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Epigenetic Evaluation of N-(2-hydroxyphenyl)-2-Propylpentanamide, a Valproic Acid Aryl Derivative with Activity Against HeLa Cells

Author(s):

Luna-Palencia Gabriela Rebeca, Correa-Basurto José, Trujillo-Ferrara José, Meraz-Ríos Marco Antonio and Vásquez-Moctezuma Ismael*   Pages 1 - 9 ( 9 )

Abstract:


Background: Valproic acid (VPA) is an HDAC inhibitor (HDACI) with anticancer activity, but it is hepatotoxic. N-(2-hydroxyphenyl)-2-propylpentanamide (o-OH-VPA) is a VPA aryl derivative designed in silico as a selective inhibitor of HDAC8 with biological properties against HeLa, rhabdomyosarcoma and breast cancer cell cultures.

Objective: We studied the epigenetic mechanism of o-OH-VPA as an HDACI and we evaluated whether it was toxic to normal cells.

Methods: HeLa cells and primary human fibroblast were used for this study as carcinogenic and normal cells, respectively. Cell survival was evaluated by MTT assay; viability and doubling time were determined by Trypan-blue method. HDAC activity was tested using the colorimetric HDAC activity assay. The expression of p21 was analyzed by PCR and HDAC8 expression was also evaluated by real-time PCR. Cell cycle and caspase-3 activity were analyzed by flow cytometry and caspase-3 colorimetric assay, respectively.

Results: o-OH-VPA (IC50 = 0.1 mM) was fifty-eight more effective than VPA (IC50 = 5.8 mM) to reduce HeLa cell survival. Furthermore, o-OH-VPA increased the doubling time of HeLa cells by 33% with respect to the control. o-OHVPA acted as HDACI in HeLa cells without affecting the HDAC8 expression, arresting the cell cycle of HeLa cells in the G0/G1 phase due to the increase in p21 expression with inhibition of caspase-3 activity without exhibiting toxicity toward normal cells.

Conclusion: Our results revealed that o-OH-VPA is an HDACI with a selective effect against HeLa cells but without the known toxicity exerted by most pan-HDACIs on normal cells.

Keywords:

Anticancer agents, histone deacetylase 8 inhibitor, valproic acid, aryl valproic acid derivative, HeLa cells, epigenetic drugs

Affiliation:

Departamento de Biotecnología y Bioingeniería, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, CDMX, 07360, Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, CDMX, 11340, Laboratorio de Bioquímica, Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, CDMX, 11340, Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Laboratorio de Morfología de la Maestría en Ciencias de la Salud, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, CDMX, 11340



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