Humans, unlike many animals, can’t produce their own vitamin C and must get it through diet to prevent diseases like scurvy.
New research from Jean Zhao, PhD, suggests that vitamin C might act as an anti-cancer immunotherapy.
With new scientific tools, researchers are finally beginning to understand how vitamin C might work against cancer.
Many animals, including house pets, produce their own vitamin C. Early human ancestors did too. But they lost the ability about 60 million years ago, trading the health benefits of vitamin C production for the ability to produce more energy.
Yet vitamin C is still an essential nutrient for humans. Without it, humans develop scurvy, a disease that results in fatigue, muscle wasting, and confusion. The first-ever clinical trial, conducted at sea in 1747, made the connection. Sailors who received citrus fruit juice – which is high in vitamin C – fared much better than shipmates who received alternatives.
Now, new work from the lab of Jean Zhao, PhD, a researcher in the Department of Cancer Biology, suggests that vitamin C might act as an anti-cancer immunotherapy. The idea of using vitamin C as a cancer treatment was first proposed nearly 50 years ago by double Nobel Laureate chemist Linus Pauling and physician Ewan Cameron. Their clinical reports suggested that administering high-dose intravenous vitamin C significantly prolonged the survival of terminal cancer patients. However, subsequent clinical trials failed to confirm these findings, leading to ongoing controversy over the role of vitamin C in cancer therapy.
“In the past, we didn’t have the scientific tools to understand how vitamin C might work against cancer,” says Zhao. “Now we do and that gives us a chance to learn more about how powerful it could be.”
The research, which was done in mice and recently published in Cell, details the mechanism behind the potential anti-cancer effects of vitamin C. It also uncovers a new form of post-translational protein modification, a cellular mechanism that changes the way a protein behaves after it has been assembled. This new mechanism, dubbed “vitcylation” by Zhao, joins a list of familiar protein modification mechanisms like phosphorylation, methylation, acetylation, and glycosylation.
“These post-translational protein modifications are very important and affect many cellular functions,” says Zhao.
According to the research, vitcylation activity increases with vitamin C dose under the body’s physiological pH levels, a measure of acidity in the blood. At a normal physiological pH of approximately 7.4, vitamin C predominantly exists in its ascorbate ion form, one of its three possible forms. In this form, vitcylation occurs.
During vitcylation, ascorbate ions modify lysine, an essential amino acid used in the body to form proteins. The modification, like other protein modifications, changes the way the affected proteins behave.
In this study, Zhao’s team specifically investigated how vitamin C affects proteins inside cancer cells. They found that ascorbate ion enters tumor cells and modifies a protein called STAT1.
This modification has two effects. First, enhances the activation of IFN-gamma, which sends a signal outside of the cell requesting aid from immune cells. Second, STAT1 increases the cell’s efforts to present tumor antigens, small fragments of abnormal, tumor-specific proteins, on the surface of the cancer cell.
“These tumor cells are now waving a red flag,” says Zhao. “They are saying ‘we’re cancer cells, we are sick cells. Come kill us!’”
After reading this, it might seem tempting to grab an orange and get this vitcylation process going at home. Zhao agrees that good nutrition is essential for wellness and to reduce cancer risks, but it is only a part of a larger, still unfolding story.
“We are talking about doses of vitamin C that are 100 or 1000 times higher than the recommended daily dose for adults,” says Zhao. “We need more research to understand this mechanism and how it might work in humans.”
One outstanding question Zhao has is why vitcylation predominantly occurs in cancer cells and not in healthy cells. It also isn’t clear how, exactly, these findings might translate to humans, though Zhao is eager to continue this line of research.
“Science is heavily weighted to the study of chemical pharmaceuticals, but there is power in nature and in the integration of nutraceuticals and pharmaceuticals that may yet be untapped,” she says.
About the Medical Reviewer
Dr. Zhao is a principal investigator in the Department of Cancer Biology at Dana-Farber Cancer Institute (DFCI) and a Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School (HMS). She leads a renowned research team investigating signaling pathways, molecular mechanisms, and therapeutic translation in cancer research. Under her visionary leadership, the team is dedicated to advancing the understanding of molecular mechanisms underlying cancer and to and developing innovative therapeutic strategies.
After earning her PhD with honors from Tufts Medical School, Dr. Zhao joined DFCI as a research fellow in the laboratory of Dr. Thomas Roberts. She became an Instructor at HMS in 2003 and joined the faculty of DFCI and HMS in 2006, where she continued to make significant contributions to the field of cancer research. Dr. Zhao's transformative cancer research has received prestigious grants and awards including the NIH Outstanding Investigator Award, V Scholar Award, Starr Foundation Award, and Department of Defense Breakthrough Award among others.