Effects Of Dibenzoylmethane Structural Analogues On The Alternative Recombination Pathway For Telomere Lengthening
Chuan-Chuan LIN, China University of Science and Technology, Taiwan (ROC)
HSIEH M. 2
1 Department of Food Science, China University of Science and Technology, Taipei, Taiwan
2 Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Purpose - Cancer cells can bypass the crisis either through telomerase reactivation or through an alternative recombination pathway for telomere lengthening (ALT). Our previous study showed that topoisomerase III (TOP3) is required for type II survivors in yeast and the ALT pathway in human cancer cells. We also reported that dibenzoylmethane (DBM) displays multiple actions toward a carcinogenesis process. In this report, we identified several structural similar DBM derivatives by computer simulated screen to look for TOP3 inhibitor. We evaluated these potential inhibitors in blocking the ALT formation pathway.
Methods - Using various telomeric assays, the ability of telomere recombination in topoisomerase deficient cells was evaluated in yeast and in human. Recombinant human topoisomerase proteins were purified and DNA relaxation assay was also performed.
Results –We use homology modeling to predict the structural of hTop3a, and the screen by molecular docking showed three potential hTop3a inhibitors, which are also the DBM structural analogues. ALT-associated PML bodies (APBs) formation assay revealed one of the potential inhibitors could decrease APB foci formation. Treated with high drug concentration, the enzyme activity of recombinant hTop3a could be inhibited, and the growth of ALT cells was also decreased when concentration increased.
Conclusions –In this report, the molecular docking model was used to predict the potential human TOP3 inhibitors. The results indicated that this screened inhibitor might be a potential anti-tumor drug in blocking the ALT formation pathway.
Funding source - Ministry of Science & Technology of Taiwan.