Tags

Type your tag names separated by a space and hit enter

Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells.
J Pharmacol Exp Ther. 2020 Jun 17 [Online ahead of print]JP

Abstract

Schizophrenia is a mental disease that results in decreased life expectancy and wellbeing, by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. While the second generation of 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 as well as 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 IRE1 and PERK, two major transducers of the UPR. Cells underwent apoptosis upon Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2 cells 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 anti-schizophrenic drug Aripiprazole has cytotoxic properties at high concentrations. This study shows that cytotoxicity is associated with the induction of endoplasmic reticulum (ER) stress and IRE1 activation, mechanisms involved in died-induced obesity. Aripiprazole induced ER stress and calcium mobilization from the ER in human and mouse hepatocytes. Our study highlights a new mechanism for the metabolic derangement associated with anti-schizophrenic drugs.

Authors+Show Affiliations

The Hebrew University of Jerusalem.The Hebrew University of Jerusalem.The Hebrew University of Jerusalem.The Hebrew University of Jerusalem.The Hebrew University of Jerusalem.The Hebrew University of Jerusalem.Instituto de Investigaciones Biomedicas Alberto Sols.Instituto de Investigaciones Biomedicas Alberto Sols.Instituto de Investigaciones Biomedicas Alberto Sols.The Hebrew University of Jerusalem.The Hebrew University of Jerusalem.Instituto de Investigaciones Biomedicas Alberto Sols.The Hebrew University of Jerusalem; boazt@ekmd.huji.ac.il.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32554435

Citation

Forno, Francesca, et al. "Aripiprazole Cytotoxicity Coincides With Activation of the Unfolded Protein Response in Human Hepatic Cells." The Journal of Pharmacology and Experimental Therapeutics, 2020.
Forno F, Maatuf Y, Boukeileh S, et al. Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells. J Pharmacol Exp Ther. 2020.
Forno, F., Maatuf, Y., Boukeileh, S., Dipta, P., Mahameed, M., Darawshi, O., Ferreira, V., Rada, P., Garcia-Martinez, I., Gross, E., Priel, A., Valverde, A. M., & Tirosh, B. (2020). Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1124/jpet.119.264481
Forno F, et al. Aripiprazole Cytotoxicity Coincides With Activation of the Unfolded Protein Response in Human Hepatic Cells. J Pharmacol Exp Ther. 2020 Jun 17; PubMed PMID: 32554435.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells. AU - Forno,Francesca, AU - Maatuf,Yossi, AU - Boukeileh,Shatha, AU - Dipta,Priya, AU - Mahameed,Mohamed, AU - Darawshi,Odai, AU - Ferreira,Vitor, AU - Rada,Patricia, AU - Garcia-Martinez,Irma, AU - Gross,Einav, AU - Priel,Avi, AU - Valverde,Angela Martinez, AU - Tirosh,Boaz, Y1 - 2020/06/17/ PY - 2019/12/08/received PY - 2020/06/08/revised PY - 2020/06/08/accepted PY - 2020/6/20/pubmed PY - 2020/6/20/medline PY - 2020/6/20/entrez KW - Ca imaging KW - cell death KW - drug toxicity KW - glutathione KW - pharmacodynamics KW - protein kinases JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. N2 - Schizophrenia is a mental disease that results in decreased life expectancy and wellbeing, by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. While the second generation of 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 as well as 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 IRE1 and PERK, two major transducers of the UPR. Cells underwent apoptosis upon Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2 cells 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 anti-schizophrenic drug Aripiprazole has cytotoxic properties at high concentrations. This study shows that cytotoxicity is associated with the induction of endoplasmic reticulum (ER) stress and IRE1 activation, mechanisms involved in died-induced obesity. Aripiprazole induced ER stress and calcium mobilization from the ER in human and mouse hepatocytes. Our study highlights a new mechanism for the metabolic derangement associated with anti-schizophrenic drugs. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/32554435/Aripiprazole_cytotoxicity_coincides_with_activation_of_the_unfolded_protein_response_in_human_hepatic_cells L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=32554435 DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.