title: PX-12 inhibits the growth of hepatocelluar carcinoma by inducing S-phase arrest, ROS-dependent apoptosis and enhances 5-FU cytotoxicity.
abstract: BACKGROUND
  1-methylpropyl 2-imidazolyl disulfide (PX-12), a thioredoxin 1 (Trx1) inhibitor, has been investigated in a number of ancers, but its effectiveness in the treatment of hepatocellular carcinoma (HCC) has not been reported. PX-12 has generated considerable interest in its use in a variety of solid tumors, yet most studies have confined their interests to using PX-12 as a single agent. The aim of this study is to investigate whether PX-12 inhibits cell growth and has a synergistic anti-tumor effect in combination with 5-fluorouracil (5-FU) in HCC.
  
  
  METHODS
  Cells were treated with different concentrations of PX-12 and 5-FU. Cell viability assays, colony formation assay, cell cycle assay, reactive oxygen species (ROS) assay, apoptosis analysis, western blot assay, immunohistochemistry and xenograft tumorigenicity assay were performed.
  
  
  RESULTS
  Treatment with PX-12 inhibited cell growth, induced S-phase arrest, and increased ROS levels. PX-12-induced apoptosis and inhibition of colony formation were associated with the generation of ROS, and inhibition of ROS attenuated PX-12-induced apoptosis and inhibition of colony formation. Treatment with PX-12 increased the expression of bax and reduced the expression of bcl-2, indicating that PX-12-mediated apoptosis is mitochondria-dependent. PX-12 also exerted a synergistic effect with 5-FU tosignificantly suppress tumorigenicity both in vitro and in vivo. Inhibition of ROS accumulation reduced the synergistic effect of PX-12 and 5-FU.
  
  
  CONCLUSIONS
  PX-12 has anti-tumor activity and a synergistic effect in combination with 5-FU in HCC. Treatment with PX-12 alone or in combination with 5-FU may have clinical use in the treatment of HCC and other cancers.
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Guang-Zhen
authors.initials: GZ
authors.lastname: Li
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liang
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liao
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Ya-An
authors.initials: YA
authors.lastname: Ni
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Er-Lei
authors.initials: EL
authors.lastname: Zhang
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Bi-Xiang
authors.initials: BX
authors.lastname: Zhang
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
keywords: 5-FU; Hepatocellular carcinoma; PX-12; ROS; thioredoxin 1