Abstract
Background: Valproic acid (VPA) is an HDAC inhibitor (HDACI) with an anticanceractivity, but is hepatotoxic. N-(2-hydroxyphenyl)-2-propylpentanamide (o-OH-VPA) is a VPA arylderivative designed in silico as a selective inhibitor of HDAC8 with biological properties againstHeLa, rhabdomyosarcoma and breast cancer cell cultures.
Objective: We studied the epigenetic mechanism of o-OH-VPA as an HDACI and evaluatedwhether it was toxic to normal cells.
Methods: HeLa cells and primary human fibroblasts were used for this study as carcinogenic andnormal cells, respectively. Cell survival was evaluated by MTT assay, whereas viability and doublingtime were determined by the Trypan-blue method. HDAC activity was tested using the colorimetricHDAC activity assay. The expression of p21 was analyzed by PCR and HDAC8 expressionwas also evaluated by real-time PCR. Cell cycle and caspase-3 activity were analyzed by flow cytometryand caspase-3 colorimetric assay, respectively.
Results: o-OH-VPA (IC50 = 0.1 mM) was fifty-eight times more effective than VPA (IC50 = 5.8mM) to reduce HeLa cell survival. Furthermore, o-OH-VPA increased the doubling time of HeLacells by 33% with respect to the control. o-OH-VPA acted as HDACI in HeLa cells without affectingthe HDAC8 expression, arresting the cell cycle of HeLa cells in the G0/G1 phase due to the increasein p21 expression with the inhibition of caspase-3 activity without exhibiting toxicity towardnormal cells.
Conclusion: Our results revealed that o-OH-VPA is an HDACI with a selective effect againstHeLa 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, epigeneticdrugs.
Graphical Abstract
Current Molecular Pharmacology
Title:Epigenetic Evaluation of N-(2-hydroxyphenyl)-2-Propylpentanamide, a Valproic Acid Aryl Derivative with Activity Against HeLa Cells
Volume: 14
Author(s):G.R. Luna-Palencia, J. Correa-Basurto, J. Trujillo-Ferrara, M.A. Meraz-Ríos and I. Vásquez-Moctezuma*
Affiliation:
- Laboratorio de Morfologia de la Maestria en Ciencias de la Salud, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, Casco de Santo Tomas, CDMX, 11340,Mexico
Keywords:Anticancer agents, histone deacetylase 8 inhibitor, valproic acid, aryl valproic acid derivative, HeLa cells, epigeneticdrugs.
Abstract:
Background: Valproic acid (VPA) is an HDAC inhibitor (HDACI) with an anticanceractivity, but is hepatotoxic. N-(2-hydroxyphenyl)-2-propylpentanamide (o-OH-VPA) is a VPA arylderivative designed in silico as a selective inhibitor of HDAC8 with biological properties againstHeLa, rhabdomyosarcoma and breast cancer cell cultures.
Objective: We studied the epigenetic mechanism of o-OH-VPA as an HDACI and evaluatedwhether it was toxic to normal cells.
Methods: HeLa cells and primary human fibroblasts were used for this study as carcinogenic andnormal cells, respectively. Cell survival was evaluated by MTT assay, whereas viability and doublingtime were determined by the Trypan-blue method. HDAC activity was tested using the colorimetricHDAC activity assay. The expression of p21 was analyzed by PCR and HDAC8 expressionwas also evaluated by real-time PCR. Cell cycle and caspase-3 activity were analyzed by flow cytometryand caspase-3 colorimetric assay, respectively.
Results: o-OH-VPA (IC50 = 0.1 mM) was fifty-eight times more effective than VPA (IC50 = 5.8mM) to reduce HeLa cell survival. Furthermore, o-OH-VPA increased the doubling time of HeLacells by 33% with respect to the control. o-OH-VPA acted as HDACI in HeLa cells without affectingthe HDAC8 expression, arresting the cell cycle of HeLa cells in the G0/G1 phase due to the increasein p21 expression with the inhibition of caspase-3 activity without exhibiting toxicity towardnormal cells.
Conclusion: Our results revealed that o-OH-VPA is an HDACI with a selective effect againstHeLa cells but without the known toxicity exerted by most pan-HDACIs on normal cells.
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Cite this article as:
Luna-Palencia G.R., Correa-Basurto J., Trujillo-Ferrara J., Meraz-Ríos M.A. and Vásquez-Moctezuma I.*, Epigenetic Evaluation of N-(2-hydroxyphenyl)-2-Propylpentanamide, a Valproic Acid Aryl Derivative with Activity Against HeLa Cells, Current Molecular Pharmacology 2021; 14 (4) .https://dx.doi.org/10.2174/1874467213666200730113828
| DOI https://dx.doi.org/10.2174/1874467213666200730113828 | Print ISSN 1874-4672 |
| Publisher Name Bentham Science Publisher | Online ISSN 1874-4702 |
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