Vulnerable Cancer Cells Are Stressed Out by Vitamin C

Researchers at NICHD and partnering institutes are investigating if vitamin C can slow the progression of metastatic pheochromocytomas and paragangliomas (PCPGs), aggressive hormone secreting tumors associated with poor survival rates. The initial studies are promising. In a subtype of PCPG cancer cells, vitamin C acts as an oxidant that causes excessive DNA damage and cell death, according to their recent publication in Clinical Cancer Research¹.

PCPGs arise in cells of the neuroendocrine system. Many cases are benign, but treatment becomes difficult when PCPG cells metastasize to other parts of the body. “We are working to clarify cellular changes and make targeted therapies, as these patients usually carry specific genetic backgrounds,” said Dr. Ying Pang, NICHD postdoctoral fellow in Dr. Karel Pacak’s laboratory (Section on Medical Neuroendocrinology) and co-lead author of the study.

Pang and colleagues found that PCPG cells increase signals to indicate a lack of oxygen—a state called pseudohypoxia—when they lack SDHB protein. These pseudohypoxic cells respond by increasing iron levels. The combination of oxidative stress and iron overload (which exacerbates oxidative stress) makes these cells vulnerable to additional insult—a condition that Pang aims to exploit with vitamin C.The team focuses on succinate dehydrogenase B (SDHB) gene mutations, commonly found in metastatic PCPG. Under normal conditions, the SDHB protein is part of a mitochondrial complex that helps process oxygen. But when this reaction is disrupted, the cell enters a condition of oxidative stress, which results in cellular damage.

High concentrations of vitamin C create cell-damaging hydrogen peroxide in cancer cells but are well tolerated by healthy tissue. Pang and colleagues hypothesized that pharmacological doses of vitamin C, combined with the oxidative stress and iron overload in SDHB-deficient PCPGs, would selectively affect the PCPG cells.

The idea was a success. The team found vitamin C induced markers for cell death and decreased colony growth in human PCPG-like cells that have decreased SDHB. To study this in a living animal, they injected pharmacological doses of vitamin C into mice with SDHB-deficient metastatic PCPG tumors. The team observed delayed metastasis and suppression of tumor growth in the mice—supporting a potential for therapeutic uses.

“This is a team effort among several institutes at NIH,” Pang emphasized. Based on their preclinical results and clinical observations from colleagues at NIDDK, Pang foresees a phase I clinical trial for metastatic PCPG using pharmacological levels of vitamin C, which has the advantage of a pre-established safety profile, as part of a novel treatment regimen.

References

1. Liu Y, Pang Y, Zhu B, Uher O, Caisova V, Huyn TT, Taieb D, Vanova KH, Ghayee HK, Neuzil J, Levine M, Yang C, Pacak K. (2020). “Therapeutic Targeting of SDHB-Mutated Pheochromocytoma/Paraganglioma With Pharmacological Ascorbic Acid.” Clinical Cancer Research: Online Ahead of Print. doi: 10.1158/1078-0432.CCR-19-2335.