title: Molecular targeting of VEGF/VEGFR signaling by the anti-VEGF monoclonal antibody BD0801 inhibits the growth and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo.
abstract: Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths with 750,000 newly diagnosed cases each year. Surgery, radiotherapy, and chemotherapy constitute the main treatment modalities for HCC, but liver cirrhosis and damage often occur. Molecular targeted drugs have been recently developed to treat HCC. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) autocrine signaling is closely related to the growth, progression, and metastasis of HCC, making the VEGF/VEGFR axis an ideal target for the development of molecular targeted agents. Here, we report the effects of the novel anti-VEGF humanized monoclonal antibody BD0801 on the growth of HCC cells in vitro and in vivo as well as the underlying mechanisms. BD0801 significantly inhibited the proliferation of HepG2, SMMC-7721, and Bel7402 cells in vitro, accompanied with an induction of apoptosis and cell cycle arrest at the G1 phase. BD0801 potently suppressed AKT, Erk1/2, and retinoblastoma (Rb) phosphorylation, while increasing p21 and decreasing cyclin D1 protein levels. BD0801 significantly inhibited growth in mouse tumor xenografts and induced cell apoptosis of HepG2 and SMMC-7721 tumor xenografts. Furthermore, BD0801 effectively reduced the vascular density and tumor tissue microvessel density (MVD). Similarly, BD0801 decreased AKT, Erk1/2, and Rb phosphorylation and cyclin D1 expression whereas it increased p21 protein expression in mouse HCC tumor xenografts. Importantly, BD0801 showed a better effect than Bevacizumab (Bev) on the inhibition of cell growth and induction of apoptosis in HCC cells in vitro and in vivo. These findings suggest that BD0801 is a potent anti-VEGF monoclonal antibody for the treatment of HCC.
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.|b Post-doctoral Scientific Research Workstation, Jin-Ling Hospital, Medical School of Nanjing University , Nanjing , China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: c Department of Oncology , 81st Hospital of the People's Liberation Army , Nanjing , China.
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.
authors.forename: Nuo
authors.initials: N
authors.lastname: Luo
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.
authors.forename: Zhengcao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: d State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices , School of Biological Sciences & Medical Engineering, Southeast University , Nanjing , China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.affiliation: a Department of Oncology , Zhong-Da Hospital, School of Medicine, Southeast University , Nanjing , China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Gu
authors.affiliation: e Jiangsu Simcere Drug Research Ltd. , Nanjing , China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Yin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Angiogenesis; BD0801; HCC; VEGF; VEGFR; apoptosis; cell growth