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Systemic application of honokiol prevents cisplatin ototoxicity without compromising its antitumor effect.

ABSTRACT: Cisplatin is a potent drug used in about 40% of cancer treatment but also leads to severe deafness in 60-80% of the cases. Although the mechanism is known to be related to the accumulation of reactive oxygen species (ROS), no drug or FDA approved treatment is currently available to prevent cisplatin ototoxicity. With this study, we show for the first time that honokiol (HNK), a pleiotropic poly-phenol prevents cisplatin-induced hearing loss. HNK also improves the wellbeing of the mice during the treatment, determined by the increase in the number of surviving animals. In a transgenic tumor mouse model, HNK does not hinder cisplatin's antitumor effect. The mechanism is related to the activation of sirtuin 3, a deacetylase in mitochondria essential for ROS detoxification. We expect a paradigm shift in cisplatin chemotherapy based on the current study and future clinical trials, where honokiol is applied to reduce side effects including hearing loss.

SUBMITTER: Tan X

PROVIDER: S-EPMC7783741 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Systemic application of honokiol prevents cisplatin ototoxicity without compromising its antitumor effect.

Tan Xiaodong X Zhou Yingjie Y Agarwal Aditi A Lim Michelle M Xu Yingyue Y Zhu Yueming Y O'Brien Joseph J Tran Elizabeth E Zheng Jing J Gius David D Richter Claus-Peter CP

American journal of cancer research 20201201 12

Cisplatin is a potent drug used in about 40% of cancer treatment but also leads to severe deafness in 60-80% of the cases. Although the mechanism is known to be related to the accumulation of reactive oxygen species (ROS), no drug or FDA approved treatment is currently available to prevent cisplatin ototoxicity. With this study, we show for the first time that honokiol (HNK), a pleiotropic poly-phenol prevents cisplatin-induced hearing loss. HNK also improves the wellbeing of the mice during the ...[more]

PMID: 33415008

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Project description:Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.

Dataset Information

Systemic application of honokiol prevents cisplatin ototoxicity without compromising its antitumor effect.

Publications

Systemic application of honokiol prevents cisplatin ototoxicity without compromising its antitumor effect.

Similar Datasets

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