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Therapeutic Targeting of SDHB-Mutated Pheochromocytoma/Paraganglioma with Pharmacologic Ascorbic Acid
Y. Liu, Y. Pang, B. Zhu, O. Uher, V. Caisova, TT. Huynh, D. Taieb, K. Hadrava Vanova, HK. Ghayee, J. Neuzil, M. Levine, C. Yang, K. Pacak
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
ZIA HD008735
Intramural NIH HHS - United States
NLK
Free Medical Journals
from 1995 to 1 year ago
Freely Accessible Science Journals
from 1995
Open Access Digital Library
from 1995-01-01
Open Access Digital Library
from 1995-01-01
- MeSH
- Antioxidants pharmacology therapeutic use MeSH
- Apoptosis drug effects MeSH
- Pheochromocytoma drug therapy genetics pathology MeSH
- Gene Knockdown Techniques MeSH
- Ascorbic Acid pharmacology therapeutic use MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mutation MeSH
- Mice MeSH
- Cell Line, Tumor transplantation MeSH
- Oxidative Stress drug effects MeSH
- Paraganglioma MeSH
- DNA Damage drug effects MeSH
- Reactive Oxygen Species metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Succinate Dehydrogenase deficiency genetics MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
References provided by Crossref.org
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- $a 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.
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