Dona Margo, Lamers Maaike, Rohde Svenja, Gorissen Marnix, Timmers Henri J L M
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Department of Animal Ecology and Physiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, 6525 AJ Nijmegen, The Netherlands.
Cancers (Basel). 2021 Oct 13;13(20):5124. doi: 10.3390/cancers13205124.
Patients with mutations in the β-subunit of the succinate dehydrogenase () have the highest risk to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic strategies in vivo. One possible molecular mechanism of -associated tumorigenesis originates in an overproduction of reactive oxygen species (ROS) due to mitochondrial dysfunction. Ascorbic acid (Vitamin C) has already been shown to act as anti-cancer agent in several clinical trials for various types of cancer. In this study, the potential of the zebrafish model to study -associated PPGLs using a drug screening approach was investigated. First, we identified increased basal ROS levels in homozygous larvae compared to heterozygous and wild-type siblings. Using a semi high-throughput drug screening, the effectiveness of different dosages of anti- and pro-oxidant Vitamin C were assessed to evaluate differences in survival, ROS levels, and locomotor activity. Low-dosage levels of Vitamin C induced a decrease of ROS levels but no significant effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan of the homozygous larvae while not affecting the lifespan of heterozygous and wild-type siblings. These results validated the zebrafish model as a powerful drug screening tool that may be used to identify novel therapeutic targets for -associated PPGLs.
琥珀酸脱氢酶（SDH）β亚基发生突变的患者患无法治愈的恶性嗜铬细胞瘤和副神经节瘤（PPGLs）的风险最高。由于在体内测试新治疗策略的可能性有限，治疗方法的开发受到阻碍。与SDH相关的肿瘤发生的一种可能分子机制源于线粒体功能障碍导致的活性氧（ROS）过度产生。在针对各种类型癌症的多项临床试验中，抗坏血酸（维生素C）已被证明可作为抗癌剂。在本研究中，研究了斑马鱼模型使用药物筛选方法研究与SDH相关的PPGLs的潜力。首先，我们发现与杂合子和野生型同胞相比，纯合子SDH幼虫的基础ROS水平升高。使用半高通量药物筛选，评估了不同剂量的抗氧化剂和促氧化剂维生素C的有效性，以评估在存活率、ROS水平和运动活性方面的差异。低剂量的维生素C可导致ROS水平降低，但对寿命无显著影响。相比之下，高剂量的维生素C缩短了纯合子SDH幼虫的寿命，而不影响杂合子和野生型同胞的寿命。这些结果验证了SDH斑马鱼模型作为一种强大的药物筛选工具，可用于识别与SDH相关的PPGLs的新治疗靶点。
