Selective inhibition of bicyclic tetrapeptide histone deacetylase inhibitor on HDAC4 and K562 leukemia cell.
Histone deacetylase (HDAC) inhibitors of cyclic peptide have been proved to be the most complex but the most stable and relative efficient inhibitors because of their large cap region. In this paper, a series of studies were carried out to evaluate the efficacy of synthetic bicyclic tetrapeptide inhibitors 1-5 containing hydroxamic acid referring molecular docking, anti-proliferation, morphology and apoptosis. Docking analysis, together with enzyme inhibitory results, verified the selective capability of inhibitor 4 to HDAC4, which might closely related to haematological tumorigenesis, with Phe227, Asp115, Pro32, His198 and Ser114 participating into hydrophobic interactions and Van der Waals force which was familiar with former study. Moreover, inhibitor 4 inhibited K562 cell line at the IC50 value of 1.22 μM which was 51-67 times more efficient than that for U937 and HL60 cell lines. Inhibitor 4 exhibited the cell cycle-arrested capability to leukemia at S phase or G2/M phase as well as apoptosis-induced ability in different degrees. Finally, we considered that bicyclic tetrapeptide inhibitors were promising inhibitors used in cancer treatment and inhibitor 4 could prevent K562 cell line well from proliferation, arrest cell cycle and induce K562 towards apoptosis to achieve the goals of reversing cancer cells which could become a potential leukemia therapeutic agent in the future.
School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China E-mail : lxhxh@dlut.edu.cn, qwang@dlut.edu.cn.
Xiao-Hui
XH
Li
Mei-Ling
ML
Huang
Shi-Miao
SM
Wang
Qing
Q
Wang
D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D019086:Bridged Bicyclo Compounds, Heterocyclic; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010446:Peptide Fragments; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases