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

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 wi...

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Published in:	European journal of pharmacology Vol. 892; p. 173736
Main Authors:	Ceballos, María Paula, Angel, Antonella, Delprato, Carla Beatriz, Livore, Verónica Inés, Ferretti, Anabela Cecilia, Lucci, Alvaro, Comanzo, Carla Gabriela, Alvarez, María de Luján, Quiroga, Ariel Darío, Mottino, Aldo Domingo, Carrillo, María Cristina
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 05-02-2021
Subjects:	Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis - drug effects Apoptosis Regulatory Proteins - metabolism ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism Carbazoles - pharmacology Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - enzymology Carcinoma, Hepatocellular - pathology Cell Cycle Proteins - metabolism Cell Movement - drug effects Cell Proliferation - drug effects Drug Resistance, Neoplasm EX-527 HCC cell lines Hep G2 Cells Hepatocellular carcinoma Histone Deacetylase Inhibitors - pharmacology Humans Liver Neoplasms - drug therapy Liver Neoplasms - enzymology Liver Neoplasms - pathology Multidrug Resistance-Associated Proteins - metabolism Naphthalenes - pharmacology Neoplasm Invasiveness Neoplasm Proteins - metabolism Pyrimidinones - pharmacology Signal Transduction Sirtuin 1 - antagonists & inhibitors Sirtuin 1 - metabolism Sirtuin 2 - antagonists & inhibitors Sirtuin 2 - metabolism Sirtuins Sorafenib Sorafenib - pharmacology Spheroids Spheroids, Cellular Sirtuins Hepatocellular carcinoma EX-527 HCC cell lines Sorafenib Spheroids
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-2999 1879-0712
DOI:	10.1016/j.ejphar.2020.173736