Dalhousie University, Department of Microbiology and Immunology, Halifax, Canada.
IWK Health Centre, Department of Pediatrics, Halifax, Canada.
Elife. 2020 Jul 28;9:e56235. doi: 10.7554/eLife.56235.
Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.
顺铂给药的剂量限制毒性，包括耳毒性和肾毒性，影响了这种有效化疗药物的临床应用，并导致终身并发症，特别是在儿科癌症幸存者中。我们使用双管齐下的药物筛选方法，利用斑马鱼侧线作为体内耳毒性读出器和基于肾细胞的肾毒性测定法，筛选了 1280 种化合物，并确定了 22 种具有耳毒性和肾毒性保护作用的化合物。其中，多巴胺和 L-千里光氨酸（一种在多巴胺途径中起作用的植物源性氨基酸）进一步进行了研究。多巴胺和 L-千里光氨酸可保护斑马鱼耳泡中的毛细胞免受顺铂引起的损伤，并维持斑马鱼幼体肾小球滤过。重要的是，这些化合物并未消除顺铂对人类癌细胞的细胞毒性作用。这项研究深入了解了顺铂引起的耳毒性和肾毒性的机制，并为多巴胺和 L-千里光氨酸在更安全地施用顺铂方面的潜在应用提供了令人信服的临床前证据。
