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Updated: Oct 11, 2025
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Cisplatin induces damage of auditory cells: Possible relation with dynamic variation in calcium homeostasis and
Hao Zhao1, Yue Xu1, Xinlei Song1
1Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Aims:
The present study was aimed to explore the possible mechanism(s) underlying the action of cisplatin on auditory cells of mice in vitro, with special attention given to the dynamic variation in calcium homeostasis and responding channels.
Methods:
The apoptosis of auditory cells was tested by flow cytometry and TUNEL staining. The expressions of inositol 1,4,5-trisphosphate receptors (IP3R), voltage-dependent anion channel 1 (VDAC1), phosphorylated protein kinase R-like ER kinase (p-PERK), activating transcription factor 6 (ATF6), caspase-12, bcl-2, bax, cleaved caspase-9, cleaved caspase-3, beclin-1 and light chain 3β (LC3B) were measured by immunofluorescence or Western blotting. The calcium variations in subcellular structures were evaluated by Rhod-2 AM and Mag-Fluo-4 AM staining. The colocalization ratio between IP3R and beclin-1 was determined by immunocytochemistry.
Results:
We found that cisplatin exposure induced the apoptosis of HEI-OC1 cells and hair cells (HCs) in a caspase-3 dependent manner. This apoptotic process was attributed to the activation of endoplasmic reticulum (ER) stress and mitochondrial pathway and, meanwhile, accompanied by variation in calcium homeostasis and responding channels. Interestingly, we also observed that IP3R might dissociate from beclin-1 to motivate autophagy under the cisplatin insult.
Conclusions:
Overall, the findings from this work indicate that cisplatin leads to auditory cell damage of mice in vitro, which is closely relevant to dynamic variation in calcium homeostasis and responding channels in subcellular structure.
Insights
Cisplatin causes auditory cell damage by disrupting calcium balance and activating cell death pathways. This damage involves endoplasmic reticulum stress and mitochondrial dysfunction, impacting calcium channels and homeostasis.
Area of Science:
- Ototoxicity research
- Cellular biology
- Calcium signaling
Background:
- Cisplatin is a widely used chemotherapy agent with known ototoxic side effects.
- The precise mechanisms by which cisplatin induces auditory cell damage remain incompletely understood.
- Auditory cells are particularly vulnerable to drug-induced toxicity, leading to hearing loss.
Purpose of the Study:
- To investigate the in vitro mechanisms of cisplatin-induced auditory cell damage in mice.
- To examine the role of calcium homeostasis and associated channels in cisplatin ototoxicity.
- To explore the interplay between endoplasmic reticulum stress, mitochondrial pathways, and autophagy in auditory cells exposed to cisplatin.
Main Methods:
- Auditory cell apoptosis was assessed using flow cytometry and TUNEL staining.
- Expression levels of key proteins involved in apoptosis, ER stress, and autophagy were measured via immunofluorescence and Western blotting.
- Subcellular calcium variations were evaluated using fluorescent indicators, and the colocalization of inositol 1,4,5-trisphosphate receptors (IP3R) and beclin-1 was determined.
Main Results:
- Cisplatin exposure induced apoptosis in HEI-OC1 cells and hair cells (HCs) in a caspase-3 dependent manner.
- The apoptotic process was linked to endoplasmic reticulum (ER) stress and mitochondrial pathway activation, alongside altered calcium homeostasis.
- Dissociation of IP3R from beclin-1 was observed, suggesting a role in motivating autophagy under cisplatin insult.
Conclusions:
- Cisplatin induces auditory cell damage in vitro through mechanisms involving dynamic variations in calcium homeostasis and responding channels.
- Endoplasmic reticulum stress and mitochondrial pathways are critical components of cisplatin-induced ototoxicity.
- The findings highlight the complex cellular responses, including potential autophagy modulation, to cisplatin exposure in auditory cells.
