Modeling Human Diseases in C. elegans Group; Genes, Diseases, and Therapies Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology, Hospital Duran i Reynals, Avda Gran via, 199-203, L'Hospitalet, 08908 Barcelona, Spain.
Dis Model Mech. 2022 Mar 1;15(3). doi: 10.1242/dmm.049161. Epub 2022 Mar 31.
Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we used C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution system for evaluating locomotion. First, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse XFe96 Analyzer, we observed a detrimental effect of cisplatin and glucose on mitochondrial respiration. Second, because catechol-O-methyltransferases (involved in dopamine degradation) are upregulated upon cisplatin exposure, we studied the protective role of dopamine against cisplatin-induced neurotoxicity. Using a Tierpsy Tracker system for measuring neurotoxicity, we showed that abnormal displacements and body postures in cat-2 mutants, which have dopamine synthesis disrupted, can be rescued by adding dopamine. Then, we demonstrated that dopamine treatment protects against the dose-dependent neurotoxicity caused by cisplatin.
顺铂是治疗实体瘤的一线化疗中最常用的药物。我们和其他人之前曾使用秀丽隐杆线虫来鉴定影响顺铂敏感性和耐药性的遗传因素。在这项研究中，我们使用秀丽隐杆线虫来探索顺铂对线粒体功能的影响，并通过评估运动的高分辨率系统来研究顺铂诱导的神经毒性。首先，我们报告高糖饮食在生理水平上使秀丽隐杆线虫对顺铂敏感，并且线粒体 CED-13 可保护细胞免受顺铂诱导的氧化应激。此外，通过 Seahorse XFe96 分析仪评估线粒体功能，我们观察到顺铂和葡萄糖对线粒体呼吸有不利影响。其次，由于儿茶酚-O-甲基转移酶（参与多巴胺降解）在顺铂暴露时上调，我们研究了多巴胺对顺铂诱导的神经毒性的保护作用。使用用于测量神经毒性的 Tierpsy Tracker 系统，我们表明，多巴胺合成受阻的 cat-2 突变体中异常位移和身体姿势可以通过添加多巴胺来挽救。然后，我们证明多巴胺处理可防止顺铂引起的剂量依赖性神经毒性。
