title: All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer.
abstract: OBJECTIVE
  Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC.
  
  
  METHODS
  In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo.
  
  
  RESULTS
  ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone.
  
  
  CONCLUSIONS
  These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation.
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dong-xian
authors.initials: DX
authors.lastname: Guan
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Jiang-sha
authors.initials: JS
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Qiu
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Wei-xing
authors.initials: WX
authors.lastname: Guo
authors.forename: Jie
authors.initials: J
authors.lastname: Xue
authors.forename: Fei-guo
authors.initials: FG
authors.lastname: Zhou
authors.forename: Meng-chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Hong-yang
authors.initials: HY
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.forename: Shu-qun
authors.initials: SQ
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D014212:Tretinoin; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: AKT; ATRA; Apoptosis; Chemo-sensitivity; Cisplatin; DMSO; Differentiation; EpCAM; FACS; HCC; Hepatocellular carcinoma; Metastasis; TIC; Tumor initiating cell; all-trans retinoic acid; cis-diammineplatinum (II); cisplatin; dimethyl surfoxide; epithelial cell adhesion molecule; fluorescence activated cell sorting; hepatocellular carcinoma; protein kinase B; tumor initiating cell