For the Nimbolide Biological Activity published version of the manuscript. Funding: This analysis received no external funding. Institutional Review Board Statement: Ethical overview and approval were waived for this study resulting from the retrospective Exendin-4 web nature with minimal threat for study subjects. Informed Consent Statement: Patient consent was waived because of the retrospective nature of this study. Data Availability Statement: Data from this study is often identified in supplementary material. Conflicts of Interest: The authors J.M.T., T.A. plus a.G. received travel grants plus a speaker honorarium from PharmaCept GmbH (Berlin, Germany). The author R.I. received a speaker honorarium from PharmaCept GmbH (Berlin, Germany).
cancersArticleTargeting the Redox Balance Pathway Working with Ascorbic Acid in sdhb Zebrafish Mutant LarvaeMargo Dona 1, , Maaike Lamers 1 , Svenja Rohde 1 , Marnix Gorissen 2 and Henri J. L. M. TimmersDepartment of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; [email protected] (M.L.); [email protected] (S.R.); [email protected] (H.J.L.M.T.) Department of Animal Ecology and Physiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, 6525 AJ Nijmegen, The Netherlands; [email protected] Correspondence: [email protected] Summary: Thus far, no curative therapies are offered for malignant SDHB-associated phaeochromocytomas and paragangliomas (PPGLs). Therapy development is severely hampered by the restricted availability of appropriate animal models. Within this study, we investigated the possible of the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs Employing a drug screening approach. Among the essential characteristics of cancer initiation and progression is redox imbalance. Initially, we identified enhanced reactive oxygen species levels in homozygous sdhbrmc200 larvae at baseline. Subsequent, we tested the impact of anti- and pro-oxidant ascorbic acid (Vitamin C) on these larvae. We validated the sdhbrmc200 zebrafish model as a powerful drug screening tool to supply precious insights into pathomechanisms, which could lead to novel therapeutic targets and therapy improvement in the future. Abstract: Individuals with mutations inside the -subunit from the succinate dehydrogenase (SDHB) possess the highest danger to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy improvement is hindered by restricted possibilities to test new therapeutic approaches in vivo. A single probable molecular mechanism of SDHB-associated tumorigenesis originates in an overproduction of reactive oxygen species (ROS) as a consequence of mitochondrial dysfunction. Ascorbic acid (Vitamin C) has already been shown to act as anti-cancer agent in various clinical trials for numerous kinds of cancer. In this study, the possible on the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs working with a drug screening approach was investigated. Initial, we identified elevated basal ROS levels in homozygous sdhb larvae in comparison with heterozygous and wild-type siblings. Employing a semi highthroughput drug screening, the effectiveness of different dosages of anti- and pro-oxidant Vitamin C had been assessed to evaluate variations in survival, ROS levels, and locomotor activity. Low-dosage levels of Vitamin C induced a decrease of ROS levels but no considerable effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan in the homozygous sdhbrmc200 larvae whilst not affecting the lifespan of heterozygous and w.