# Hearing Protection in Cisplatin Chemotherapy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $400,000

## Abstract

Project Summary / Abstract
Cisplatin is a potent antitumor drug used in ~40% of cancer chemotherapy regimens together with
other platinum-based drugs. Unfortunately, cisplatin also induces multiple unwanted toxic effects
such as ototoxicity, which contributes to ~100-300 thousand new hearing impairment cases
annually among the cancer patients in the US alone. Cisplatin-induced hearing loss (CIHL) is
related to the generation of reactive oxygen species (ROS), causing cochlear damage, particularly
the loss of outer hair cells (OHCs). In this regard, antioxidants working as free radical scavengers
are proposed for treating CIHL). However, antioxidants generate lots of issues such as
deactivating cisplatin and protecting tumor cells. To date, no effective clinical treatment for CIHL
has been approved. Different to the antioxidants, honokiol (HNK) is a multifunctional molecule
that can both protect normal cells from oxidative damage and potentiate the antitumor effect of
cisplatin. The protective effects of HNK against CIHL is verified in our recent publication. The
mechanism is associated with the activation of sirtuins, the critical regulators of the anti-ROS
system in the cells. The sirtuin family is composed of 7 members of deacetylase, expressing in
different intracellular locations including cytoplasm (SIRT1, 2), mitochondria (SIRT3-5), and
nucleus (SIRT1, 2, 6, 7) and forming an intrinsic network for ROS detoxification.
In this study, the roles of the sirtuin family in the protective effects of HNK against CIHL will be
further investigated. First, the hearing protective effects of HNK against CIHL and the activation
of sirtuins will be further verified in a tumor bearing mouse model undergoing chemotherapy.
Second, the significance of cytosolic sirtuins (SIRT1) will be verified in a SIRT1 deficiency model.
Third, the role of mitochondria sirtuins (SIRT3 and SIRT5) and their potential compensation to
each other will be verified using SIRT3 knockout mice and isocitrate dehydrogenase 2 knockout
mice. Auditory brainstem response and distortion product otoacoustic emission will be measured
to assess hearing function. X-ray fluorescence microscopy will be used to verify the distribution
of platinum in the inner ear. Immunostaining, confocal imaging, and X-ray micro-computed
tomography will be applied for studying morphological changes such as OHC loss. A more
comprehensive understanding of the mechanism of the CIHL and its protection will be obtained.
This project is of great clinical significance by laying the groundwork for human tests using HNK
for hearing protection in chemotherapy. Furthermore, the proposed study will also provide insight
into hearing protection against other types of hearing impairment, such as noise-induced, drug-
induced and age-related hearing loss.

## Key facts

- **NIH application ID:** 10766196
- **Project number:** 5R01DC019434-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Xiaodong Tan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766196

## Citation

> US National Institutes of Health, RePORTER application 10766196, Hearing Protection in Cisplatin Chemotherapy (5R01DC019434-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10766196. Licensed CC0.

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