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Therapeutic Targeting of SDHB-Mutated Pheochromocytoma/Paraganglioma with Pharmacologic Ascorbic Acid
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.
Insights
Targeting redox balance with ascorbic acid shows promise for treating SDHB-mutated pheochromocytomas and paragangliomas (PCPG). Pharmacologic ascorbic acid effectively suppressed metastatic lesions and improved survival in preclinical models.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Pheochromocytomas and paragangliomas (PCPG) are neuroendocrine tumors, often benign.
- Mutations in succinate dehydrogenase B subunit (SDHB) are linked to poor prognosis and metastasis in PCPG.
- SDHB-mutated PCPGs show altered oxygen metabolism, including pseudohypoxia and reactive oxygen species, suggesting redox pathways as therapeutic targets.
Purpose of the Study:
- To investigate the therapeutic effect of ascorbic acid on PCPGs, particularly those with SDHB mutations.
- To explore the role of iron metabolism and oxidative stress in SDHB-mutated PCPG pathogenesis.
- To evaluate ascorbic acid's potential to disrupt redox homeostasis and induce cancer cell death.
Main Methods:
- Comparative genetic analysis of PCPG clusters.
- In vitro studies using PCPG cell lines with low SDHB levels.
- In vivo preclinical animal models with PCPG allografts.
Main Results:
- Low SDHB levels lead to pseudohypoxia, increased iron transport proteins (TF, TFR2, DMT1), and iron accumulation.
- Iron overload exacerbates oxidative stress in PCPG cells.
- Pharmacologic ascorbic acid induces DNA oxidative damage and apoptosis in SDHB-low PCPG cells.
- Ascorbic acid treatment suppressed metastatic lesions and prolonged survival in a preclinical animal model.
Conclusions:
- Targeting redox homeostasis is a viable strategy for SDHB-mutated PCPGs.
- Pharmacologic ascorbic acid demonstrates therapeutic potential against aggressive PCPGs.
- Ascorbic acid may represent a novel treatment for patients with SDHB-mutated PCPGs.
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