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

// Arturo Contis-Montes de Oca 1, * , Estefania Rodarte-Valle 2, * , Martha Cecilia Rosales-Hernandez 2 , Edgar Abarca-Rojano 3 , Saul Rojas-Hernandez 1 , Manuel Jonathan Fragoso-Vazquez 4 , Jessica Elena Mendieta-Wejebe 2 , Ana Maria Correa-Basurto 2 , Ismael Vazquez-Moctezuma 2 and Jose Correa-Basurto 2, 5 1 Laboratorio de Inmunobiologia Molecular y Celular, Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico 2 Laboratorio de Biofisica y Biocatalisis, Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico 3 Laboratorio de Respiracion Celular, Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico 4 Departamento de Quimica Organica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico 5 Laboratorio de Modelado Molecular y Bioinformatica y Diseno de Farmacos, Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico * These authors contributed equally to this work Correspondence to: Edgar Abarca Rojano, email: rojanoe@yahoo.com Jose Correa Basurto, email: corrjose@gmail.com Keywords: histone deacetylase inhibitors; high-mobility group box 1 protein; reactive oxygen species; valproic acid derivatives; OH-VPA Received: December 27, 2017      Accepted: August 21, 2018      Published: September 07, 2018 ABSTRACT 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.