Vitamin C and cancer

I have now read a key publication on vitamin C and my type of cancer.  On Wednesday, when I next speak to my oncologist, I will need to demand a modification to my therapy.  I have the feeling that I’m being denied better chances to survive.  The paper claims that Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.  It was published in Science, one of the beacons of scientific publishing, in 2015 with an associated commentary in the same issue.  The reason this paper isn’t just exciting but relevant is that I have a mutation in KRAS.  The two cell lines used in the paper carry the same mutation as my cancer, KRAS^G13D.

Title of Yun et al. (2015).

Let’s get started with the commentary, which should bring a bit more perspective than either research article.  It explains the complicated history of vitamin C and cancer.  It was Linus Pauling of all people who first showed cancer patients’ increased survival when they were injected high doses of vitamin C.  It's ironic that he is now primarily – and less flatteringly – associated with orally administered vitamin C.  It's even more ironic that clinical trials following up on Pauling’s research came back negative – because they also gave vitamin C orally.  It took a long time for science to recover from this mix-up and the resulting confusion.

Vitamin C is taken up by cells through dedicated vitamin C transporters.  This is of no therapeutic interest.  The oxidized form of vitamin C, which is called dehydroascorbate and always exists in equilibrium with regular vitamin C, gets into cells with the help of a glucose transporter.  This is relevant for some cancer cells whose glucose transporters are particularly active.  Inside cells, the reduction of dehydroascorbate back to vitamin C causes a spike in reactive oxygen species that block glucose metabolism (by direct inactivation of a key enzyme called glyceraldehyde 3-phosphate dehydrogenase, the GAPDH in the paper's title).  When the resulting shortage of energy inside the cell reaches crisis point, the cells die.

If the last sentence of the previous paragraph sounds vaguely familiar it’s because I’ve already written about this in a different context.  A drastically reduced food intake does of course also lead to cellular energy crises and, such is the hope behind my periodic fasting strategy, to cell death.  The point that these two approaches are synergistic is made in another paper.  Before I talk about this, I need to get into and clarify some complications.

The glucose receptor behind the uptake of vitamin C is upregulated in KRAS-mutated cancer cells.  This is why they take up more dehydroascorbate than unoxidized vitamin C, but this alone doesn’t explain the cytotoxic effect.  KRAS-mutated cancer cells reprogram their metabolism to proliferate faster.  In the process, they generate a lot of reactive oxygen species.  The antioxidant defenses that are essential for the cells to survive under high oxidative stress are inhibited by vitamin C, which contributes to the killing of the cancer cells.  It is, to make this clear, their high proliferation rate, this key feature of cancer cells that every therapy seeks to reduce, that makes them a target of vitamin C.  This is not only true for solid tumors but also, and especially, for metastatic tumor cells.  They survive the oxidizing environment of the blood by increasing their antioxidant defenses.  Vitamin C is thus expected to kill circulating metastatic tumor cells as well.  This works, as the paper shows, even when the cells are grown in normal glucose conditions.

It’s not as easy as this, of course.  One can’t take basic research and transfer it into the clinic.  What works in cell culture might not work in patients.  From the results it is unclear whether vitamin C has a therapeutic use for the treatment of KRAS-mutated cancers.  At the time the paper was published in 2015, there was an early clinical trial that looked at the effect of vitamin C in conjunction with platinum-based chemotherapy.  I haven’t had the time yet to dig into this and see what the outcome was and whether there have been related trials since then.

This post is full of information that’s not of the most easily digestible kind.  It’s probably best I stop at this point, but not before summarizing in the clearest language I can manage:

Cancer cells with KRAS mutations are killed by high levels of vitamin C.  The biochemistry works like this:

• Cancer cells primarily consume the oxidized form of vitamin C.
• The reduction of oxidized vitamin C inside the cell causes oxidative stress.
• Oxidative stress leads to the inactivation of an enzyme that helps turn glucose into energy.
• Lack of this enzyme leads to a scarcity of available energy to which cells respond by conking out.

The question of a possible synergy between vitamin C and fasting will be the topic of the next post.