Src is the primary target of aripiprazole, an atypical antipsychotic drug, in its anti-tumor action

Kim, Mi Seon; Yoo, Byong Chul; Yang, Woo Seok; Han, Sang Yun; Jeong, Deok; Song, Junmin; Kim, Kyung Hee; Aravinthan, Adithan; Kim, Ji Hye; Kim, Jong Hoon; Kim, Seung Cheol; Cho, Jae Youl

doi:10.18632/oncotarget.23192

Cited by 25 publications

(30 citation statements)

References 55 publications

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“…Taken together, it seems that this drug can be mentioned as a good cytotoxic compound. As reported here, the cytotoxicity of aripiprazole on MKN45 cancer cell line is consistent with some other researches (5,21) . Anti-cancer effects of aripiprazole on various malignant tumor cells and its molecular mechanism were examined by using cell proliferation assay, xenograft mouse model, immunoblotting analysis, migration assay, luciferase reporter gene assay, kinase assay, and overexpression strategy.…”

Section: Mtt Assaysupporting

confidence: 93%

“…Anti-cancer effects of aripiprazole on various malignant tumor cells and its molecular mechanism were examined by using cell proliferation assay, xenograft mouse model, immunoblotting analysis, migration assay, luciferase reporter gene assay, kinase assay, and overexpression strategy. Treatment with aripiprazole induced cytotoxicity in U251 glioma cells, MKN-1 gastric adenosquamous carcinoma cells, and CT26 colon carcinoma cells (5) . Moreover, the effects of aripiprazole alone and in combination with chemotherapeutic agents in order to test growth ability, the ability to form stem cells/differentiation/ chemical resistance, the markers of cancer stem cells, cancer cells and normalized cells was investigated.…”

Section: Mtt Assaymentioning

confidence: 96%

“…cell line MDA-MB-231, the colon carcinoma cell line CT26, the human embryonic kidney cell line HEK293, serum-cultured cancer cells and cancer stem cells (5,6) . In this study, anti-cancer effects of aripiprazole on MKN45 cancer cell line and NIH3T3 cell line were carefully examined by using methyl tetrazolium (MTT) assay.…”

Section: Cytotoxic Effects Of Aripiprazole On Mkn45 and Nih3t3 Cell Lmentioning

confidence: 99%

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Cytotoxic Effects of Aripiprazole on Mkn45 and Nih3t3 Cell Lines and Genotoxic Effects on Human Peripheral Blood Lymphocytes

Shokrzadeh

Mohammadpour

Modanloo

et al. 2019

Arq. Gastroenterol.

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BACKGROUND: Gastric cancer is known as the fourth most common cancer. Current treatments for cancer have damaged the sensitive tissues of the healthy body, and in many cases, cancer will be recurrent. Therefore, need for treatments that are more effective is well felt. Researchers have recently shifted their attention towards antipsychotic dopamine antagonists to treat cancer. The anticancer activities of aripiprazole remain unknown. OBJECTIVE: This study aimed to evaluate the efficacy and safety of aripiprazole on gastric cancer and normal cell lines. METHODS: In this regard, the cytotoxicity and genotoxicity of aripiprazole were investigated in MKN45 and NIH3T3 cell lines by methyl tetrazolium assay and on peripheral blood lymphocytes by micronucleus assay. For this purpose, cells were cultured in 96 wells plate. Stock solutions of aripiprazole and cisplatin were prepared. After cell incubation with different concentrations of aripiprazole (1, 10, 25, 50, 100 and 200 μL), methyl tetrazolium solution was added. For micronucleus assay fresh blood was added to RPMI culture medium 1640 supplemented, and different concentrations of aripiprazole (50, 100 and 200 μL) were added. RESULTS: The finding of present study showed that the IC50 of aripiprazole in the cancer cell line (21.36 μg/mL) was lower than that in the normal cell line (54.17 μg/mL). Moreover, the micronucleus assay showed that the frequency of micronuclei of aripiprazole at concentrations below 200 μM was much less than cisplatin. CONCLUSION: Aripiprazole can be a good cytotoxic compound and good candidate for further studies of cancer therapy.

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Section: Mtt Assaysupporting

confidence: 93%

Section: Mtt Assaymentioning

confidence: 96%

Section: Cytotoxic Effects Of Aripiprazole On Mkn45 and Nih3t3 Cell Lmentioning

confidence: 99%

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Cytotoxic Effects of Aripiprazole on Mkn45 and Nih3t3 Cell Lines and Genotoxic Effects on Human Peripheral Blood Lymphocytes

Shokrzadeh

Mohammadpour

Modanloo

et al. 2019

Arq. Gastroenterol.

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“…The transition between adaptive to terminal UPR is dependent on the stressor and the cell type. Cytotoxicity of Ari has been previously demonstrated, but the mechanism is not well understood and was postulated to involve inhibition of tyrosine kinases such as Src and Syk (Kim et al, 2017;Yoo et al, 2018). In dopaminergic neurons, Ari protected from glutamate-induced cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

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

Forno

Maatuf

Boukeileh

et al. 2020

J Pharmacol Exp Ther

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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.

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“…Aripiprazole is also an atypical antipsychotic which is widely used to treat schizophrenia. Kim et al ( 2018 ) recently proved that aripiprazole inhibits the glioma cell migration and induces apoptosis by directly inhibiting oncogenic Src kinase. It has been reported that the Src and Akt are common downstream signaling kinases of BDNF (Zhang et al, 2013 ), so these findings are consistent with the increase of BDNF in glioma patients.…”

Section: The Similar Mechanisms Involved In Glioma Tumorigenesis and mentioning

confidence: 99%

Glioma in Schizophrenia: Is the Risk Higher or Lower?

Gao

Guo

et al. 2018

Front. Cell. Neurosci.

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Whether persons with schizophrenia have a higher or lower incidence of cancer has been discussed for a long time. Due to the complex mechanisms and characteristics of different types of cancer, it is difficult to evaluate the exact relationship between cancers and schizophrenia without considering the type of tumor. Schizophrenia, a disabling mental illness that is now recognized as a neurodevelopmental disorder, is more correlated with brain tumors, such as glioma, than other types of tumors. Thus, we mainly focused on the relationship between schizophrenia and glioma morbidity. Glioma tumorigenesis and schizophrenia may share similar mechanisms; gene/pathway disruption would affect neurodevelopment and reduce the risk of glioma. The molecular defects of disrupted-in-schizophrenia-1 (DISC1), P53, brain-derived neurotrophic factor (BDNF) and C-X-C chemokine receptors type 4 (CXCR4) involved in schizophrenia pathogenesis might play opposite roles in glioma development. Many microRNAs (miRNAs) such as miR-183, miR-9, miR-137 and miR-126 expression change may be involved in the cross talk between glioma prevalence and schizophrenia. Finally, antipsychotic drugs may have antitumor effects. All these factors show that persons with schizophrenia have a decreased incidence of glioma; therefore, epidemiological investigation and studies comparing genetic and epigenetic aberrations involved in both of these complex diseases should be performed. These studies can provide more insightful knowledge about glioma and schizophrenia pathophysiology and help to determine the target/strategies for the prevention and treatment of the two diseases.

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Src is the primary target of aripiprazole, an atypical antipsychotic drug, in its anti-tumor action

Cited by 25 publications

References 55 publications

Cytotoxic Effects of Aripiprazole on Mkn45 and Nih3t3 Cell Lines and Genotoxic Effects on Human Peripheral Blood Lymphocytes

Cytotoxic Effects of Aripiprazole on Mkn45 and Nih3t3 Cell Lines and Genotoxic Effects on Human Peripheral Blood Lymphocytes

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

Glioma in Schizophrenia: Is the Risk Higher or Lower?

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