Therapeutic Targeting ofSDHB-Mutated Pheochromocytoma/Paraganglioma with Pharmacologic Ascorbic Acid

Abstract

Purpose: Pheochromocytomas and paragangliomas (PCPGs) 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. SDHBmutated PCPGs exhibit dysregulation in oxygen metabolic pathways, including pseudohypoxia and formation of reactive oxygen species (ROS), 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 to 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. Besides, 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.

Mitochondrial complex II and reactive oxygen species in disease and therapy

“…This is in line with CII being an important player in cell death induction. Additionally, it has recently been shown that tumors carrying SDHB mutations produce more ROS and accumulate iron, and disruption of redox hemostasis by ascorbic acid to induce cell death seems to be a promising tool for the treatment of SDHB-mutated PGL/PHEO [114].…”

Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

“…ARE luciferase reporter assay (QIAGEN) with Dual-Luciferase Reporter Assay System (Promega) as previously described (53,54). Nine hundred nanograms of the reporter plasmid and 100 nanograms of pRL-TK plasmid were transfected to 100,000 cells by Lipofectamine 2000 (Invitrogen).…”

Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers

“…Most important of all, IDH1-mutated tumor showed an increased percentage of apoptotic cells after combining use ML309 and VC. It is also critical to note that high doses of VC can exert its anticancer effect via multiple mechanism of actions, including modulating infiltration of the tumor microenvironment by cells in immune system to delay cancer growth [ 111 ], accumulating ROS and inhibiting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to kill the colorectal cancer cells harboring KRAS or BRAF mutations [ 112 ], targeting redox homeostasis in pheochromocytomas and paragangliomas (PCPG) cells with low levels of succinate dehydrogenase B subunit (SDHB) to suppress metastatic lesion and prolong overall survival [ 113 ], and et al Therefore, this synergetic therapy needs to be further investigated. Collectively, these results strongly illustrate that combinatorial therapy is of great interest to rescue TET activity and treat IDH1/2-mutated cancers.…”