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.
Onco Targets Ther. 2013 Aug 19;6:1129-38. doi: 10.2147/OTT.S49148. eCollection 2013.
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.
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.
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.
ATO may have the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins in vitro and in vivo.
sonic hedgehog（SHH）信号通路的过度表达是胰腺癌细胞干细胞（PCSCs）的一个重要特征，三氧化二砷（ATO）被描述为 SHH 抑制剂。本研究评估 ATO 是否通过与 SHH-Gli 蛋白结合而具有抑制 PCSCs 活力的潜力。
细胞计数试剂盒-8 和流式细胞术用于体外分析细胞凋亡。动物模型为皮下接种 SW1990 胰腺癌细胞的裸鼠模型。末端脱氧核苷酸转移酶 dUTP 缺口末端标记法和免疫组织化学用于肿瘤组织分析。通过共聚焦系统和紫外吸收光谱法检测 Gli1 与 ATO 的相互作用。
ATO 诱导胰腺癌细胞，特别是体外 CD24(+)CD44(+)细胞凋亡。ATO 与低剂量吉西他滨联合治疗抑制肿瘤生长 60.9%（P = 0.004），并显著降低体内 CD24、CD44 和醛脱氢酶 1 家族成员 A1 的表达。ATO 在无细胞条件下改变重组 Gli1 锌指肽的结构，并在培养的胰腺癌细胞中观察到 ATO 与重组 Gli1 的结合作用。
ATO 可能通过与 SHH-Gli 蛋白结合在体外和体内抑制 PCSCs 的活力。
