Vitamin C

What Is It?

Vitamin C (also known as ascorbic acid) is an essential micronutrient that is especially abundant in citrus fruits, but can also be found in a variety of other fruits and vegetables$^{1}$. The functions of vitamin C are vast; it is needed to form bones and blood vessels, as well as to maintain a healthy immune system$^{2,3}$. Potential anticancer properties of vitamin C have been the subject of hundreds of studies over many decades. Some of these studies have shown that under certain conditions (such as when used in combination with other drugs), vitamin C may potentially help kill cancer cells through mechanisms such as apoptosis (programmed cell death), autoschizis (cell death by loss of cytoplasm), or via energy depletion$^{4,5}$. Other trials have examined whether vitamin C can reduce oxidative stress in cells, possibly decreasing the risk of some cancers$^{6,7,8,9,10}$. 

What Are Its Other Names?

Vitamin C is also referred to as L-ascorbic acid, ascorbic acid, or ascorbate$^{11}$. Its IUPAC name is (2R)-2-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2H-furan-5-one$^{11}$.

What Foods Have It?

Vitamin C is found in various fruits and vegetables. Some types of peppers, guava, kiwi, broccoli, strawberries, and citrus fruits (such as oranges, lemons, and limes) are particularly good sources of vitamin C. Below is a table of foods and their vitamin C content.

The above data was obtained from the U.S. Department of Agriculture FoodData Central$^{12}$. Note that these values for vitamin C content are averages, and that vitamin C content may substantially differ based on the produce’s variety and region of origin. Vitamin C was measured as ‘total ascorbic acid’ by this database.

What Are Its Main Benefits?

Vitamin C may be potentially beneficial for the prevention and treatment of some types of cancers. However, it is important to note that these benefits may only extend to specific patient populations in certain clinical settings. The effects of vitamin C can vary drastically based on patient and disease characteristics. Improvement of Precancerous Conditions Vitamin C may help improve conditions that have a risk of becoming cancerous. For instance, vitamin C may aid in the regression of gastric lesions caused by H. pylori infection$^{13}$. Along these lines, vitamin C might also slow the progression of gastric mucosal atrophy (weakening of the stomach lining which can also be caused by H.pylori)$^{14,15}$. That being said, these claims are contentious, as another study found no significant effect of vitamin C on gastric atrophy$^{16}$. Further studies are needed to determine whether vitamin C is useful in the treatment of gastric lesions and atrophy. Another example involves polyposis coli (polyps in the intestinal tract), a condition that significantly increases the risk of colorectal cancer and other types of cancer$^{17}$. One study found that oral vitamin C capsules may potentially decrease both the number and total area of polyps in those with polyposis coli$^{18}$. Benefits for Cancer Treatment Select studies have shown that vitamin C as an adjuvant may potentially enhance the effectiveness of some chemotherapies in certain patients. For instance, in one study, intravenous (IV) vitamin C administered with FOLFOX ± bevacizumab chemotherapy for metastatic colorectal cancer increased progression-free survival in patients with a specific RAS mutation$^{19}$. Another study showed that IV vitamin C may also potentially increase the efficacy and reduce the toxicity of carboplatin + paclitaxel chemotherapy for ovarian cancer$^{20}$. As well, an arsenic trioxide/bortezomib/ascorbic acid (IV) combination treatment has shown potentially beneficial effects in patients with multiple myeloma$^{21}$. Furthermore, oral vitamin C was observed to induce epigenetic changes that may increase the efficacy of azacitidine treatment for myeloid cancer$^{22}$. Aside from being used as an adjuvant for chemotherapies, vitamin C may potentially exert anticancer properties on its own or when combined with other drugs. Two clinical trials conducted by Cameron and Pauling in the 1970s utilized a combination of both IV and oral administration and found that vitamin C significantly increased the survival time and quality of life of terminal cancer patients$^{23,24}$. An unrelated clinical trial suggested that menadione (vitamin K3) could possibly interact with oral ascorbic acid in a way that triggers autoschizis (cell death by loss of cytoplasm) in prostate cancer cells$^{5}$. In the treatment of basal cell carcinoma (a common type of skin cancer), a clinical trial noted that topical vitamin C could clear low-risk nodular and superficial lesions while producing fewer adverse effects than imiquimod (a standard drug therapy)$^{25}$.

Benefits for the Side-Effects of Cancer Treatment Vitamin C can potentially reduce levels of serum oxidative stress caused by radioactive iodine therapy for thyroid cancer patients$^{26}$. While this could be a biomarker of decreased toxicity, a true clinical benefit has yet to be confirmed, and more studies are needed$^{26}$. Benefits for Cancer Prevention Dietary intake studies have found that increased vitamin C consumption could be correlated with a decreased risk of pancreatic and prostate cancer, as well as a reduced risk of mortality from breast cancer$^{27,28,29}$. It is important to note that dietary intake studies do not directly supply vitamin C to participants, and instead analyze plasma concentrations or estimate their consumption based on dietary questionnaires. Thus, it is unclear whether these effects can be attributed to vitamin C or other aspects of their diet. Many of the effects observed in dietary intake studies are not seen in clinical trials, and thus this information alone is insufficient to prove a causative relationship between vitamin C and cancer prevention$^{30}$. The possible cancer-preventing effects of vitamin C still remain an active area of investigation, for instance, some randomized clinical trials have shown that vitamin C supplementation can decrease biomarkers of DNA damage and oxidative stress$^{6,7,8}$. However, it has not been shown whether this actually manifests into a decreased risk of cancer.  Benefits from Trials using Multivitamin Supplements that Included Vitamin C Some randomized controlled trials have tested the anticancer properties of supplements that include several antioxidants and vitamins in combination. Due to the high number of ingredients in these supplements, the effects observed in said trials cannot be attributed to any single vitamin in particular. That being said, some of these trials investigating multivitamin supplements that contain vitamin C found beneficial effects regarding cancer prevention. For example, the SU.VI.MAX trial found that 7.5 years of supplementation (120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 µg selenium, and 20 mg zinc) decreased total cancer incidence and all-cause mortality in men, but not in women$^{31}$. In women, they found that the same supplementation led to an increased risk of skin cancer (see ‘What are its main drawbacks?’), but again, this effect cannot be attributed to a single vitamin or antioxidant$^{32}$. Another study in Shangdong, China found that vitamin supplementation (250 mg vitamin C, 100 IU vitamin E, and 37.5 μg selenium from yeast) led to reduced gastric cancer incidence and mortality$^{33}$. However, a separate study in Linxian, China showed no effect of 120 mg vitamin C + 30 μg molybdenum on gastric cancer incidence and mortality, elucidating the need for more studies investigating the relationship between vitamin C and gastric cancer$^{34,35}$. Disclaimer It is essential to note that these claimed benefits may stem from clinical trials conducted under specific conditions involving certain subgroups of patients. It is always best to consult your healthcare provider before starting a new supplement regime.

What Are Its Main Drawbacks?

Low Bioavailability with Oral Administration One of the drawbacks of vitamin C is that some of its benefits with regards to cancer cell toxicity require concentrations that cannot be achieved via oral administration. While many of the benefits discussed above still pertain to oral vitamin C, the sub-section entitled “Benefits for Cancer Treatment” consisted of several potential benefits in general terminal cancer, colorectal cancer, ovarian cancer, and multiple myeloma that were only observed with intravenous vitamin C$^{19,20,21,23,24}$. While the tolerable upper limit for oral vitamin C is roughly 2 g/day in adults, IV doses of up to 3 g/kg of bodyweight (i.e., 210 g in a 70 kg person) are tolerable if conducted in a safe manner, although this is typically not administered for as long a duration$^{37}$. This means that IV delivery can produce plasma vitamin C levels 30 to 70 times higher than what could be tolerated through oral administration$^{38}$. Oral intake leads to lower plasma vitamin C concentrations compared to IV administration for numerous reasons such as reduced bioavailability, saturation of sodium-dependent vitamin C transporters in the gut, and faster urinary excretion$^{39,40}$. Possible Adverse Events Caution is required when administering high doses of vitamin C, as although adverse events are rare, it can lead to serious side effects such as oxalate nephrology (a type of kidney damage) and hypernatremia (high blood sodium level)$^{41}$. High-dose vitamin C can also cause hemolysis (red blood cell destruction) in patients with a glucose-6-phosphate dehydrogenase deficiency$^{41}$. Potential/Preclinical Drawbacks (still under investigation) There is some cell line evidence that suggests vitamin C may potentially interfere with the efficacy of some kinds of chemotherapy. One study found that vitamin C treatment decreased the levels of cancer cell apoptosis induced by several antineoplastic agents (doxorubicin, vincristine, cisplatin, methotrexate, imatinib) used on lymphoma and leukemia cell lines$^{42}$. In xenograft mice (mice with human cancer cells transplanted onto them), vitamin C reduced the anti-tumor efficacy of doxorubicin$^{42}$. The authors of this study suggested that vitamin C decreased the cytotoxicity of these drugs by inhibiting the mitochondrial membrane depolarization that they would normally induce$^{42}$. A separate study demonstrated that vitamin C binds to and inactivates bortezomib (a proteasome inhibitor used to treat multiple myeloma), decreasing apoptosis in human cancer cell lines$^{43}$. It is essential to note that these observations were from cell line and mice studies, and the effect of vitamin C in relation to chemotherapy drugs can drastically differ when administered in humans. In fact, many clinical studies in humans have shown that vitamin C might enhance the effectiveness of some chemotherapies (see ‘What are its main benefits?’). Drawbacks from Trials using Multivitamin Supplements that Included Vitamin C As mentioned above, trials utilizing a multivitamin supplement contain too many ingredients to ascribe any observed effects to one particular vitamin. However, it is worth noting some of the drawbacks found in these trials that used a multivitamin supplement which included vitamin C. One such trial, the SU.VI.MAX trial in France, found that daily usage of a multivitamin supplement (120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 µg selenium, and 20 mg zinc) resulted in an increased risk of skin cancer (including melanoma) in women, but not in men$^{32}$. The SU.VI.MAX trial also reported that in men with an elevated prostate specific antigen (PSA) level at baseline, administration of this same multivitamin supplement led to an increased risk of prostate cancer of borderline statistical significance$^{44}$. On the other hand, in men with normal PSA levels, a significant reduction in the incidence of prostate cancer was recorded in those taking that same supplement$^{44}$. This is further testament to the importance of consulting a physician and considering a variety of physiological factors before commencing any new supplement regime.

How Does It Work?

Pro-oxidant vs. Antioxidant Effects Vitamin C can function as either a pro-oxidant or antioxidant, and each state may lend to its own mechanisms of action against cancer$^{45}$. For instance, the antioxidant mechanisms protect cells from free radical damage (damage caused by unstable atoms that can affect DNA), which may prevent cancer in the first place$^{45}$. On the other hand,  the pro-oxidant mechanisms may result in the generation of free radicals within cancer cells in order to kill them$^{45}$.  There are a variety of factors that determine whether vitamin C will act as an antioxidant or pro-oxidant45. At physiological (standard body) concentrations, vitamin C usually acts as an antioxidant, while at much higher concentrations (greater than one millimolar), vitamin C is more likely to act as a pro-oxidant, especially in the presence of catalytic metal ions such as iron$^{45,46}$. Cancer cells tend to have higher concentrations of reactive metal ions, which could explain their heightened sensitivity to vitamin C-induced cytotoxicity (cell death) compared to normal cells$^{45}$.

What Are Its Mechanisms of Action?

Pro-oxidant Mechanisms

1. Generation of Reactive Oxygen Species (ROS): Once imported into cancer cells, vitamin C increases the intracellular levels of hydrogen peroxide (increases ROS)$^{46}$. This occurs due to vitamin C auto-oxidation, which is catalyzed by the metal ions contained within cancer cells$^{46}$. Subsequently, high levels of reactive oxygen species can mediate cancer cell death through a variety of pathways such as the activation of protein kinase Cδ (PKCδ), and the induction of apoptosis (programmed cell death)$^{4}$.
2. Induction of Autoschizis (cell death by loss of cytoplasm): The hydrogen peroxide produced by high-dose vitamin C is also implicated in cell death by autoschizis as shown in human prostate cancer cell lines$^{5}$. It is hypothesized that the ROS build-up damages the cell’s ATP pools and parts of its cytoskeleton, contributing to autoschizis$^{5}$. Further evidence of this mechanism is that cancer cells are often deficient in catalase (an enzyme that breaks down hydrogen peroxide), and exogenous administration of catalase appeared to inhibit autoschizis$^{5}$.
3. Inhibition of Energy Metabolism: Once cancer cells absorb high doses of vitamin C, a series of oxidative reactions convert vitamin C to hydrogen peroxide$^{4}$. The oxidative stress induced by hydrogen peroxide results in the depletion of an important molecule called NAD+ within cancer cells$^{4}$. NAD+ is a cofactor (an essential molecular component) of the enzyme GAPDH, which is necessary for glycolysis (glucose breakdown into energy) to occur$^{4}$.  Therefore, the depletion of NAD+ by vitamin C prevents cancer cells from generating energy in the form of ATP, which eventually leads to cell death$^{4}$.

Antioxidant Mechanisms

4. Protection of Cells from Oxidative Damage: As an antioxidant, Vitamin C neutralizes free radicals and it is hypothesized that this could prevent cancer by reducing oxidative stress within cells. Some studies have found that vitamin C supplementation reduces biomarkers of DNA damage and oxidative stress in patients$^{6,7,8}$. This evidence is not conclusive, and other studies have found no effect of supplementation on these biomarkers$^{9,10}$.

Potential/Preclinical Mechanisms (still under investigation)

5. Oxidative Stress Due to Dehydroascorbate (DHA) Uptake: Some cancer cells are adapted to grow in low-nutrient conditions, thus they overexpress glucose transporters on the cell surface$^{47}$. The oxidized form of vitamin C, DHA, is also imported into cells by glucose transporters, making cancer cells vulnerable to overloading with DHA$^{47}$. It is hypothesized that DHA can cause oxidative stress within cancer cells, however there is a lack of evidence that DHA can reach sufficient levels in humans for this to be significant$^{48}$.
6. Regulation of Hypoxia-inducible Transcription Factors: Hypoxia-inducible Transcription Factors (HIFs) have been found to drive the rate of tumor growth$^{48}$. Vitamin C is a cofactor in enzymes that regulate the activity of these HIFs$^{48}$. Preclinical evidence shows that vitamin C concentrations are inversely correlated to HIF activation, thus leading investigators to hypothesize that vitamin C may potentially reduce tumor growth rates via this mechanism$^{48}$.
7. Stimulation of Epigenetic Changes in Cancer Cells: Numerous studies have suggested that vitamin C may induce epigenetic changes in cancer cells that could be beneficial for treatment$^{48}$. For example, vitamin C may enhance the activity of TET and JMJC enzymes (which are instrumental in DNA demethylation)$^{48}$. Early-stage studies have suggested that this might potentially play a role in restoring some normal cell functionality in cancer cells, thereby making them easier to treat, but this research is in its early-stages$^{48,49}$.

What Are Typical Doses and Durations?

Studies examining the chemotherapeutic effects of vitamin C have used a wide variety of dosages and durations based on the purpose of the therapy and the mode of administration. In terms of studies using IV vitamin C alongside cancer therapies, the dosages ranged from a fixed 1 g of vitamin C to a scaled dose of 1.5 g/kg of bodyweight (e.g. 105 g of vitamin C for a 70 kg male)$^{19,21}$. In these trials, the period of vitamin C treatment ranged from 1 week to 12 months, and was largely dependent on the course of chemotherapy that the patients were on$^{20,50}$. For the trials that used oral vitamin C as an adjuvant to cancer therapy, doses ranged from 0.3 g to 10 g, and durations from 6 days to over 2 years$^{51,52}$. When it came to mitigating the side effects of cancer therapy, these studies used a much narrower range of doses for shorter periods. Doses were between 0.8 g and 2 g and was typically conducted in and around the treatment period which lasted anywhere from a few days to a few months$^{28,53,54}$.  Some trials administering vitamin C to terminal cancer patients continued treatment until the patient’s death, significant disease progression, or the patient’s inability to continue$^{52,55}$. Studies investigating vitamin C for usage against gastric disorders caused by H.pylori utilized oral dosages between 0.5 g and 5 g, and durations spanning from 1 month to 7.3 years$^{56,57}$. Finally, studies evaluating the effects of vitamin C on its own or part of a multivitamin supplement used oral doses containing 0.06 g to 6 g from 1 month to 9.4 years$^{58,59,60,61}$. It should be noted that very long-term studies (several years) used lower doses between 0.12 g to 0.5 g$^{61,62,63}$.

Summary of Data

Summary of clinical trials administering vitamin C on its own or as an adjuvant to cancer therapy. A total of 17 studies that fit this criteria were found using the PubMed database.

Summary of dietary intake association/correlation studies assessing the relationship between vitamin C consumption and cancer. A total of 9 studies that fit this criteria were found using the PubMed database.

Summary of trials that administered a multivitamin or multi-antioxidant supplement that included vitamin C and assessed its effect on the prevention or treatment of cancer. A total of 31 studies that fit this criteria were found using the PubMed database.

Summary of trials that administered vitamin C for conditions that increase the risk of gastric cancer (i.e. H.pylori infection, gastritis, gastric atrophy). A total of 4 studies that fit this criteria were found using the PubMed database.

Summary of results from 4 papers about a single long-term trial in Shangdong, China, that tested the effects of multi-antioxidant supplementation (that included vitamin C) on conditions that lead to a high risk of gastric cancer$^{33,56,64,65}$.

Summary of results from 6 papers on the SU.VI.MAX study, a long-term trial in France that tested the effect of a multi-antioxidant supplement on various health outcomes including the incidence and mortality from cancer$^{31,32,44,66,67,68}$.

Summary of results from 6 papers about a single group of participants involved in a long-term trial in Linxian, China that tested the effects of various combinations of supplements (including vitamin C combined with molybdenum) on the incidence and mortality from cancer$^{34,35,62,69,70}$. (Note: One paper included a second subsidiary trial thus it appears in the table twice, once under ‘General’ and once under ‘Esophageal’)$^{71}$.

Summary of results from 2 papers on the ‘Physicians’ Health Study II (PHSII)’ , a single long-term trial conducted in the USA$^{30,72}$.

Summary of trials that administered vitamin C to examine its effect on markers of oxidative stress in either healthy patients or patients with cancer. A total of 9 studies that fit this criteria were found using the PubMed database.

Summary of trials that administered vitamin C to examine its effect on side effects of cancer therapy. A total of 3 studies that fit this criteria were found using the PubMed database.

Below are links to detailed vitamin C human clinical trial study notes analyzed by Anticancer.ca.

📄 Detailed vitamin C (administered alone or with cancer therapy) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (dietary intake) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (as part of a multivitamin supplement) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (for gastric conditions) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (Shangdong trial) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (SU.VI.MAX trial) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (Linxian trial) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (Physicians' Health Study II Trial) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (oxidative stress) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin C (for side effects of cancer treatment) human clinical trial study notes analyzed by Anticancer.ca

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• Vitamin C
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• How Does It Work?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
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