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.

CONCLUSION:

This study highlights the potential therapeutic efficacy of the anti-cancer compound TH-39 in treatment-resistant chronic myeloid leukemia.

• Authors: Yongxia Zhu, Wei Wei, Tinghong Ye, Zhihao Liu, Li Liu, Yong Luo, Lidan Zhang, Chao Gao, Ningyu Wang, Luoting Yu
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 40 Issue 1-2 Pg. 297-308 ( 2016) ISSN: 1421-9778 [Electronic] Germany
• PMID: 27855372 (Publication Type: Journal Article)
• Copyright: © 2016 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Cinnamates
• Cytoskeletal Proteins
• NDC80 protein, human
• Nuclear Proteins
• Reactive Oxygen Species
• Small Molecule Libraries
• TH-39 thiazole compound
• Thiazoles
• NEK2 protein, human
• NIMA-Related Kinases

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• Cinnamates (chemical synthesis, chemistry, pharmacology)
• Cytoskeletal Proteins
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Hydrogen-Ion Concentration
• K562 Cells
• NIMA-Related Kinases (metabolism)
• Nuclear Proteins (metabolism)
• Protein Binding (drug effects)
• Reactive Oxygen Species (metabolism)
• Resting Phase, Cell Cycle (drug effects)
• Small Molecule Libraries (chemistry, pharmacology)
• Thiazoles (chemical synthesis, chemistry, pharmacology)