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Updated: Aug 9, 2025
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
SIRT3/GLUT4 signaling activation by metformin protect against cisplatin-induced ototoxicity in vitro
Peiyu Du1, Tianyi Liu2, Pan Luo3
1Department of Otolaryngology-Head and Neck Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
Cisplatin is highly effective for killing tumor cells. However, as one of its side effects, ototoxicity limits the clinical application of cisplatin. The mechanisms of cisplatin-induced ototoxicity have not been fully clarified yet. SIRT3 is a deacetylated protein mainly located in mitochondria, which regulates a variety of physiological processes in cells. The role of SIRT3 in cisplatin-induced hair cell injury has not been founded. In this study, primary cultured cochlear explants exposed to 5 μM cisplatin, as well as OC-1 cells exposed to 10 μM cisplatin, were used to establish models of cisplatin-induced ototoxicity in vitro. We found that when combined with cisplatin, metformin (75 μM) significantly up-regulated the expression of SIRT3 and alleviated cisplatin-induced apoptosis of hair cells. We regulated the expression of SIRT3 to explore the role of SIRT3 in cisplatin-induced auditory hair cell injury. Overexpression of SIRT3 promoted the survival of auditory hair cells and alleviated the apoptosis of auditory hair cells. In contrast, knockdown of SIRT3 impaired the protective effect of metformin and exacerbated cisplatin injury. In addition, we found that the protective effect of SIRT3 may be achieved by regulating GLUT4 translocation and rescuing impaired glucose uptake caused by cisplatin. Our study confirmed that upregulation of SIRT3 may antagonize cisplatin-induced ototoxicity, and provided a new perspective for the study of cisplatin-induced ototoxicity.
Insights
Metformin upregulates SIRT3, protecting against cisplatin-induced ototoxicity and hair cell apoptosis by regulating glucose uptake. This finding offers a new perspective on mitigating cisplatin side effects.
Area of Science:
- Ototoxicity research
- Mitochondrial biology
- Cancer therapeutics
Background:
- Cisplatin is a vital chemotherapy drug but causes ototoxicity, limiting its use.
- The mechanisms behind cisplatin-induced ototoxicity remain unclear.
- Sirtuin 3 (SIRT3), a mitochondrial deacetylase, plays roles in cellular physiology, but its function in ototoxicity is unknown.
Purpose of the Study:
- To investigate the role of SIRT3 in cisplatin-induced ototoxicity.
- To explore metformin's protective effects against cisplatin-induced hair cell injury.
- To elucidate the molecular mechanisms underlying SIRT3's potential protective role.
Main Methods:
- Established in vitro models of cisplatin-induced ototoxicity using cochlear explants and OC-1 cells.
- Administered cisplatin, metformin, and manipulated SIRT3 expression (overexpression and knockdown).
- Assessed hair cell apoptosis, SIRT3 expression, GLUT4 translocation, and glucose uptake.
Main Results:
- Metformin (75 μM) with cisplatin significantly increased SIRT3 expression and reduced hair cell apoptosis.
- SIRT3 overexpression enhanced auditory hair cell survival and decreased apoptosis.
- SIRT3 knockdown negated metformin's protective effects and worsened cisplatin injury.
- SIRT3's protective mechanism involves regulating GLUT4 translocation and restoring cisplatin-impaired glucose uptake.
Conclusions:
- Upregulation of SIRT3 antagonizes cisplatin-induced ototoxicity.
- SIRT3 plays a crucial role in protecting auditory hair cells from cisplatin damage.
- Targeting SIRT3 offers a potential therapeutic strategy to mitigate cisplatin-induced ototoxicity.
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