Salubrinal Protects Against Cisplatin-Induced Cochlear Hair Cell Endoplasmic Reticulum Stress by Regulating Eukaryotic Translation Initiation Factor 2α Signalling

Wen, Li; Ni, Kun; Li, Zhuangzhuang; Xiao, Lv; Li, Yini; Jiang, Yan; Zhang, Jincheng; Shi, Haibo

doi:10.3389/fnmol.2022.916458

Cited by 9 publications

(3 citation statements)

References 50 publications

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“…The current findings suggest that the UPR may be a common mechanism in ototoxicity relating to noise and cisplatin. The efficacy of ISRIB corroborates prior findings: tauroursodeoxycholic acid, a non-specific modulator of the UPR, was effective at mitigating cisplatin ototoxicity in vivo (45–46), and salubrinal, which targets eIF2a and, like ISRIB, modulates the PERK/CHOP pathway, protects against cisplatin toxicity in vitro (47). Taken together, these findings suggest that targeting the UPR may be a valuable broad strategy to treat acquired hearing loss.…”

Section: Discussionsupporting

confidence: 85%

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity

Li,

Rouse,

Matthews

et al. 2023

Preprint

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Cisplatin is a common chemotherapy drug with a nearly universal side effect of ototoxicity. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate, is associated with reduced survival in disseminated hepatoblastoma, highlighting the need for more specific drugs. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact the cytotoxic effects of cisplatin on HNSCC cell viability. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.

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Section: Discussionsupporting

confidence: 85%

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity

Li,

Rouse,

Matthews

et al. 2023

Preprint

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“…Endoplasmic reticulum (ER) stress also triggers cisplatin-induced apoptosis following activation of caspase 12 localized at the cytosolic membrane of ER. Both activating eukaryotic translation initiation factor2α (eIF2α) signaling pathway and its dephosphorylation inhibitor salubrinal significantly reduced cisplatin-induced cochlear hair cell ERS levels and attenuated cell injury, while eIF2α knockdown inhibited the protective effect ( Lu et al, 2022a ). A novel acetophenone compound can act as nucleophilic substitutes for cisplatin in platinum-cysteine thiolate site interactions which is responsible for cisplatin ototoxicity.…”

Section: Protective Measures Against Cisplatin Ototoxicitymentioning

confidence: 99%

Cisplatin ototoxicity mechanism and antagonistic intervention strategy: a scope review

Zhang

Song

et al. 2023

Front. Cell. Neurosci.

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Cisplatin is a first-line chemotherapeutic agent in the treatment of malignant tumors with remarkable clinical effects and low cost. However, the ototoxicity and neurotoxicity of cisplatin greatly limit its clinical application. This article reviews the possible pathways and molecular mechanisms of cisplatin trafficking from peripheral blood into the inner ear, the toxic response of cisplatin to inner ear cells, as well as the cascade reactions leading to cell death. Moreover, this article highlights the latest research progress in cisplatin resistance mechanism and cisplatin ototoxicity. Two effective protective mechanisms, anti-apoptosis and mitophagy activation, and their interaction in the inner ear are discussed. Additionally, the current clinical preventive measures and novel therapeutic agents for cisplatin ototoxicity are described. Finally, this article also forecasts the prospect of possible drug targets for mitigating cisplatin-induced ototoxicity. These include the use of antioxidants, inhibitors of transporter proteins, inhibitors of cellular pathways, combination drug delivery methods, and other mechanisms that have shown promise in preclinical studies. Further research is needed to evaluate the efficacy and safety of these approaches.

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“…Salubrinal is selective inhibitor of eIF2α phosphatase ( Lu et al, 2022 ). Salubrinal upregulates eIF2α phosphorylation and reduces ER stress-induced cytotoxicity in PC12 cells ( Boyce et al, 2005 ).…”

Section: Endoplasmic Reticulum Stress As a Therapeutic Target For Alsmentioning

confidence: 99%

Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis

Jeon

Kwon²,

Lee³

2023

Front. Aging Neurosci.

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The endoplasmic reticulum (ER) is a major organelle involved in protein quality control and cellular homeostasis. ER stress results from structural and functional dysfunction of the organelle, along with the accumulation of misfolded proteins and changes in calcium homeostasis, it leads to ER stress response pathway such as unfolded protein response (UPR). Neurons are particularly sensitive to the accumulation of misfolded proteins. Thus, the ER stress is involved in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, prion disease and motor neuron disease (MND). Recently, the complex involvement of ER stress pathways has been demonstrated in experimental models of amyotrophic lateral sclerosis (ALS)/MND using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive response to ER stress. Here, we aim to provide recent evidence demonstrating that the ER stress pathway is an essential pathological mechanism of ALS. In addition, we also provide therapeutic strategies that can help treat diseases by targeting the ER stress pathway.

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Salubrinal Protects Against Cisplatin-Induced Cochlear Hair Cell Endoplasmic Reticulum Stress by Regulating Eukaryotic Translation Initiation Factor 2α Signalling

Cited by 9 publications

References 50 publications

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity

Cisplatin ototoxicity mechanism and antagonistic intervention strategy: a scope review

Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis

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