Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells

Francesca Forno, Yossi Maatuf, Shatha Boukeileh, Priya Dipta, Mohamed Mahameed, Odai Darawshi, Vitor Ferreira, Patricia Rada, Irma García-Martinez, Einav Gross, Avi Priel, Ángela M. Valverde, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Schizophrenia is a mental disease that results in decreased life expectancy and well-being by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. Although the second-generation antipsychotics (SGA), Olanzapine and Aripiprazole, are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain, and dyslipidemia. Endoplasmic reticulum (ER) stress is induced when ER homeostasis of lipid biosynthesis and protein folding is impaired. This leads to the activation of the unfolded protein response (UPR), a signaling cascade that aims to restore ER homeostasis or initiate cell death. Chronic conditions of ER stress in the liver are associated with diabetes and perturbed lipid metabolism. These metabolic dysfunctions resemble the pharmacological side effects of SGAs. We therefore investigated whether SGAs promote the UPR in human and mouse hepatocytes. We observed full-fledged activation of ER stress by Aripiprazole not by Olanzapine. This occurred at low micromolar concentrations and to variable intensities in different cell types, such as hepatocellular carcinoma, melanoma, and glioblastoma. Mechanistically, Aripiprazole caused depletion of ER calcium, leading to activation of inositol-requiring enzyme 1 (IRE1)and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), two major transducers of the UPR. Cells underwent apoptosis with Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2, a human liver cancer cell line, protected cells from Aripiprazole toxicity. Our study reveals for the first time a cytotoxic effect of Aripiprazole that involves the induction of ER stress. SIGNIFICANCE STATEMENT The antischizophrenic drug Aripiprazole exerts cytotoxic properties at high concentrations. This study shows that this cytotoxicity is associated with the induction of endoplasmic reticulum (ER) stress and IRE1 activation, mechanisms involved in diet-induced obesity. Aripiprazole induced ER stress and calcium mobilization from the ER in human and mouse hepatocytes. Our study highlights a new mechanism of Aripiprazole that is not related to its effect on dopamine signaling.

Original languageAmerican English
Pages (from-to)452-461
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume374
Issue number3
DOIs
StatePublished - 1 Sep 2020

Bibliographical note

Funding Information:
This research was funded by grants from the David R. Bloom Center for Pharmacy, the Dr. Adolph and Klara Brettler Center for Research in Pharmacology. F.F., P.D., and V.F. are supported by H20202 Marie Sklodowska-Curie ITN, European Commission [TREATMENT, Grant Agreement-721236]. A.M.V., P.R., and I.G.-M. were supported by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea [Grant RTI2018-094052-B-100], Comunidad de Madrid, Spain [Grant S2017/BMD-3684], and CIBERdem (ISCIII, Spain). The authors declare no financial conflict of interest. https://doi.org/10.1124/jpet.119.264481. s This article has supplemental material available at jpet.aspetjournals.org.

Funding Information:
This research was funded by grants from the David R. Bloom Center for Pharmacy, the Dr. Adolph and Klara Brettler Center for Research in Pharmacology. F.F., P.D., and V.F. are supported by H20202 Marie Sklodowska-Curie ITN, European Commission [TREATMENT, Grant Agreement- 721236]. A.M.V., P.R., and I.G.-M. were supported by Ministerio de Ciencia e Innovaci?n/Agencia Estatal de Investigaci?n/Fondo Europeo de Desarrollo Regional, Uni?n Europea [Grant RTI2018-094052-B-100], Comunidad de Madrid, Spain [Grant S2017/BMD-3684], and CIBERdem (ISCIII, Spain). The authors declare no financial conflict of interest.

Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

Fingerprint

Dive into the research topics of 'Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells'. Together they form a unique fingerprint.

Cite this