Modulating the unfolded protein response with ISRIB mitigates cisplatin ototoxicity

Area of Science:

• Ototoxicity research
• Cancer chemotherapy mechanisms
• Cellular stress response pathways

Background:

• Cisplatin chemotherapy frequently causes sensorineural hearing loss, a side effect with poorly understood mechanisms.
• Current strategies to prevent ototoxicity focus on oxidative stress and apoptosis, but sodium thiosulfate (STS) has shown reduced survival in some pediatric cancers.
• Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in hearing loss and cisplatin cytotoxicity, suggesting UPR as a therapeutic target.

Purpose of the Study:

• To investigate if targeting the UPR can prevent cisplatin-induced ototoxicity.
• To evaluate the drug ISRIB (Integrated Stress Response Inhibitor) for its protective effects against cisplatin ototoxicity.
• To assess if ISRIB interferes with cisplatin's effectiveness against cancer cells.

Main Methods:

• Exposed neonatal cochlear cultures and HEK cells to cisplatin, measuring UPR markers and cell death.
• Treated mice with ISRIB to assess protection against cisplatin-induced hearing loss and hair-cell death.
• Evaluated ISRIB's impact on cisplatin cytotoxicity in head and neck squamous cell carcinoma (HNSCC) cell lines.

Main Results:

• Cisplatin induced a dose-dependent cell death and apoptosis, correlating with UPR marker expression.
• ISRIB treatment significantly protected against cisplatin-induced hearing loss and hair-cell death in vivo and in vitro.
• ISRIB did not diminish cisplatin's cytotoxic effects on HNSCC cells, unlike STS.

Conclusions:

• Targeting the pro-apoptotic PERK/CHOP pathway of the UPR with ISRIB mitigates cisplatin ototoxicity.
• ISRIB offers a potential therapeutic strategy for preventing hearing loss during cisplatin chemotherapy without compromising anti-cancer efficacy.
• This approach presents a more specific alternative to STS for managing cisplatin-induced ototoxicity.