PURPOSE: Pheochromocytomas and paragangliomas (PCPG) are usually benign neuroendocrine tumors. However, PCPGs with mutations in the succinate dehydrogenase B subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions. SDHB-mutated PCPGs exhibit dysregulation in oxygen metabolic pathways, including pseudohypoxia and formation of reactive oxygen species, suggesting that targeting the redox balance pathway could be a potential therapeutic approach. EXPERIMENTAL DESIGN: We studied the genetic alterations of cluster I PCPGs compared with cluster II PCPGs, which usually present as benign tumors. By targeting the signature molecular pathway, we investigated the therapeutic effect of ascorbic acid on PCPGs using in vitro and in vivo models. RESULTS: By investigating PCPG cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (SLC11A2; DMT1), leading to iron accumulation. This iron overload contributed to elevated oxidative stress. Ascorbic acid at pharmacologic concentrations disrupted redox homeostasis, inducing DNA oxidative damage and cell apoptosis in PCPG cells with low SDHB levels. Moreover, through a preclinical animal model with PCPG allografts, we demonstrated that pharmacologic ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival. CONCLUSIONS: The data here demonstrate that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for SDHB-mutated PCPGs.

Department of Internal Medicine Division of Endocrinology University of Florida College of Medicine and Malcom Randall VA Medical Center Gainesville Florida

Department of Medical Biology Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic

Department of Nuclear Medicine La Timone University Hospital CERIMED Aix Marseille University Marseille France

Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai P R China

Mitochondria Apoptosis and Cancer Research Group School of Medical Science and Menzies Health Institute Queensland Griffith University Southport Queensland Australia

Molecular and Clinical Nutrition Section Intramural Research Program National Institute of Diabetes and Digestive and Kidney Diseases NIH Bethesda Maryland

Molecular Therapy Group Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

Neuro Oncology Branch Center for Cancer Research NCI NIH Bethesda Maryland

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland

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Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma

Mitochondrial complex II and reactive oxygen species in disease and therapy