Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-Cho, Iwate, Shiwa-gun, 028-3695, Japan.
Division of Integrated Information for Pharmaceutical Sciences, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Iwate, Shiwa-gun, 028-3694, Japan.
Cancer Chemother Pharmacol. 2024 Oct;94(4):561-569. doi: 10.1007/s00280-024-04706-z. Epub 2024 Aug 14.
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.
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.
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.
DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.
顺铂（CDDP）是一种常见的抗癌药物，其副作用是导致毛细胞损伤，从而降低了患者的生活质量。在复发性癌症中，金属硫蛋白-2（mt2）通过重金属解毒是一种常见的 CDDP 耐药机制。在这里，我们发现，在斑马鱼幼虫中，地塞米松（DEX）通过增强 mt2 表达来减少 CDDP 诱导的毛细胞损伤。
使用在毛细胞和神经元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）。斑马鱼在受精后 52 小时（hpf）时用 DEX 预处理 8 小时，然后用 CDDP 处理 12 小时。在 72 hpf 时，通过荧光显微镜观察 CDDP 处理的斑马鱼的侧线毛细胞。
使用不良事件数据库进行报告比值比（ROR）分析表明，DEX 作为癌症化疗的止吐治疗药物，与降低 CDDP 诱导的耳毒性之间存在关联。DEX 预处理可保护 72 hpf 斑马鱼毛细胞免受 CDDP 诱导的损伤。DEX 与 CDDP 联合使用可显著增加 mt2 mRNA 的表达。mt2 基因编辑逆转了 DEX 对 CDDP 诱导的毛细胞损伤的保护作用。
DEX 通过增加 mt2 表达来保护毛细胞免受 CDDP 诱导的损伤，这是铂类抗癌药物的一种耐药机制。
