Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2.

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI:10.1007/s00280-024-04706-z
Haruki Ujiie, Naoyuki Nishiya, Ami Yamamoto, Takeru Takada, Megumi Onodera, Ayana Sasaki, Takuya Oikawa
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Abstract

Purpose: Hair cell damage is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced hair cell damage by enhancing mt2 expression.

Methods: Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX at 52 h post-fertilization (hpf) for 8 h, followed by CDDP treatment for 12 h. The lateral line hair cells of CDDP-treated zebrafish at 72 hpf were observed by fluorescence microscopy.

Results: Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells.

Conclusion: DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.

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地塞米松通过金属硫蛋白-2诱导顺铂抗性,从而减轻顺铂诱导的毛细胞损伤。
目的:毛细胞损伤是抗癌药物顺铂(CDDP)引起的常见副作用,会降低患者的生活质量。复发性癌症中出现的一种 CDDP 抵抗机制是金属硫蛋白-2(mt2)对重金属的解毒作用。在这里,我们发现在斑马鱼幼体中,地塞米松(DEX)可通过增强 mt2 的表达来减少 CDDP 诱导的毛细胞损伤:方法:使用在神经细胞和毛细胞中分别表达绿色和红色荧光蛋白的转基因斑马鱼(cldn: gfp; atoh1: rfp)。在受精后52 hpf用DEX预处理斑马鱼8 h,然后用CDDP处理12 hpf,用荧光显微镜观察72 hpf时CDDP处理斑马鱼的侧线毛细胞:结果:利用不良事件数据库进行的报告几率比(ROR)分析表明,CDDP诱发的耳毒性降低与作为癌症化疗止吐药的DEX之间存在关联。预处理DEX可保护72 hpf斑马鱼毛细胞免受CDDP诱导的损伤。10 µM DEX与CDDP联用可显著增加mt2 mRNA的表达。mt2的基因编辑逆转了DEX对CDDP诱导的毛细胞损伤的保护作用:结论:DEX通过增加mt2的表达保护毛细胞免受CDDP诱导的损伤,而mt2是铂类抗癌药物的一种抗药机制。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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