Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/β-catenin pathway

• Published in: Cancer letters Vol. 380; no. 1; pp. 134 - 143
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 28.09.2016
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Proliferation - drug effects; Combretastatin A-1 phosphate; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3 beta - metabolism; Hematology, Oncology and Palliative Medicine; Hep G2 Cells; Hepatocellular carcinoma; Humans; Inhibitory Concentration 50; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Stilbenes - pharmacology; Transforming Growth Factor beta - metabolism; Tubulin Modulators - pharmacology; Tumor Burden - drug effects; Tumor Microenvironment; Tumor Necrosis Factor-alpha - metabolism; Tumor-associated macrophage; Wnt Signaling Pathway - drug effects; Wnt/β-catenin; Xenograft Model Antitumor Assays; TAM; CA1P; Tumor microenvironment; CA4P; Wnt/β-catenin; Hepatocellular carcinoma; HCC; Combretastatin A-1 phosphate; Tumor-associated macrophage; WB; TME; GFP; BSA; MMP; CA1; TUNEL; FBS; IC50; ROS; BMDMs; combretastatin A1; Western blot; combretastatin A-4 phosphate; half maximal inhibitory concentration; bone marrow-derived macrophages; reactive oxygen species; mitochondrial membrane potential; green fluorescent protein; terminal deoxynucleotidyltransferase-mediate ddUTP nick end-labeling; fetal bovine serum; bovine serum albumin
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2016.06.020

•CA1P inhibited the Wnt/β-catenin pathway through tubulin depolymerization mediated AKT deactivation.•CA1P could eliminate HCC cells together with tumor-associated macrophages by inducing apoptosis.•CA1P exhibited an outstanding anti-HCC potency in vitro and vivo. 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.