Ascorbic acid (vitamin C) and Cancer

Nobel laureate Pauling and Cameron advocated use of high doses of ascorbic acid (vitamin C) (> 10 g/day) to cure and prevent cold infections and in the treatment of cancer [34,59]. The benefits included were increased sense of well being/ much improved quality of life, prolongation of survival times in terminal patients and complete regression in some cases [60-62]. However, clinical studies on cancer patients carried out at Mayo Clinic showed no significant differences between vitamin C and placebo groups in regard to survival time [63]. Cameron and Pauling [23] believed that ascorbic acid combats cancer by promoting collagen synthesis and thus prevents tumors from invading other tissues. However, researchers now believe that ascorbic acid prevents cancer by neutralizing free radicals before they can damage DNA and initiate tumor growth and or may act as a pro-oxidant helping body's own free radicals to destroy tumors in their early stages [64-66].

Extensive animal, clinical and epidemiological studies were carried out on the role of ascorbic acid in the prevention of different types of cancers. A mixture of ascorbic acid and cupric sulfate significantly inhibited human mammary tumor growth in mice, while administered orally [67]. Ascorbic acid decreased the incidence of kidney tumors by estradiol or diethylstilbesterol in hamsters due to decrease in the formation of genotoxic metabolites viz., diethylstilbesterol-4'-4"-qunione [68]. Ascorbic acid and its derivatives were shown to be cytotoxic and inhibited the growth of a number of malignant and non-malignant cell lines in vitro and in vivo [69-72]. Ascorbic acid has been reported to be cytotoxic to some human tumor cells viz., neuorblastoma [73], osteosarcoma and retinoblastoma [74]. A number of ascorbic acid isomers/ derivatives were synthesized and tested on tumor cell lines. Roomi et al., 1998 [75] demonstrated that substitution at 2- or 6- and both at 2,6-positions in ascorbic acid have marked cytotoxicity on malignant cells. Ascorbate-6-palmitate and ascorbate-6-stearate, the fatty acid esters of ascorbic acid were found to be more potent inhibitors of growth of murine leukemia cells compared to ascorbate 2-phosphate, ascorbate 6-phosphate and or ascorbate 6-sulfate respectively [75].

Among ascorbic acid derivatives, fatty acid esters of ascorbic acid viz., ascorbyl palmitate and ascorbyl stearate have attracted considerable interest as anticancer compounds in view of their lipophilic nature as they can easily cross cell membranes and blood brain barrier [76]. Ascorbic acid and ascorbyl esters have been shown to inhibit the proliferation of mouse glioma and human brain tumor cells viz., glioma (U-373) and glioblastoma (T98G) cells and renal carcinoma cells [77-79]. Ascorbyl stearate was found to be more potent than sodium ascorbate in inhibiting proliferation of human glioblastoma cells [80]. Ascorbyl-6-O-palmitate and ascorbyl-2-O-phosphate-6-O-palmitate also showed anti-metastatic effect by inhibiting invasion of human fibrosarcoma HT-1080 cells through matrigel and pulmonary metastasis of mouse melanoma model systems [81].

Numerous reports are available in literature on cytotoxic and anti-carcinogenic effect of ascorbic acid and its derivatives in different tumor model systems. However, the molecular mechanisms underlying the anti-carcinogenic potential of ascorbic acid are not completely elucidated. Recently, Naidu et al [80] demonstrated that ascorbyl stearate inhibited cell proliferation by interfering with cell cycle, reversed the phenotype and induced apoptosis by modulation of insulin-like growth factor 1-receptor expression in human brain tumor glioblastoma (T98G) cells. They also studied the effect of ascorbyl stearate on cell proliferation, cell cycle, apoptosis and signal transduction in a panel of human ovarian and pancreatic cancer cells. Treatment with ascorbyl stearate resulted in concentration-dependent inhibition of cell proliferation and also clonogenicity of ovarian/ pancreatic cancer cells [82,83]. The anti-proliferative effect was found to be due to the arrest of cells in S/G2-M phase of cell cycle, with increased fraction of apoptotic cells. The cell cycle perturbations were found to be associated with ascorbyl stearate induced reduction in the expression and phosphorylation of IGF-I receptor, while the expression of EGFR and PDGFR remained unchanged. These changes were also associated with activated ERK1/2 but late reduction in AKT phosphorylation. Overexpression of IGF-I receptor in OVCAR-3 cells had no protective effect, however ectopic expression of a constitutively active AKT2 did offer protection from the cytotoxic effects of ascorbyl stearate. In conclusion, ascorbyl stearate-induced anti-proliferative and apoptotic effects in ovarian cancer were found to be mediated through cell cycle arrest and modulation of the IGF-IR and PI3K/AKT2 survival pathways [83].

A plethora of epidemiological studies were carried out to find out the association of ascorbic acid with various types of cancers including breast, esophageal, lung, gastric, pancreatic, colorectal, prostate, cervical and ovarian cancer etc. The results were found to be inconclusive in most types of cancers except gastric cancer [84]. One of the most consistent epidemiological findings on vitamin C has been an association with high intake of ascorbic acid or vitamin C rich foods and reduced risk of stomach cancer. Considerable biochemical and physiological evidence suggests that ascorbic acid functions as a free radical scavenger and inhibit the formation of potentially carcinogenic N-nitroso compounds from nitrates, nitrite in stomach and thus offer protection against stomach cancer [85-87].

Low intake of ascorbic acid and other vitamins was associated with an increased risk of cervical cancer in two of three studies reported [88-91]. This relationship needs further study because the results suggest that other nutrients including vitamin E, carotenoids, retinoic acid either individually or in synergy with ascorbic acid may impart a protective effect against various cancers. Current evidences suggest that vitamin C alone may not be sufficient as an intervention in the treatment of most active cancers, as it appears to be preventive than curative. However, vitamin C supplementation has shown to improve the quality of life and extend longevity in cancer patients, hence it could be considered as an adjuvant in cancer therapy.

Dehydroascorbic acid, the oxidized form of ascorbic acid was shown to cross the blood brain barrier by means of facilitative transport and was suggested to offer neuroprotection against cerebral ischemia by augmenting antioxidant levels of brain [92].