title: Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression.
abstract: OBJECTIVE
  In recent years, anti-angiogenesis drugs have shown promising clinical effects against many tumors, particularly in combination with chemotherapy. Although the combination has become a standard of care for many tumors, the mechanisms of the chemosensitizing activity of anti-angiogenic drugs are not fully understood. Here, we sought to determine if anti-angiogenesis drug bevacizumab could enhance the chemosensitivity of HCC by inhibition of survivin.
  
  
  METHODS
  After treatment of human umbilical vein endothelial cells (HUVECs) and hepatocellular carcinoma (HCC) cell line PLC/PRF/5 (PLC) with bevacizumab or/and adriamycin, the direct effects were examined by survival assays, and the expression of Akt, Phospho-Akt and survivin were evaluated by western blot. Tumor growth was observed in a human HCC xenograft nude mouse model treated with different drugs, and the expression of PCNA, CD31 and survivin in tumor tissues were evaluated by means of immunohistochemistry.
  
  
  RESULTS
  Bevacizumab enhanced the chemosensitivity of HCC by inhibiting the VEGF-PI3 K/Akt-survivin signaling cascade in endothelial cells. The combination of bevacizumab with adriamycin therapy resulted in better outcomes compared with monotherapy in hepatocellular carcinoma xenografts; bevacizumab significantly inhibited tumor angiogenesis and growth. In addition, bevacizumab reduced survivin expression in tumor tissues, including tumor vascular endothelial cells in vivo, although it did not inhibit survivin expression in tumor cells in vitro.
  
  
  CONCLUSIONS
  These results implicate the bevacizumab-increased efficacy of adriamycin via an inhibition of survivin expression in malignant cells as well as tumor vasculature cells, which provides other insights into the mechanism of enhanced efficacy by combination of VEGF blocker and chemotherapeutic agents.
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Xiong
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Zhuang
authors.forename: Ju-Bo
authors.initials: JB
authors.lastname: Zhang
authors.forename: Hua-Xiang
authors.initials: HX
authors.lastname: Xu
authors.forename: Ling-Qun
authors.initials: LQ
authors.lastname: Kong
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Wu
authors.forename: Lun-Xiu
authors.initials: LX
authors.lastname: Qin
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D000068258:Bevacizumab; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases