Vitamin C: the antioxidant with beneficial pro-oxidant effects?
To continue on the subject of antioxidants and cancer, I will now turn to the particular case of vitamin C. A recent study, also published in Science Translational medicine, suggests that high concentrations of vitamin C (the kind that you can only get from intravenous infusions) could be of benefit in combination with conventional chemotherapy in the treatment of ovarian cancer (1). Considering that vitamin C is commonly known as an antioxidant, it is worth noting that in this case it is toxic to cancer cells by acting locally as a pro-oxidant.
The antioxidant with a pro-oxidant effect that can kill cancer cells
Vitamin C is generally known as an antioxidant and as such is heavily advertised as a dietary supplement helping in the prevention and/or treatment of many diseases, from the common cold to cancer.
As I have said before, the word “antioxidant” represents a chemical property shared by many different molecules. What these antioxidant chemical species have in common is that they can give electrons to potentially dangerous free radicals, thereby neutralizing them before they can do any harm (by inducing DNA damage for example). However, this ability to give an electron may depend on the chemical milieu: a molecule that acts as an antioxidant in one situation may act as a pro-oxidant in another.
-> Context matters.
In healthy people, the typical concentration of vitamin C in plasma (the liquid part of blood that is left after removing blood cells) is between 0.04 and 0.08 millimolars (mM). At such levels, it functions as an antioxidant. By contrast, at levels in the millimolar range (at least about 20 times higher than the levels found in human plasma), vitamin C can have a pro-oxidant effect and promote the formation of hydrogen peroxide, a reactive oxygen species.
-> Quantity matters.
Vitamin C, though usually categorized as an antioxidant, can therefore also act as a pro-oxidant at very high concentrations and as such be deleterious to cancer cells. Indeed, a research team showed in two articles published in PNAS in 2005 and 2007 that high concentrations of vitamin C (millimolar range) could lead to the formation of ascorbate radicals (ascorbate, or ascorbic acid, is the chemical name of vitamin C). These ascorbate radicals in turn promoted the production of hydrogen peroxide at concentrations that were toxic to cancer cells in vitro (2-3).
Vitamin C, cancer prevention and cancer treatment
Before moving on to the recent Science Translational Medicine study on high-dose vitamin C and ovarian cancer treatment, let’s look first at the general story of vitamin C and cancer and what has been shown on the subject.
Why do we entertain the idea that vitamin C supplements may be useful in preventing cancer? The main rationale is the same as for all other dietary antioxidants: large epidemiological studies such as the EPIC study in Europe have shown that some cancers are less common in people eating a diet rich in fruits and vegetables (4).
However, while this might be enough for the dietary supplement industry to advertise the benefits of antioxidant pills, it only shows that favoring a diet rich in fruits and vegetables (which contain not just one antioxidant but lots of different antioxidants and other chemical substances) may be of benefit in terms of cancer prevention compared to a diet low in these types of foods.
As I wrote in the first post of this series on antioxidants, when it comes to supplements, no large clinical trial has demonstrated any real positive impact of dietary antioxidant supplementation in terms of cancer prevention. This holds true for vitamin C (5–6–7).
Here is now a very different setting: we are no longer looking at healthy people and trying to prevent cancer to develop, but considering whether vitamin C might be useful in the treatment of people who have already developed cancer.
The idea that taking vitamin C might be useful in the treatment of cancer essentially comes from an initial study carried out in the 1970’s and suggesting that very high doses of vitamin C given to people with terminal cancer and for whom no treatment was available anymore could help prolong survival by about a 300 days on average (8). The fact that a co-author of this study was no less than a Nobel Prize (Linus Pauling) helped give vitamin C a boost (and that is certainly a fact that can be used to impress people), however it does not make the study in itself any better: data is data, and how convincing a study is depends on the quality of the data shown, not on who produced them. In fact, this early study drew criticism because it was not properly controlled. Later on, two randomized placebo-controlled trials carried out in the US found no benefit from taking vitamin C as a cancer treatment (9–10), and vitamin C was no longer considered an effective cancer treatment option by the medical community.
Interest in vitamin C was renewed after two studies published in PNAS in 2005 and 2007 showed that high doses of vitamin C were toxic to cancer cells in vitro and that these kinds of doses could only be achieved in vivo if vitamin C was administered intravenously or intraperitoneally (the study was done on rats) (2–3). In view of these data, it became possible that the two earlier clinical trials had failed to detect any positive effect of vitamin C in the treatment of cancer because patients had taken vitamin C orally (tablets) and blood concentrations high enough to have any effect had not been reached. Consequently, the authors of the PNAS studies suggested that it might be worth reevaluating any efficacy vitamin C might have in cancer treatment in the context of intravenous administration.
Oral supplements vs intravenous infusions
Before finally moving on to what the latest study shows regarding vitamin C use in the treatment of ovarian cancer, I’d like to throw in a few numbers about the difference between taking vitamin C supplements in the form of tablets, and receiving vitamin C infusions.
Normal (physiological) levels of vitamin C in plasma are between 0.04 and 0.08 mM. The amount of vitamin C that can be absorbed in the gut is limited, and vitamin C is readily excreted. As a result, plasma concentrations obtained from an oral vitamin C intake cannot exceed about 0.2 mM, even with oral supplementation 100 times higher than the recommended dietary allowance (90 mg/day for an adult) (11). By contrast, vitamin C plasma concentrations can reach the millimolar range when it is given intravenously and studies report that concentration of about 10 mM can be safely achieved in healthy humans (people with normal renal function and G6PD enzymatic activity). This difference between the vitamin C plasma levels reached after oral intake or intravenous infusion is important because only the concentrations achieved by intravenous infusion correspond to those needed for vitamin C to have a pro-oxidant effect and be toxic to cancer cells (those are pharmacological levels, as opposed to physiological levels).
To sum up, taking vitamin C tablet supplements is not going to help people with cancer. No matter how much vitamin C is ingested, the amount actually absorbed will reach a limit and the blood concentration will not be high enough to lead to a cancer cell-killing effect. However, investigating the use of high-dose intravenous infusions of vitamin C in clinical practice as an addition to currently available cancer treatments may be worth a try.
What the new study shows
Finally, let’s have a look at what the study published last week in Science Translation Medicine shows.
1. Molecular mechanism of vitamin C toxicity towards cancer cells
The researchers show that high doses of vitamin C (millimolar range) are toxic to human ovarian cancer cells in vitro and that this effect is dependent on the formation of hydrogen peroxide (meaning it is dependent on a pro-oxidant effect of vitamin C). The experimental data further suggests that high-dose ascorbate (vitamin C) exerts its toxic effect on cancer cells via the induction of DNA damage and metabolic stress (decreased levels of ATP, the energy of the cell), with an end result of reduced levels of the protein mTOR (a protein involved in protein synthesis and cell proliferation).
Of course, other mechanisms of action are also possible. Scientists generally accept that the antitumor effect of high-dose ascorbate comes from the formation of ascorbate radical and hydrogen peroxide in the milieu surrounding the cells. Aside from the downstream mechanisms looked at in this study, it is also possible that hydrogen peroxide leads to the formation of other reactive oxygen species, thereby affecting other pathways possibly involved in the killing of cancer cells.
2. Combination of high-dose ascorbate with conventional chemotherapeutic drugs in a mouse model of ovarian cancer
The researchers next looked at how high-dose ascorbate would affect the efficacy of two chemotherapeutic drugs used as a first-line treatment in ovarian cancer (carboplatin and paclitaxel). Using a mouse model of ovarian cancer, they found that the combination of high-dose ascorbate and carboplatin was more effective at reducing tumor size than either agent alone. Similarly, the combination of high-dose ascorbate and carboplatin killed more human ovarian cancer cells in vitro than either agent alone. Although the addition of high-dose ascorbate did not significantly increase the efficacy of paclitaxel in reducing tumor size in the mouse model used, the combination of paclitaxel+carboplatin+ascorbate was more effective than paclitaxel+carboplatin. To give some perspective on the efficacy of high-dose ascorbate alone in this mouse model of ovarian cancer, high-dose ascorbate was found to be the least effective agent to reduce tumor size when given alone, then came carboplatin, and paclitaxel was the most effective.
An interesting point of these experimental data is that if high-dose ascorbate can also enhance the killing power of carboplatin towards ovarian cancer cells in humans, it could allow for a reduction of the doses of carboplatin used, and therefore reduce the side effects of chemotherapy, while still achieving similar antitumor effects.
3. Phase I/IIa clinical trial of high-dose vitamin C in ovarian cancer patients
Finally, the researchers performed a small clinical trial to investigate the safety and potential toxicity of administering high-dose intravenous ascorbate to ovarian cancer patients (phase I/IIa trial). 25 patients newly diagnosed with stage III or IV ovarian cancer were randomized to either standard treatment (carboplatin + paclitaxel) or to standard treatment + high-dose ascorbate. The standard treatment was given for 6 months, and ascorbate was given for 12 months, with infusions done twice a week (escalating dose protocol, with a target peak plasma concentration of about 20 mM). Patients were then followed for five years.
The trial did not show any adverse effect associated with infusions of high-dose ascorbate. If anything, ascorbate infusions tended to slightly decrease the toxicity associated with the chemotherapy. No significant difference in survival at 5 years was apparent between the two groups, although relapse was slightly delayed in patients having received high-dose ascorbate. However, this trial aimed at investigating safety and toxicity issues and therefore involved too few patients to really look at efficacy, so no conclusions can reliably be drawn at this point.
Usefulness of high-dose vitamin C in cancer treatment still requires further investigation
As always in scientific research, it is important to have results from any given study confirmed by other independently conducted studies. In the case of high-dose vitamin C, most of the research has been done by the same group of researchers, more studies are therefore needed. (A quick search on ClinicalTrials.gov shows that a fair number of trials looking at vitamin C and cancer are indeed planned or already ongoing.)
Two other small pilot clinical trials have been done to look at the safety of high-dose vitamin C in the management of metastatic pancreatic cancer (both trials involved some of the same principal investigators as the study on vitamin C and ovarian cancer). Regular infusions of high-dose ascorbate seemed well tolerated by patients in these trials. One study found that addition of ascorbate infusions to standard treatment with gemcitabine increased progression-free survival from 9 to 26 weeks (only 9 patients since it was a phase I pilot study) and decreased treatment toxicity (12). The other study found no difference between standard treatment (gemcitabine + erlotinib) and standard treatment + high-dose ascorbate in terms of overall survival (14 patients) (13). The main goal of these studies was however to assess the safety of giving high-dose ascorbate to patients, and larger trials are needed to properly evaluate efficacy (or lack thereof) of high-dose vitamin C.
Finally, even if high-dose intravenous ascorbate turns out to be of use in combination with certain chemotherapeutic agents for the treatment of certain cancers, it is important to keep in mind that cancers come in many different varieties, and the effect of high-dose vitamin C would have to be evaluated in each situation, also making sure that it does not interfere with the mechanism of action of the chemotherapeutic drug used. This is especially important since the mechanisms of action of high-dose ascorbate are not fully elucidated yet.
Two final remarks
High-dose vitamin C (achieved by intravenous infusions) does not cure cancer but it seems to be worth investigating further to see if it could be added to the toolbox currently available for cancer treatment, either to enhance the antitumor effect of certain drugs in certain types of cancer or to reduce the toxicity associated with these drugs.
It is also important to keep in mind that oral supplementation and intravenous infusions will yield very different blood levels of vitamin C, which will in turn modify how vitamin C acts – as an antioxidant or as a pro-oxidant. This is all the more important to remember since there are concerns about oral dietary supplements limiting the efficacy of certain cancer treatments by their antioxidant activity (14).
1. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. Sci Transl Med. 2014 Feb 5;6(222):222ra18. doi: 10.1126/scitranslmed.3007154
2. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Chen Q, et al. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9. link
3. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Chen Q, et al. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8749-54. link
4. Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study. Boeing H, et al. Cancer Causes Control. 2006 Sep;17(7):957-69. link
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8. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Cameron E & Pauling L. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4538-42. link
9. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. Creagan ET, et al. N Engl J Med. 1979 Sep 27;301(13):687-90. link
10. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. Moertel CG, et al. N Engl J Med. 1985 Jan 17;312(3):137-41. link
11. Vitamin C pharmacokinetics: implications for oral and intravenous use.Padayatty SJ, et al. Ann Intern Med. 2004 Apr 6;140(7):533-7. link
12. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Welsh JL, et al. Cancer Chemother Pharmacol. 2013 Mar;71(3):765-75. link
13. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. Monti DA, et al. PLoS One. 2012;7(1):e29794. link
14. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? Lawenda BD, et al. J Natl Cancer Inst. 2008 Jun 4;100(11):773-83. link
Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, & Chen Q (2014). High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Science translational medicine, 6 (222) PMID: 24500406