMs in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-β and TNF-α was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic.
磷酸考布他汀A-1（CA1P）是一种微管聚合抑制剂，可与微管蛋白的秋水仙碱结合位点结合。我们证明，CA1P在体外和体内对肝细胞癌（HCC）均具有出色的抗癌活性。通过荧光染色和蛋白质免疫印迹（WB）测定，CA1P诱导HepG2细胞中活性氧（ROS）积累和凋亡，同时Mcl-1表达下调。进一步研究表明，CA1P诱导微管解聚介导的AKT失活，从而导致GSK-3β激活、Wnt/β-连环蛋白通路抑制以及Mcl-1下调。GSK-3β特异性抑制剂可阻止CA1P诱导的HepG2细胞凋亡。此外，对肝细胞癌小鼠模型的免疫组织化学研究表明，CA1P对肿瘤相关巨噬细胞（TAM）具有活性。CA1P在体外通过与HepG2细胞相同的机制诱导TAM凋亡，并在体内消除肿瘤微环境（TME）中的TAM。在TME中，TGF-β和TNF-α的表达也发生了改变。巨噬细胞的过继转移部分挽救了被CA1P抑制的肿瘤生长。这些发现表明，CA1P在影响癌细胞和微环境方面具有巨大潜力，我们的研究结果应能加速CA1P在临床肝癌治疗中的应用。
