Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents

• Type of Material: Article
• Authors: Subhasish Tapadar, Georgia Institute of Technology; Shaghayegh Fathi, Georgia Institute of Technology; Bocheng Wu, Georgia Institute of Technology; Carrie Q. Sun, Emory University; Idris Raji, Georgia Institute of Technology; Samuel G. Moore, Georgia Institute of Technology; Rebecca Arnold, Emory University; David A. Gaul, Sophia Bioscience, Inc.; John Petros, Emory University; Adegboyega K. Oyelere, Georgia Institute of Technology
• Language: English
• Date: 2020-11-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers12113095
• Title of Journal or Parent Work: CANCERS
• Volume: 12
• Issue: 11
• Start Page: 1
• End Page: 19
• Grant/Funding Information: This work was supported by NIH (R43CA224642) and by the Vasser-Woolley Fellowship (A.K.O.); and by the Georgia Institute of Technology’s Systems Mass Spectrometry Core Facility.
• Keywords: EXPRESSION; Science & Technology; zinc binding group; histone deacetylase isoforms; macrolide; AZITHROMYCIN; hepatocellular cancer; PROSTATE-CANCER; histone deacetylase; OPTIMIZATION; TISSUE; liver tissue accumulation; molecular docking; CYTOTOXICITY; immunoblot; Oncology; orthotopic model; APOPTOSIS; THERAPY; histone deacetylase inhibitors; BELINOSTAT; Life Sciences & Biomedicine; CARCINOMA
• Research Categories: Health Sciences, Immunology; Biology, Cell; Health Sciences, Oncology

Abstract

Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors. Inhibition of the deacetylase activity of HDACs is a clinically validated cancer therapy strategy. However, current HDAC inhibitors (HDACi) have elicited limited therapeutic benefit against solid tumors. Here, we disclosed a class of HDACi that are selective for sub-class I HDACs and preferentially accumulate within the normal liver tissue and orthotopically implanted liver tumors. We observed that these compounds possess exquisite on-target effects evidenced by their induction of dose-dependent histone H4 hyperacetylation without perturbation of tubulin acetylation status and G0/G1 cell cycle arrest. Representative compounds 2 and 3a are relatively non-toxic to mice and robustly suppressed tumor growths in an orthotopic model of HCC as standalone agents. Collectively, our results suggest that these compounds may have therapeutic advantage against HCC relative to the current systemic HDACi. This prospect merits further comprehensive preclinical investigations.