Identification of novel neuroprotective N,N-dimethylaniline derivatives that prevent oxytosis/ferroptosis and localize to late endosomes and lysosomes

Hirata, Yoko; Tsunekawa, Yoshiyuki; Takahashi, Mamoru; Oh‐hashi, Kentaro; Kawaguchi, Kyoka; Hayazaki, Masumi; Watanabe, Miyu; Koga, Kenichi; Hattori, Yurika; Takemori, Hiroshi; Furuta, Kyoji

doi:10.1016/j.freeradbiomed.2021.08.015

Cited by 17 publications

(20 citation statements)

References 41 publications

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“…The effects of haloperidol were lesser against RSL3, a direct inhibitor of glutathione peroxidase 4, than those against glutamate and erastin (Figure S3). These characteristics are very similar to those of N,N-dimethylaniline derivatives, such as GIF-2114 and GIF-2115, 20 suggesting critical roles of lysosomal ferrous ions in oxytosis/ferroptosis. In conclusion, haloperidol is a strong ferroptosis inhibitor that decreases intracellular ROS production by reducing the accumulation of ferrous ions in late endosomes and lysosomes.…”

Section: Haloperidol-protected Ht22 Cells Against Oxytosis/supporting

confidence: 54%

“…The protective action of haloperidol on glutamate- and erastin-induced cytotoxicity was confirmed by a cell viability assay using a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2 H -tetrazolium monosodium salt (WST-8) reagent (Figure D). The protective potency of haloperidol against glutamate- and erastin-evoked cell damage is equivalent to that of GIF-2114 and GIF-2115, which are N , N -dimethylaniline derivatives and the lipid ROS scavenger ferrostatin-1, but it is much stronger than that of iron chelator deferoxamine (DFO). As reported previously, haloperidol alone induced cell death at 50 μM and exacerbated glutamate-induced cell death at 10 μM (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…33 Transfection. CD63-mCherry-pcDNA3.1 and Rab7-mCherry-pcDNA3.1 were prepared as previously described 20 and transfected using Lipofectamine LTX following the manufacturer's recommended protocol (Thermo Fisher Scientific). After 1 day, Hal-NBD was added and incubated for 15 min at 37 °C.…”

Section: ■ Methodsmentioning

confidence: 99%

“…The characteristics of haloperidol in the prevention of oxytosis/ferroptosis in Figures 2 and 4 are similar to those of N,N-dimethylaniline derivatives, which localize to late endosomes and lysosomes and decrease the cellular content of ferrous ions. 20 Therefore, the haloperidol-nitrobenzoxadiazole (Hal-NBD) fluorescent probe was developed by our group to understand the neuroprotective effects of haloperidol by coupling a fluorescent A previous study reported diffusion of 3 H-labeled ligands, including haloperidol through the cell membrane and accumulation in the lysosomal compartment. 28 This phenomenon appears to be a common property of weak bases.…”

Section: Haloperidol-protected Ht22 Cells Against Oxytosis/mentioning

confidence: 99%

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Haloperidol Prevents Oxytosis/Ferroptosis by Targeting Lysosomal Ferrous Ions in a Manner Independent of Dopamine D2 and Sigma-1 Receptors

Hirata

Oka

Yamamoto

et al. 2022

ACS Chem. Neurosci.

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Haloperidol is a widely used antipsychotic agent that exerts antipsychotic effects through a strong antagonism of dopamine D2 receptors. In addition, haloperidol is classified as a sigma-1 receptor (S1R) antagonist that prevents endogenous oxidative stress in cultured cells. However, pharmacological activities of haloperidol against oxidative stress remain unclear. Oxytosis/ferroptosis are iron-dependent nonapoptotic oxidative cell deaths that are regarded as two names for the same cell death pathway and the potential physiological relevance of oxytosis/ferroptosis in multiple diseases is suggested. In the present study, the effects of haloperidol on oxytosis/ferroptosis were investigated in S1R-knockdown mouse hippocampal HT22 cells. The results indicate that haloperidol is a strong inhibitor of oxytosis/ferroptosis independent of S1R. Imaging of HT22 cells with a newly developed fluorescent probe showed that haloperidol was localized to late endosomes and lysosomes and reduced the accumulation of lysosomal ferrous ions, resulting in reduced production of intracellular reactive oxygen species and inhibition of cell death. These results indicate that haloperidol is useful not only as an antipsychotic agent but also as a neuroprotective agent against endogenous oxidative stress via distinct mechanisms. Furthermore, lysosome-targeting ferroptosis inhibitors could be useful for the treatment of various diseases, including cancers, ischemia-reperfusion injury, and neurodegenerative disorders, which have been associated with ferroptosis.

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Section: Haloperidol-protected Ht22 Cells Against Oxytosis/supporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

Section: Haloperidol-protected Ht22 Cells Against Oxytosis/mentioning

confidence: 99%

See 2 more Smart Citations

Haloperidol Prevents Oxytosis/Ferroptosis by Targeting Lysosomal Ferrous Ions in a Manner Independent of Dopamine D2 and Sigma-1 Receptors

Hirata

Oka

Yamamoto

et al. 2022

ACS Chem. Neurosci.

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“…The latest study has developed drugs localized to lysosomes that inhibit or promote ferroptosis. For example, N, N-dimethylaniline derivatives localize to late endosomes and lysosomes, which are able to prevent ferroptosis ( Hirata et al, 2021 ). Dichloroacetate promotes ferroptosis in colorectal cancer cells by chelating iron in lysosomes ( Sun J. et al, 2021 ).…”

Section: Regulatory Mechanism Of Ferroptosismentioning

confidence: 99%

Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer

Zhang

et al. 2022

Front. Pharmacol.

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Ferroptosis is an iron-dependent regulated form of cell death caused by excessive lipid peroxidation. This form of cell death differed from known forms of cell death in morphological and biochemical features such as apoptosis, necrosis, and autophagy. Cancer cells require higher levels of iron to survive, which makes them highly susceptible to ferroptosis. Therefore, it was found to be closely related to the progression, treatment response, and metastasis of various cancer types. Numerous studies have found that the ferroptosis pathway is closely related to drug resistance and metastasis of cancer. Some cancer cells reduce their susceptibility to ferroptosis by downregulating the ferroptosis pathway, resulting in resistance to anticancer therapy. Induction of ferroptosis restores the sensitivity of drug-resistant cancer cells to standard treatments. Cancer cells that are resistant to conventional therapies or have a high propensity to metastasize might be particularly susceptible to ferroptosis. Some biological processes and cellular components, such as epithelial–mesenchymal transition (EMT) and noncoding RNAs, can influence cancer metastasis by regulating ferroptosis. Therefore, targeting ferroptosis may help suppress cancer metastasis. Those progresses revealed the importance of ferroptosis in cancer, In order to provide the detailed molecular mechanisms of ferroptosis in regulating therapy resistance and metastasis and strategies to overcome these barriers are not fully understood, we described the key molecular mechanisms of ferroptosis and its interaction with signaling pathways related to therapy resistance and metastasis. Furthermore, we summarized strategies for reversing resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy and inhibiting cancer metastasis by modulating ferroptosis. Understanding the comprehensive regulatory mechanisms and signaling pathways of ferroptosis in cancer can provide new insights to enhance the efficacy of anticancer drugs, overcome drug resistance, and inhibit cancer metastasis.

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The key roles of organelles and ferroptosis in Alzheimerʼs disease

Long

Cheng

Zhou

et al. 2022

J of Neuroscience Research

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Alzheimerʼs disease (AD), an age-related neurodegenerative disease, is a striking global health problem. Ferroptosis is a newly discovered form of cell death characterized by iron-dependent lipid peroxidation products and the accumulation of lethal reactive oxygen species. Strict regulation of iron metabolism is essential to ensure neuronal homeostasis. Excess and deficiency of iron are both associated with neurodegeneration.Studies have shown that oxidative stress caused by cerebral iron metabolism disorders in the body is involved in the process of AD, ferroptosis may play an important role in the pathogenesis of AD, and regulating ferroptosis is expected to be a new direction for the treatment of AD. Various organelles are closely related to ferroptosis: mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome are involved in the regulation of ferroptosis from the aspects of iron metabolism and redox imbalance. In this review, the relationship between AD and the dysfunction of organelles (including mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus) and the role of organelles in ferroptosis of AD were reviewed to provide insights for understanding the relationship between organelles and ferroptosis in AD and the treatment of AD.

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Identification of novel neuroprotective N,N-dimethylaniline derivatives that prevent oxytosis/ferroptosis and localize to late endosomes and lysosomes

Cited by 17 publications

References 41 publications

Haloperidol Prevents Oxytosis/Ferroptosis by Targeting Lysosomal Ferrous Ions in a Manner Independent of Dopamine D2 and Sigma-1 Receptors

Haloperidol Prevents Oxytosis/Ferroptosis by Targeting Lysosomal Ferrous Ions in a Manner Independent of Dopamine D2 and Sigma-1 Receptors

Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer

The key roles of organelles and ferroptosis in Alzheimerʼs disease

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