OPINION

Targeting cancer vulnerabilities with high-dose vitamin C

Abstract

Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer.

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Fig. 1: Integrated pro-oxidant mechanism of vitamin C and cancer cell cytotoxicity.
Fig. 2: Regulation of TET enzymes by ascorbate.
Fig. 3: Ascorbate and HIF1α regulation.

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Acknowledgements

The authors thank S. Wang in the Yun laboratory for helpful discussions and proofreading of the manuscript. The authors apologize for any references left uncited owing to space limitations. This work was supported by the US National Institutes of Health (NIH) grant R35 CA197588 (L.C.C.), Stand Up to Cancer–American Association for Cancer Research grant SU2C-AACR-DT22-17 (L.C.C.), the Cancer Prevention and Research Institute of Texas (CPRIT) grant RR170039 (J.Y.), the US National Cancer Institute (NCI) grant 1K22CA216036 (J.Y.), the US National Science Foundation Graduate Research Fellowship Program grant DGE1257284 (B.N.) and NCI grant 1F99CA234950-01 (B.N.). L.C.C. is a founder and member of the senior advisory boards of Agios Pharmaceuticals and Petra Pharmaceuticals, which are developing novel therapies for cancer. The L.C.C. laboratory also receives financial support from Petra Pharmaceuticals.

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Nature Reviews Cancer thanks J. Cullen, G. Dachs and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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L.C.C. and J.Y. contributed to the discussion of content of the article. J.Y. and B.N. researched data for the article. J.Y. and B.N. wrote the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Lewis C. Cantley or Jihye Yun.

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Glossary

2-Phosphate l-ascorbic acid

A derivative of ascorbate that is not oxidized in culture or serum but releases ascorbate once it is inside the cells via hydrolysis mediated by alkaline phosphatase on the plasma membrane.

5-Aza-CdR (decitabine)

A cytidine antimetabolite analogue that incorporates into DNA and inhibits DNA methyltransferase (DNMT) activity, which results in DNA demethylation (hypomethylation).

Biomarkers

Any biological measurable indicators of the severity or presence of some disease state.

Fenton reaction

A chemical reaction that converts hydrogen peroxide into a highly toxic hydroxyl radical in the presence of labile iron.

Ferritin

A protein that contains iron and is the primary form of iron stored inside of cells.

Free radicals

Molecules possessing unpaired electrons and thus are reactive and short-lived in a biological setting.

Haem

An iron-containing group that gives myoglobin and haemoglobin the ability to bind oxygen.

Hydroxyl radical

(OH). A highly reactive and short-lived radical that attacks any molecule in its immediate vicinity, especially DNA, protein and lipids, eventually leading to cell death.

Imatinib

A BCR-ABL-selective tyrosine kinase inhibitor, also known as Gleevec. Imatinib has been used to treat chronic myelogenous leukaemia and acute lymphocytic leukaemia.

Intraperitoneal (IP) injection

Giving medicines or fluids into the peritoneum (body cavity), which is more often applied to animals than to humans.

Intravenous injection

Giving medicines or fluids through a needle or tube inserted into a vein, allowing them to enter the bloodstream immediately.

Michaelis constant

(Km). The substrate concentration at the half of the maximum velocity (Vmax). An enzyme with a high Km has a low affinity for its substrate and requires a greater concentration of substrate to achieve Vmax.

Parenteral injection

Giving medicine or fluids intravenously (into a vein), subcutaneously (under the skin) and intraperitoneally (into the peritoneum).

Pharmacodynamics

The study of the biochemical and physiological effects of drugs. Generally refers to the dose–response relationship for a particular drug.

Pharmacokinetics

The activity of drugs in the body over a period, including the processes by which drugs are absorbed, distributed in the body, localized in the tissues and excreted.

Pharmacological ascorbate

Intravenous or intraperitoneal delivery of vitamin C, which allows for plasma concentrations to reach the millimolar scale.

Physiological ascorbate

An oral dose of dietary vitamin C, usually resulting in a peak plasma concentration of 200 μM.

Predictive biomarkers

A biomarker that gives information about the effect of a therapeutic intervention.

Prosthetic

A group that is a tightly bound, specific non-polypeptide unit required for the biological function of some proteins. It may be organic or inorganic (such as a metal ion), but not amino acids.

Randomized controlled trials

(RCTs). A study design that randomly assigns participants into an experimental group or a control group (or placebo group).

Reactive oxygen species

(ROS). Derivatives of oxygen that are more reactive than molecular oxygen.

Single-nucleotide polymorphisms

(SNPs). A variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some high degree within a population (for example, >1%).

Therapeutic window

The range of doses of a drug that can treat disease effectively without having toxic effects.

Transferrin

(Tf). The main protein in the blood that binds to iron and transports it throughout the body.

Vemurafenib

A selective V600E mutant BRAF kinase inhibitor, also known as PLX4032. It has been used to treat BRAF V600E mutant melanoma.

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Ngo, B., Van Riper, J.M., Cantley, L.C. et al. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer 19, 271–282 (2019). https://doi.org/10.1038/s41568-019-0135-7

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