Targeting breast cancer stem cells by novel HDAC3-selective inhibitors

• Published in: European journal of medicinal chemistry Vol. 140; pp. 42 - 51
• Main Authors: Hsieh, Hao-Yu, Chuang, Hsiao-Ching, Shen, Fang-Hsiu, Detroja, Kinjal, Hsin, Ling-Wei, Chen, Ching-Shih
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 10.11.2017; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer stem cell (CSC); Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Histone deacetylase 3 (HDAC3); Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Life Sciences & Biomedicine; Molecular Structure; Neoplastic Stem Cells - drug effects; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Triple-negative breast cancer (TNBC); β-Catenin; β-Catenin; Triple-negative breast cancer (TNBC); Histone deacetylase 3 (HDAC3); Cancer stem cell (CSC); AR-42; STABILITY; beta-Catenin; LEUKEMIA; HISTONE DEACETYLASE INHIBITORS; WNT; CHALLENGES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.08.069

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. [Display omitted] •HDAC inhibitors could suppress cancer stem cells in multiple types of cancer.•HDAC isoform, HDAC3, plays a key role in regulating triple-negative breast CSCs.•HDAC3 mechanistically links to CSC homeostasis by regulating β-catenin expression.•HDAC3 inhibitor, 28 suppresses triple-negative breast CSCs in vitro and in vivo.