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01-10-2021 | PRECLINICAL STUDIES

A novel histone deacetylase inhibitor LT-548-133-1 induces apoptosis by inhibiting HDAC and interfering with microtubule assembly in MCF-7 cells

Authors: Jinbing Xue, Gang Wu, Umer Ejaz, Fahad Akhtar, Xinyu Wan, Yong Zhu, Aixing Geng, Yadong Chen, Shuying He

Published in: Investigational New Drugs | Issue 5/2021

Summary

Many studies have indicated that histone deacetylase inhibitors (HDACis) have a significant antitumor effect in cancer. Here we report a compound named LT-548-133-1 that not only acts as an HDAC inhibitor but also interferes with microtubule assembly to inhibit MCF-7 cell proliferation and induce apoptosis. Consistent with Chidamide, LT-548-133-1 inhibited HDAC activity and increased histone H3 acetylation. But the difference is that it significantly induced cell cycle G2/M arrest while Chidamide caused G0/G1 arrest in MCF-7 cells. By Western blotting, we found the accumulation of CyclinB1 and phosphorylated histone H3 in LT-548-133-1 treated cells. Immunofluorescence based microtubule-repolymerization experiments and immunofluorescence staining of cell microtubules and nuclei showed that LT-548-133-1inhibited microtubule-repolymerization and induced mitotic abnormalities. The decreased expression of Bcl-2 and the increased expression of Bax, p53, p21, and cleaved-Caspase3 indicated the occurrence of apoptosis. Flow cytometry results also showed an increase in the proportion of apoptotic cells after administration of LT-548-133-1 or Chidamide. Therefore, we demonstrated that LT-548-133-1 could act as an HDAC inhibitor while inhibiting microtubule-repolymerization, causing mitosis to be arrested in G2/M. These two effects ultimately lead to proliferation inhibition and apoptosis of MCF-7 cells.

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Title: A novel histone deacetylase inhibitor LT-548-133-1 induces apoptosis by inhibiting HDAC and interfering with microtubule assembly in MCF-7 cells
Authors: Jinbing Xue
Gang Wu
Umer Ejaz
Fahad Akhtar
Xinyu Wan
Yong Zhu
Aixing Geng
Yadong Chen
Shuying He
Publication date: 01-10-2021
Publisher: Springer US
Published in: Investigational New Drugs / Issue 5/2021
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-021-01102-9

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