For the published version on the manuscript. Funding: This study received no external funding. Institutional Review Board Statement: Ethical critique and approval were DSP Crosslinker Epigenetic Reader Domain waived for this study due to the retrospective 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 can be located in supplementary material. Conflicts of Interest: The authors J.M.T., T.A. and also a.G. received travel grants as well as 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 Employing Ascorbic Acid in sdhb Zebrafish Mutant LarvaeMargo Dona 1, , Maaike Lamers 1 , Svenja Rohde 1 , Marnix Gorissen two 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.) Division 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: Therefore far, no curative therapies are readily available for malignant SDHB-associated phaeochromocytomas and paragangliomas (PPGLs). Therapy development is severely hampered by the limited availability of suitable animal models. In this study, we investigated the prospective from the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs utilizing a drug screening method. One of the crucial characteristics of cancer initiation and progression is redox imbalance. Very first, we identified enhanced reactive oxygen species levels in homozygous sdhbrmc200 larvae at baseline. Next, we tested the effect of anti- and pro-oxidant ascorbic acid (Vitamin C) on these larvae. We validated the sdhbrmc200 zebrafish model as a effective drug screening tool to supply precious insights into pathomechanisms, which might cause novel therapeutic targets and therapy development inside the future. Abstract: Individuals with mutations within the -subunit of your succinate dehydrogenase (SDHB) possess the highest threat to develop AS-0141 In Vitro incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic methods in vivo. 1 possible 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 forms of cancer. In this study, the potential in the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs utilizing a drug screening strategy was investigated. Initial, we identified enhanced basal ROS levels in homozygous sdhb larvae in comparison with heterozygous and wild-type siblings. Making use of a semi highthroughput drug screening, the effectiveness of various dosages of anti- and pro-oxidant Vitamin C had been 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 considerable effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan with the homozygous sdhbrmc200 larvae although not affecting the lifespan of heterozygous and w.
