Aripiprazole Cytotoxicity Coincides with Activation of the Unfolded Protein Response in Human Hepatic Cells

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.

Aripiprazole sensitizes head and neck cancer cells to ionizing radiation by enhancing the production of reactive oxygen species

“…Thus, the ROS produced by adding Ari increases the therapeutic effect of IR. Forno et al reported that the cytotoxicity of Ari in human hepatic cells was due to activation of the unfolded protein response 14 . Although the unfolded protein response is a mechanism that is generally induced when endoplasmic reticulum stress occurs, and this stress accompanies the generation of ROS 15,16 , the IR‐sensitizing effect of Ari can be attributed to the enhanced generation of ROS by Ari and IR, although further studies are needed to define the exact mechanism.…”

Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells

“…Total RNA from INS-1 cells was extracted with Trizol ® reagent (15596026; Thermo Fisher Scientific, USA), and reverse transcription was performed using a High-Capacity cDNA Reverse Transcription Kit (436881; Thermo Fisher Scientific, USA) using random primers and Superscript III enzyme (18080093; Thermo Fisher Scientific; USA) according to the manufacturer’s instructions. RT-PCR was used for the detection of XBP1 mRNA splicing with forward (5′-CCTTGTAATTGAGAACCAGG-3′) and reverse (5′-CCAAAAGGATATCAGACTCGG-3′) primers as described [ 36 ].…”

The Role of Calcium Signaling in Melanoma

“…Since calcium homeostasis is pivotal in ER stress and mitochondria-mediated cell death, several studies applied Ca 2+ -induced cell death to cancer treatment, including melanoma treatments such as luteolin, N-acetyl-S-(p-chlorophenylcarbamoyl) cysteine (NACC), and sanguinarine [107,117,118], which mechanically revealed their potential pathways. In particular, aripiprazole is not only an antipsychotic drug but a compound capable of depleting ER calcium in melanoma, thereby leading to activation of the unfolded protein response via protein kinase R-like ER kinase (PERK) and inositol-requiring enzyme 1 [119]. Another study found that the anti-tumor effects of polyphenols was also mediated by PERK-directed Ca 2+ release [120].…”