Vitamin C & Cancer

M. Waheed Roomi, Ph.D.
LPI Nutritional Biochemistry
and Cancer Group

Photo of M. Waheed Roomi, Ph.D.

Cancer is a dreaded disease. As human longevity increases, its incidence is arguably increasing, and it is now the second major cause of death in the western world. Many human cancers are considered to be related to environment and/or behavior, i.e. tobacco smoking, poor diet, occupational factors, excess alcohol consumption, and sedentary lifestyle. Both human and animal studies strongly suggest that the cancer cell originates by a slow process of cellular evolution involving multiple steps (initiation, promotion, progression) over a period of several years or even decades.

DNA damage, mainly oxidative in nature, is considered to be one of the most important steps in cancer. Although DNA repair enzymes correct most of this damage, some damaged cells may not be repaired. Lesions to DNA caused by oxidative damage increase with age, as does the risk of cancer. A cell containing damaged DNA that divides before being repaired results in a permanent genetic alteration that can be one of the first steps in cancer development. Cells that divide rapidly are more susceptible to carcinogens than slowly dividing cells because there is less opportunity for DNA repair before cell division. The pathological criteria of cancer include: 1) hyperplasia (increased number of cells and division), 2) invasion of adjacent tissue and 3) metastasis (cellular migration to distant tissues).

Cancer chemoprevention

Photo of Dr. Waheed Roomi examining a gel in which proteins have been separated electrophoretically.
Dr. Waheed Roomi examines a gel in which proteins have been separated electrophoretically.
Interest in the chemopreventive functions of antioxidants has grown considerably in recent years. Vitamin C (ascorbic acid), the major water soluble antioxidant in blood, tissue and intracellular fluid, is a very potent free- radical scavenger and has attracted tremendous attention. Epidemologic, animal, human and cell culture studies consistently and strongly suggest that vitamin C has a protective effect against a variety of cancers. Vitamin C has a wide variety of biochemical and physiological roles, including the synthesis of collagen, which is a principal component of tendons, ligaments, skin, bone, teeth, cartilage, heart valves, intervertebral disks, cornea, lens and the structural substances between cells.

Vitamin C acts as a scavenger that reacts directly with superoxide and hydroxy radicals and singlet oxygen produced during normal cellular metabolism. Vitamin C also helps protect DNA, enzymes, proteins and lipids from oxidative damage, thereby protecting against degenerative diseases, aging, coronary heart disease, cataract formation and cancer. Oxygen radicals have been implicated not only in initiation and post-initiation stages of the carcinogenic process, but in invasion and metastatic processes as well. Vitamin C may act by neutralizing these radicals.

Evidence accumulated over the years shows that people with high dietary intakes of fruits and vegetables are less likely to develop cancer than people who have low dietary intake of these foods. While many phytochemicals and micronutrients in fruits and vegetables may have anticancer properties, much interest has focused on vitamin C. In addition to its antioxidant functions, possible mechanisms of protection by vitamin C include preventing the formation of carcinogenic nitrosamines and fecal mutagens, enhancing the immune system, accelerating the action of detoxifying liver enzymes, and blocking the toxicological effects of carcinogens such as polycyclic hydrocarbons, organochlorine pesticides, and heavy metals.

Epidemologic studies show that the incidence of many cancers, including those of the stomach, oral cavity, esophagus, pancreas, colorectum, cervix, bladder, skin, breast, and larynx, inversely correlates with a diet high in fruits and vegetables containing vitamin C. However, vitamin C seems to have no protective effect on non-Hodgkin's lymphoma, and studies on thyroidal cancer and lung cancer are inconclusive.

Animal studies

Much of the evidence for the preventive effect of vitamin C has come from animal studies. Studies by Linus Pauling and his colleagues have shown that a large dietary intake of vitamin C delayed the onset of spontaneous mammary tumors in mice and had a pronounced effect in decreasing the incidence and delaying the onset of malignant dermal tumors in mice initiated by exposure to ultraviolet light. Other investigators have also found that vitamin C and its lipophilic derivative, ascorbyl palmitate, are effective in preventing skin cancer. Colon, kidney and bladder cancer in animals can be controlled by vitamin C intake, which also significantly inhibits lung cancer in mice exposed to fiberglass dust. Additionally, many investigators have observed that animals treated with vitamin C had well-encapsulated tumors that were thus less invasive.

Cell cultures

Other evidence for the anticancer efficacy of vitamin C comes from cell culture studies. Vitamin C is cytotoxic to several malignant melanoma cell lines, mouse sarcoma cells and mouse ascities tumor cells. At very low concentrations, vitamin C is cytotoxic to mouse lymphocytic leukemia cells, mouse cells from a lymphoid neoplasm, human fibrosarcoma cells, and an acute lymphoblastic leukemic human cell line. At much higher concentrations, vitamin C is also cytotoxic to some non-malignant cell lines. Japanese researchers have recently demonstrated the anticancer effect of benzylidene ascorbate against human tumors of the ovary, stomach, pancreas, uterus, bile duct, and lung. Benzylidene ascorbate has also been shown to induce apoptosis, or cell death, in a human myelogenous leukemic cell line, rat hepatocellular carcinoma cells, and in an HIV-replicating human lymphoma cell line.

Photo of Dr. Ewan Cameron
Dr. Ewan Cameron (1922-1991) at Vale of Leven Hospital, Lock Lomonside, Scotland. Dr. Cameron's and Dr. Paulings's clinical colaboration on cancer and vitamin C spanned several decades. (Photographer unknown, ca 1978)
Chemical structure

LPI investigators have demonstrated the anticancer effect of vitamin C on human breast cancer by implanting small tumor fragments in mice, which were given vitamin C or its chemical derivatives formed by oxidation. We have further tested the relationship between the chemical structure and cytotoxic effect of vitamin C and its derivatives in malignant cell lines. Vitamin C has reactive hydroxyl groups at four positions in the molecule (see diagram).

Molecule of vitamin C showing the reactive hydroxyl groups at positions 2, 3, 5 and 6.
Specifically, we tested 1) vitamin C and its isomers, 2) substitution at the 2-position with PO4, SO4, O-Me, or O-octadecyl, 3) substitution at the 6-position with PO4, SO4, palmitate, or stearate, 4) substitution at the 2- and 6-position with dipalmitate, 5) 6-deoxy derivative with substitution at the 6-position with Cl, Br, or NH2, and 6) dihydroxy gamma-crotonolactone with substitutions at the 4-position with H, CH3, CH2-CH3, CH=CH2, or CHOH-CH3. All 6-substituted and 6-deoxy derivatives were as toxic as vitamin C to cancer cells. However, 2-substituted and 2, 6-disubstituted derivatives were nontoxic. Interestingly, dihydroxy gamma-crotonolactone with or without substitution at the 4-position also exhibited toxicity. These results suggest that the underlying feature for vitamin C toxicity resides in the dihydroxy gamma-crotonolactone moiety. We do not yet understand this cytotoxic mechanism, and much more research needs to be done to evaluate the potential of these compounds for human therapy.

Clinical studies show benefit

Human cancer patients typically have a significantly reduced level of vitamin C in serum. Large doses of vitamin C can correct these serum levels and improve immune function and other critical physiological functions. Clinical studies carried out by Drs. Ewan Cameron and Linus Pauling showed, on average, that terminal cancer patients who were prescribed 10 grams/day of vitamin C survived significantly longer than similar cancer patients who didn't get vitamin C supplementation, with tumor regression reported in some patients with cancer of the lung, pancreas, small intestine, colon, breast, or kidney. Drs. Cameron and Pauling estimated that no response or minimal response to vitamin C would be observed in about 45% of patients but that the majority of patients would experience therapeutic responses of tumor retardation, cytostasis, or regression. Patients also reported a greater sense of well-being, improved appetite, increased mental alertness and physical strength, and decreased requirement for pain-killing drugs. These studies showed vitamin C therapy to be more effective when started early rather than at later stages. Dr. Abram Hoffer has reported similar results in cancer patients on a regimen that includes 12 grams/day of vitamin C, as well as vitamin E, B vitamins, beta-carotene, selenium, and other minerals.

While Dr. Cameron reported rare instances of complete tumor regression, most evidence suggests that the major beneficial anticancer effect of vitamin C may be in reducing risk and prolonging the survival time of cancer patients. Other factors in fruits and vegetables, such as folate, beta-carotene and other carotenoids, vitamin E, fiber, selenium, and presently unidentified compounds, certainly play important roles in chemoprevention. Their potential therapeutic roles also need to be thoroughly examined.

Last updated May, 1997

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