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Artículo

Sirtuin 1 and 2 inhibitors enhance the inhibitory effect of sorafenib in hepatocellular carcinoma cells

Ceballos Mancini, María PaulaIcon ; Angel, Antonella; Delprato, Carla Beatriz; Livore, Veronica InesIcon ; Ferretti, AnabelaIcon ; Lucci, AlvaroIcon ; Comanzo, Carla GabrielaIcon ; Alvarez, María de LujánIcon ; Quiroga, Ariel DarioIcon ; Mottino, Aldo DomingoIcon ; Carrillo, Maria CristinaIcon
Fecha de publicación: 02/2021
Editorial: Elsevier Science
Revista: European Journal of Pharmacology
ISSN: 0014-2999
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Fisiología

Resumen

Multidrug resistance (MDR) counteracts the efficiency of sorafenib, an important first-line therapy for hepatocellular carcinoma (HCC). Sirtuins (SIRTs) 1 and 2 are associated with tumor progression and MDR. We treated 2D and 3D cultures (which mimic the features of in vivo tumors) from HCC cells with sorafenib alone or in the presence of SIRTs 1 and 2 inhibitors (cambinol or EX-527; combined treatments). Cultures subjected to combined treatments showed a greater fall in cellular viability, proliferation (PCNA, cyclin D1 and Ki-67 expression and cell cycle analysis), migration and invasion when compared with cultures treated only with sorafenib. Similarly, combined treatments produced more apoptosis (annexin V/PI, caspase-3/7 activity) than sorafenib alone. Since cell cycle dysregulation and apoptotic blockage are reported mechanisms of MDR, the modulation found in PCNA, cyclin D1, Ki-67 and caspase-3/7 proteins by cambinol and EX-527 are probably playing a role in enhancing the sensitivity of HCC cell lines to sorafenib. EX-527 reduced MRP3 and BCRP expression in sorafenib-treated HCC cells. Since ABC transporters contribute to MDR, MRP3 and BCRP could be also influencing in the response of HCC cells to sorafenib. Overall, 2D and 3D cultures behave similarly except that 3D cultures were less sensitive to treatments, reinforcing the clinical relevance of the current study. Findings presented in this manuscript support a potential application for SIRTs 1 and 2 inhibitors since we demonstrated that these compounds enhance the inhibitory effect of sorafenib upon treatment of hepatocellular carcinoma cells lines.
Palabras clave: EX-527 , HCC CELL LINES , HEPATOCELLULAR CARCINOMA , SIRTUINS , SORAFENIB , SPHEROIDS
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/145467
URL: https://linkinghub.elsevier.com/retrieve/pii/S0014299920308281
DOI: https://doi.org/10.1016/j.ejphar.2020.173736
Colecciones
Articulos(IFISE)
Articulos de INST.DE FISIOLOGIA EXPERIMENTAL (I)
Citación
Ceballos Mancini, María Paula; Angel, Antonella; Delprato, Carla Beatriz; Livore, Veronica Ines; Ferretti, Anabela; et al.; Sirtuin 1 and 2 inhibitors enhance the inhibitory effect of sorafenib in hepatocellular carcinoma cells; Elsevier Science; European Journal of Pharmacology; 892; 2-2021; 1-44
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