Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2

<b>Background:</b> Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells...

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Autores principales:	Roberta Rinaldi, Rocchina Miglionico, Ilaria Nigro, Rosarita D’Orsi, Lucia Chiummiento, Maria Funicello, Paolo Lupattelli, Ilaria Laurenzana, Alessandro Sgambato, Magnus Monné, Faustino Bisaccia, Maria Francesca Armentano
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	HIV-1 protease inhibitors apoptosis ER stress UPR proteasome autophagy Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4f869766409b445eb03c8b269d245fe7
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spelling	oai:doaj.org-article:4f869766409b445eb03c8b269d245fe72021-11-25T17:10:52ZTwo Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG210.3390/cells101130522073-4409https://doaj.org/article/4f869766409b445eb03c8b269d245fe72021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3052https://doaj.org/toc/2073-4409<b>Background:</b> Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. <b>Methods</b>: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. <b>Results:</b> RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. <b>Conclusions:</b> These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.Roberta RinaldiRocchina MiglionicoIlaria NigroRosarita D’OrsiLucia ChiummientoMaria FunicelloPaolo LupattelliIlaria LaurenzanaAlessandro SgambatoMagnus MonnéFaustino BisacciaMaria Francesca ArmentanoMDPI AGarticleHIV-1 protease inhibitorsapoptosisER stressUPRproteasomeautophagyBiology (General)QH301-705.5ENCells, Vol 10, Iss 3052, p 3052 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV-1 protease inhibitors apoptosis ER stress UPR proteasome autophagy Biology (General) QH301-705.5
spellingShingle	HIV-1 protease inhibitors apoptosis ER stress UPR proteasome autophagy Biology (General) QH301-705.5 Roberta Rinaldi Rocchina Miglionico Ilaria Nigro Rosarita D’Orsi Lucia Chiummiento Maria Funicello Paolo Lupattelli Ilaria Laurenzana Alessandro Sgambato Magnus Monné Faustino Bisaccia Maria Francesca Armentano Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
description	<b>Background:</b> Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. <b>Methods</b>: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. <b>Results:</b> RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. <b>Conclusions:</b> These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.
format	article
author	Roberta Rinaldi Rocchina Miglionico Ilaria Nigro Rosarita D’Orsi Lucia Chiummiento Maria Funicello Paolo Lupattelli Ilaria Laurenzana Alessandro Sgambato Magnus Monné Faustino Bisaccia Maria Francesca Armentano
author_facet	Roberta Rinaldi Rocchina Miglionico Ilaria Nigro Rosarita D’Orsi Lucia Chiummiento Maria Funicello Paolo Lupattelli Ilaria Laurenzana Alessandro Sgambato Magnus Monné Faustino Bisaccia Maria Francesca Armentano
author_sort	Roberta Rinaldi
title	Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
title_short	Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
title_full	Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
title_fullStr	Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
title_full_unstemmed	Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
title_sort	two novel precursors of the hiv-1 protease inhibitor darunavir target the upr/proteasome system in human hepatocellular carcinoma cell line hepg2
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4f869766409b445eb03c8b269d245fe7
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Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2

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