title: Small Molecule TH-39 Potentially Targets Hec1/Nek2 Interaction and Exhibits Antitumor Efficacy in K562 Cells via G0/G1 Cell Cycle Arrest and Apoptosis Induction.
abstract: BACKGROUND
  Cancer is still a major public health issue worldwide, and new therapeutics with anti-tumor activity are still urgently needed.
  
  
  METHODS
  The anti-tumor activity of TH-39, which shows potent anti-proliferative activity against K562 cells with an IC50 of 0.78 µM, was investigated using immunoblot, co-immunoprecipitation, the MTT assay, and flow cytometry.
  
  
  RESULTS
  Mechanistically, TH-39 may disrupt the interaction between Hec1 and Nek2 in K562 cells. Moreover, TH-39 inhibited cell proliferation in a concentration- and time-dependent manner by influencing the morphology of K562 cells and inducing G0/G1 phase arrest. G0/G1 phase arrest was associated with down-regulation of CDK2-cyclin E complex and CDK4/6-cyclin D complex activities. Furthermore, TH-39 also induced cell apoptosis, which was associated with activation of caspase-3, down-regulation of Bcl-2 expression and up-regulation of Bax. TH-39 could also decrease mitochondrial membrane potential (Δψm) and increase reactive oxygen species (ROS) accumulation in K562 cells. The results indicated that TH-39 might induce apoptosis via the ROS-mitochondrial apoptotic pathway.
  
  
  CONCLUSIONS
  This study highlights the potential therapeutic efficacy of the anti-cancer compound TH-39 in treatment-resistant chronic myeloid leukemia.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Tinghong
authors.initials: T
authors.lastname: Ye
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Luo
authors.forename: Lidan
authors.initials: L
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Ningyu
authors.initials: N
authors.lastname: Wang
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003598:Cytoskeletal Proteins; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020014:K562 Cells; D000072379:NIMA-Related Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002934:Cinnamates; D003598:Cytoskeletal Proteins; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; C000614091:TH-39 thiazole compound; D013844:Thiazoles; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases