Therapeutic Targeting of SDHB-Mutated Pheochromocytoma/Paraganglioma with Pharmacologic Ascorbic Acid.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Yang LiuK Pacak

Abstract

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. 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. 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, thr...Continue Reading

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Citations

Apr 22, 2020·Proceedings of the National Academy of Sciences of the United States of America·Di YuChunzhang Yang
Apr 16, 2020·Redox Report : Communications in Free Radical Research·Katerina Hadrava VanovaJakub Rohlena
Nov 14, 2020·Current Opinion in Oncology·Charles DarianeJudith Favier
Aug 25, 2021·Journal of Experimental & Clinical Cancer Research : CR·Kun YaoHong Tao

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