title: A novel therapeutic combination sequentially targeting aurora B and Bcl-xL in hepatocellular carcinoma.
abstract: BACKGROUND
  Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition.
  
  
  METHODS
  This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models.
  
  
  RESULTS
  The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy.
  
  
  CONCLUSIONS
  Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsunaga
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.forename: Kousuke
authors.initials: K
authors.lastname: Ogawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ban
authors.forename: Takanori
authors.initials: T
authors.lastname: Ochiai
authors.forename: Takumi
authors.initials: T
authors.lastname: Irie
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kudo
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nakamura
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arii
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanabe
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013449:Sulfonamides / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; C494811:BCL2L1 protein, human; D013449:Sulfonamides; D051020:bcl-X Protein; D064107:Aurora Kinase B; C528561:navitoclax