Targeting breast cancer stem cells by novel HDAC3-selective inhibitors
Journal
European Journal of Medicinal Chemistry
Journal Volume
140
Pages
42-51
Date Issued
2017
Author(s)
Abstract
Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of β-catenin. ? 2017 Elsevier Masson SAS
Subjects
Cancer stem cell (CSC); Histone deacetylase 3 (HDAC3); Triple-negative breast cancer (TNBC); β-Catenin
SDGs
Other Subjects
antineoplastic agent; ar 42; beta catenin; glycogen synthase kinase 3beta; histone deacetylase 1; histone deacetylase 2; histone deacetylase 3; histone deacetylase 4; histone deacetylase 5; histone deacetylase 6; histone deacetylase 7; histone deacetylase 8; histone deacetylase inhibitor; protein kinase B; unclassified drug; antineoplastic agent; histone deacetylase; histone deacetylase 3; histone deacetylase inhibitor; Akt signaling; animal experiment; animal model; Article; cancer inhibition; cancer stem cell; carcinogenesis; cell subpopulation; cell viability; controlled study; down regulation; drug efficacy; drug targeting; enzyme inhibition; female; histone acetylation; IC50; in vitro study; in vivo study; mouse; nonhuman; protein expression; structure activity relation; triple negative breast cancer; Breast Neoplasms; cancer stem cell; cell proliferation; chemical structure; chemistry; dose response; drug effects; drug screening; human; metabolism; pathology; synthesis; tumor cell line; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Structure; Neoplastic Stem Cells; Structure-Activity Relationship
Type
journal article