title: Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli.
abstract: OBJECTIVE
  Overexpression of the sonic hedgehog (SHH) signaling pathway is an essential characteristic of pancreatic cancer stem cells (PCSCs) and arsenic trioxide (ATO) is described as a SHH inhibitor. This study evaluates whether ATO has the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins.
  
  
  METHODS
  Cell counting kit-8 and flow cytometry were used for analyzing apoptosis in cells in vitro. The animal model was an athymic nude mouse model bearing subcutaneous xenografts of SW1990 pancreatic cancer cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry were used for tumor tissue analysis. The interaction between Gli1 and ATO was examined by a confocal system and an ultraviolet absorption spectrum assay.
  
  
  RESULTS
  ATO induced apoptosis in pancreatic cancer cells, especially CD24(+)CD44(+) cells in vitro. Combination treatment of ATO and low dose gemcitabine inhibited tumor growth by 60.9% (P = 0.004), and decreased the expression of CD24, CD44, and aldehyde dehydrogenase 1 family, member A1 significantly in vivo. ATO changed the structure of the recombinant Gli1 zinc finger peptides in a cell-free condition and the binding action of ATO to recombinant Gli1 was observed in cultured pancreatic cancer cells.
  
  
  CONCLUSIONS
  ATO may have the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins in vitro and in vivo.
authors.affiliation: Department of integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jin-Bin
authors.initials: JB
authors.lastname: Han
authors.forename: Feng
authors.initials: F
authors.lastname: Sang
authors.forename: Jin-Jia
authors.initials: JJ
authors.lastname: Chang
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Hua
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Shi
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Tang
authors.forename: Lu-Ming
authors.initials: LM
authors.lastname: Liu
keywords: Gli; arsenic trioxide; gemcitabine; pancreatic cancer; sonic hedgehog; stem cells