Introduction to Vitamin C

Vitamin C can affect cancer in a multitude of ways, but the mechanisms are still poorly understood in spite of the relatively large number of studies conducted. As we have seen, various studies have reported that vitamin C inhibits cancer, has no effect on cancer, or it facilitates cancer progression.

A primary reason for the slow progress and conflicting results in vitamin C research is that its effects on cancer are largely mediated through redox reactions, and the study of these in biological systems is a complex undertaking. Like all antioxidants, vitamin C can act as both an antioxidant and prooxidant. Its prooxidant effects are mediated through the vitamin C free radical, which in high concentrations inhibits tumor growth but in low concentrations may stimulate it. Unfortunately, much of our understanding of the effects of free radicals in health and disease has come only recently, and the role the vi-

tamin C free radical plays in the vitamin's anticancer effects was not fully appreciated in early studies. Consequently, early studies were not always careful to account for its production and involvement, making the results of different investigations difficult to interpret. The study of vitamin C also is difficult and results are conflicting because in addition to re-dox-mediated effects, vitamin C may affect cancer through a number of indirect means, such as through immune enhancement.

Mechanisms of Action

As an antioxidant, vitamin C may inhibit cancer progression through a variety of actions, listed in Table 15.1. Its ability to stimulate apoptosis is mediated by its prooxidant effect.

Any of the actions listed may contribute to tumor inhibition in vivo, but some actions will likely be more active than others. Nearly all mechanistic studies conducted so far have focused on vitamin C's ability to directly inhibit cancer cells by acting as a prooxidant, thereby inducing apoptosis. Much less is known about its ability to inhibit cancer through the indirect means listed, such as inhibition of invasion. Additional study is required to determine the role each of these indirect mechanisms may play, but we now use the available evidence to make preliminary conclusions about both direct and indirect effects, with the latter discussion necessarily more brief.

Indirect Effects of Vitamin C

Most of the activities listed in Table 15.1 are those that would indirectly inhibit cancer, including actions that inhibit angiogenesis, invasion, and metastasis and those that support the immune system. Although data are scarce, it appears that indirect means will likely play a lesser role in tumor inhibition in vivo than direct means. Furthermore, we can estimate that the inferred actions listed are less likely to be involved than the known actions. Indeed, inhibition of metastasis is listed as an inferred activity, yet vitamin C increased metastasis in






Chapter 2: Mutations, Gene Expression, and Proliferation

Act as an antioxidant


Chapter 3: Results of Therapy at the Cellular Level

Induce apoptosis


Chapter 5: Transcription Factors and Redox Signaling

Inhibit NF-kB activity



Chapters 7 and 8: Angiogenesis

Inhibit angiogenesis



Inhibit bFGF effects


Inhibit histamine effects


Inhibit TNF effects


Inhibit VEGF effects


Chapters 9 and 10: Invasion and Metastasis

Inhibit invasion


Inhibit hyaluronidase and beta-glucuronidase


Inhibit collagenase effects

stimulates collagen synthesis


Inhibit cell migration


Inhibit metastasis


Chapters 11 and 12: Immune System

Support the immune system


some animal studies when used alone or in combinations with other vitamins.22'43

The known indirect activities listed in Table 15.1 are inhibition of histamine, support of the immune system, and support of ECM integrity (via inhibition of hyalu-ronidase and beta-glucuronidase and stimulation of collagen synthesis).3 Although the ability of vitamin C to inhibit histamine and improve immune response has been demonstrated in healthy humans, it is unlikely these effects alone would be sufficient to produce the antitumor effects observed in some animal studies. His-tamine is one of many secondary mediators of angio-genesis, and its reduction alone would not be expected to influence angiogenesis dramatically.

a The effects of vitamin C on the ECM and immune system are apparent in scurvy, or vitamin C deficiency. Symptoms of scurvy are bleeding gums, poor wound healing, extensive bruising, and susceptibility to infection.

Likewise, Vitamin C can support the immune system through a number of mechanisms, but it is not an immune stimulant per se; its role is supportive in nature, so effects on the immune system are not likely responsible by themselves for the observed antitumor effects. Indeed, the antitumor effects in some animal studies were seen within a short enough time period to exclude major immune involvement.13 Interestingly, one way vitamin C supports the immune system is by inhibiting histamine production.44 Excess histamine can have a suppressive effect on the immune system.

Lastly, the effects of vitamin C on the ECM are also unlikely to account for observed antitumor effects. The effects of vitamin C on the ECM have been studied in cancer-bearing animals and humans, but results have varied. One study on tumor-bearing mice reported that orally administered vitamin C affected the architecture of implanted ascites tumors; in a human study, however, the authors reported as a minor observation that no correlations were evident between plasma vitamin C concentrations and the architectural changes of skin cancers.45,46 Furthermore, two in-vitro studies reported that vitamin C does not reduce collagenase production by tumor cells or make the ECM more resistant to tumor degradation.47,48

In summary, while the above-mentioned indirect effects may add to an anticancer action, their contribution is likely to be relatively minor, except possibly in cases of overt vitamin C deficiency.

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