Michael J. Gonzalez

Anticancer Mechanisms of Vitamin C

Vitamin C is considered a very strong reductant and radical scavenger. Vitamin C reduces unstable oxygen, nitrogen, and sulfur radicals.

Advances in Vitamin C Research

The recent publication by the Levine group of the National Institutes of Health (NIH) reporting that pharmacologic concentrations of ascorbic acid selectively kill cancer cells has received worldwide attention. The reason for this is that vitamin C (ascorbic acid, ascorbate) is a relatively cheap, nontoxic nutrient with a history of being used as a therapeutic tool against cancer. Nevertheless, this history has been full of controversy. The classical controversy was between Linus Pauling (Linus Pauling Institute) and Charles Moertel (Mayo Clinic). Varied results were published by the different camps, which initiated a seemingly never-ending debate. The reality is that the studies were not done the same way. Moertel never replicated the Pauling experiments. The most critical point is that both studies used oral doses of about 10 g, but Pauling also used the intravenous route. These oral doses were not high enough to reach plasma concentrat ions needed for vitamin C to achieve antineoplastic activity. Another more recent modern controversy has ensued with vitamin C and conventional cancer treatment. There has been a concern that vitamin C might reduce the effectiveness of chemotherapy and radiation by reducing the potency of the free radicals necessary for killing the cancer cells. This misconception was due in part to an article published by Golde’s group at Memorial Sloan Kettering in 1999 in which they described how cancer cells acquire and concentrate vitamin C. They suggest that these intracellular concentrations of ascorbate may provide malignant cells with a “metabolic advantage.” This published suggestion has been embraced by most practitioners without any question or further evaluation, although no data demonstrating this suggestion has been published. In contrast, a vast body of literature challenging these suggestions has been published and was summarized by Lamson and Brignall. Moss also published a book reviewing this subject in detail. The study by Levine and his group validates our earlier results published in 2002 in which we demonstrated in vitro antineoplastic activity by high-dose ascorbic acid. In addition to this in vitro study, we have also published an in vivo study with guinea pigs and a report on clinical cases also showing antineoplastic activity with high-dose vitamin C. In addition, we also published a comprehensive review on the topic, and more recently, the first clinical trial on the safety of high-dose intravenous vitamin C on terminal cancer patients was accepted for publication and will be available in January 2006. We are very excited with the results of the NIH. We believe this may lead to a new era in research, education, and healing in an integrated manner. We also think these reports may advance the goal of our cancer research initiative, the RECNAC II project, aimed at the development of effective, nontoxic cancer therapies. We believe that by changing the biochemical conditions that promote, develop, and sustain the malignant state, we can inhibit malignant cell proliferation, increase aerobic metabolism, and achieve redifferentiation. Our research indicates that vitamin C is just one of various substances that can have a selective effect in modulating cancer cell metabolism either toward redifferentiation or apoptosis. There is much research to do, but the emerging light makes the future look brighter. The RECNAC II project was inspired and supported by the late Hugh D. Riordan, a medical maverick from the Center for the Improvement of Human Functioning (The Bright Spot for Health) in Wichita, Kansas. Dr Riordan and his son Neil pioneered the use of high-dose intravenous vitamin C in cancer patients.

ANTIOXIDANTS AND PRO-OXIDANTS : A COMMENTARY ABOUT THEIR APPARENT DISCREPANT ROLE IN CARCINOGENESIS

The specific role of dietary antioxidants in carcinogenesis and tumorigenesis has not been unequivocally elucidated. Earlier studies suggested a protective role of dietary antioxidants against carcinogen-induced malignancies (1-4). The main mechanism proposed for this protective action against carcinogenesis exhibited by antioxidants is related to their free radical scavenging power. It is known that once normal cells are exposed to a free radical rich environment, the probability of these cells suffering relevant genetic damage is highly increased. This, in turn, increases the chances of mutations, amplifications and translocation of cellular oncogenes or the loss of repressor genes. This detrimental free radical-induced genetic damage can transform a normal cell into a malignant one in this phase; this is where dietary antioxidants may have a protective role against carcinogenesis. Once this transformation stage has been achieved, inducing further damage to the cell can only lead to either of two terminal paths: 1) to further enhance cancer progression (malignancy, aggressiveness); in other words, the cancer cell can become more invasive. This can probably occur by increasing production of cell proteases, favoring malignant dissemination throughout the organism, or 2)the cell will suffer unsurvivable genetic damage that will lead to cell death. Having all this in mind, we encounter a paradoxical role of free radical pathology or oxidative damage pertaining to the cancerous process. Of interest is the number and concentration of different oxidative species that originate during lipid peroxidation or any other oxidative process. This aspect requires special attention since it has been demonstrated that low concentrations of superoxide and hydrogen peroxide (two oxidative species) are effective stimulators of transformed cell growth (5). In contrast, high concentrations of these same oxidative species have exhibited cytotoxic activity against cell lines in vitro (6). In general, the type and quantity of oxidative species that arise in metabolism depend on many variables. Probably the main one is the type and quantity of dietary fat consumed. This variable itself brings yet another variable within, the issue of fatty acid composition. In addition the formation of oxidative by-prod ucts will also depend on the environment where these reactions are taking place and the particular sensitivity of the cellsthat will be exposed to the resulting oxidative species. In relation to the effect of diets high in fish oil on tumors in vivo,we believe that the high concentration of secondary products of oxidation (e.g. aldehydes) of cytotoxic nature impedes cell proliferation, thereby inhibiting tumorigenesis (7). The production of growth-inhibiting oxidative species can be favored in vitro by the presence of divalent cations (such as iron or copper) and in vivo bythe presence of various forms of these minerals (free or bound). The lower pH environment in the tumor (which can increase cation dissociation from bound protein sources) can significantly enhance this action leading to a higher cell death. Antioxidants, by preventing or delaying further oxidation of highly polyunsaturated fatty acids, can potentially negate the formation of these secondary products of oxidation, hence protecting the proliferative capacity of tumor cells. Nevertheless, we should also have in mind that certain antioxidants may have a role increasing certain parameters of the immune system and in this way affect tumor growth negatively in an indirect manner. Antioxidants in very high doses have the potential of creating oxidative species, although this particular aspect, to our knowledge, has not been observed in vivo.

Overview of Vitamin C and Cancer

In 1536, the French explorer Jacques Cartier, while exploring the St. Lawrence River, used the local natives’ herbal medicine knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree to make the healing tea (that was later shown to contain about 50 mg of vitamin C per 100 g) (Martini in Vesalius 8(1):2–6, 2002 [1]).

Potential Therapeutics for Vitamin C and Cancer

High-dose vitamin C has proven to be cytotoxic to a wide variety of cancer cell lines (Fain et al. in BMJ 316:1661–1662, 1998; Mayland et al. in Palliat Med 19(1):17–20, 2005; Agus et al. in Cancer Res 59:4555–4558, 1999; Prasad et al. in J Am Coll Nutr 18:13–25, 1999; Hart in Alt Complement Ther 18:91–97, 2012), as well as to boost the cytotoxicity of several common chemotherapy drugs.