Correction: N-(2´-Hydroxyphenyl)-2-propylpentanamide (OH-VPA), a histone deacetylase inhibitor, induces the release of nuclear HMGB1 and modifies ROS levels in HeLa cells.

[This corrects the article DOI: 10.18632/oncotarget.26077.].

N-(2'-Hydroxyphenyl)-2-propylpentanamide (OH-VPA), a histone deacetylase inhibitor, induces the release of nuclear HMGB1 and modifies ROS levels in HeLa cells.

N-(2'-Hydroxyphenyl)-2-propylpentanamide (OH-VPA) is a valproic acid (VPA) derivative with improved antiproliferative activity toward breast cancer (MCF-7, MDA-MB-231, and SKBr3) and human cervical cancer cell lines (HeLa) compared to that of VPA. However, the pharmacological mechanism of OH-VPA activity remains unknown. High-mobility group box 1 (HMGB1) is an important enzyme that is highly expressed in tumor cells and has a subcellular localization that is dependent on its acetylation or oxidative state. Therefore, in this study, we analyzed changes in HMGB1 sub-cellular localization and reactive oxygen species (ROS) as well as changes in HeLa cell viability in response to treatment with various concentrations of OH-VPA. This compound is formed by the covalent bond coupling VPA to a phenol group, which is capable of acting as a free radical scavenger due to its chemical similarities to quercetin. Our results show that OH-VPA induces nuclear to cytoplasmic translocation of HMGB1, as demonstrated by confocal microscopy observations and infrared spectra that revealed high quantities of acetylated HMGB1 in HeLa cells. Cells treated with 0.8 mM OH-VA exhibited decreased viability and increased ROS levels compared with the lower OH-VPA concentrations tested. Therefore, the antiproliferative mechanism of OH-VPA may be related to histone deacetylase (HDAC) inhibition, as is the case for VPA, which promotes high HMBG1 acetylation, which alters its subcellular localization. In addition, OH-VPA generates an imbalance in cellular ROS levels due to its biochemical activity.

Design, Synthesis and Biological Evaluation of a Phenyl Butyric Acid Derivative, N-(4-chlorophenyl)-4-phenylbutanamide: A HDAC6 Inhibitor with Anti-proliferative Activity on Cervix Cancer and Leukemia Cells.

BACKGROUND: The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc. OBJECTIVE: Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference. METHOD: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations. RESULTS: These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM). CONCLUSION: These results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.