【摘 要】
：
Combretastatin A1 phosphate (CA1P) is a tubulin polymerization inhibitor that binds to the colchicinebinding site of tubulin and shows potential antitumor activity to acute myelocytic leukemia as repo
【机 构】
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State Key Laboratory of Natural Medicines,Center for New Drug Safety Evaluation and Research,China P
论文部分内容阅读
Combretastatin A1 phosphate (CA1P) is a tubulin polymerization inhibitor that binds to the colchicinebinding site of tubulin and shows potential antitumor activity to acute myelocytic leukemia as reported.We demonstrated that CA1P also showed an outstanding anticancer effect on hepatocellular carcinoma (HCC) in vivo and in vitro.As determined by DCFHDA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the downregulation of Mcl1.Additonal western blot and immunofluorescence assays further indicated that CA1P inhibited Wnt/βcatenin pathway through GSK3β activition with an increasing of Mcl phosphorylation and subsequent degradation mediated by tubulindynactin p150AKT signaling pathway axis.Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK3β inhibitor (CHIR99021).Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage (TAM) apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGFβ were also altered.Adoptive transfer of macrophages reinstated tumor growth treated by CA1P.These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel antiHCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment.The findings would be beneficial for exploring new application of antimicrotubular drugs on oncotherapy.
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