title: Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/β-catenin pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Mao
authors.affiliation: 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.
authors.forename: Duowei
authors.initials: D
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Xianjing
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Duan
authors.affiliation: 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.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hongbao
authors.initials: H
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Linjun
authors.initials: L
authors.lastname: You
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Bian
authors.affiliation: 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. Electronic address: cz@cpu.edu.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 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. Electronic address: yy@cpu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017382:Reactive Oxygen Species; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D050257:Tubulin Modulators; D014409:Tumor Necrosis Factor-alpha; C063690:combretastatin A-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Combretastatin A-1 phosphate; Hepatocellular carcinoma; Tumor microenvironment; Tumor-associated macrophage; Wnt/β-catenin