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In recent years, increasing numbers of studies demonstrated that high-dose ascorbate, which can be achieved by intravenous infusion, has cytotoxic effects on cancer cells in vitro and in vivo. There are many hypotheses of anti-cancer mechanisms of high dose ascorbate including a pro-oxidative mechanism, inhibition of angiogenesis and inflammation, enhancement of the anticancer effect of chemotherapy and reduction of chemotherapy-induced side effects. In addition, in recent years there were studies showing that ascorbic acid has effect on gene expression and epigenetic phenomena. In our study we analyzed, by using animal model, the effect of pharmacological concentrations of ascorbic acid on several gene expressions involved in tumorigenesis. To test the effects of ascorbic acid on gene expression, we treated mice with two different concentrations of ascorbic acid after intraperitoneal administration with sarcoma S-180 cells. The injected doses of ascorbic acid were equivalent to 15 g per 70 kg human and 50 g per 70 kg human. Tissue from tumors, liver and kidney was obtained from mice at the end of three weeks of treatment. The gene expression analysis was computed by real time PCR. The results showed significant difference in expression of gene p53 (p<0.02) in tumor tissue between treated and non-treated groups, and reduction of p53 gene expression by size and spreading of tumors. Ascorbate therapy significantly increased expression of NRF2. The experimental data showed that the maximum ascorbate dosage reduced expression of the tumor promoting gene HIF. The dependence of gene expression on the size of tumors was found for P53, HIF and NF-kB. In summary, the results of our study demonstrated that ascorbate therapy had a significant effect on the expression of several genes relevant to the development or inhibition of cancer. Reduced expression of tumor promoting genes as HIF and increased expression of tumor suppression genes such as p53 support the hypothesis that ascorbic acid can act as a potential agent for the suppression of tumor development. Background Ascorbic acid (AA, ascorbate, vitamin C) is an essential water soluble antioxidant that has been studied for decades for its potential role in preventing chronic diseases [1]. Ascorbate plays a role in limiting inflammation, regulating cytokine production, and boosting the immune system [2-8]. It has a variety of properties that have generated interest in using it against cancer [9-13]: it enhances natural killer cell activity [14,15], increases collagen synthesis [16], inhibits capillary tubule formation (angiogenesis) [17,18], reduces inflammation in cancer patients [3], at millimolar concentrations, shows cytotoxicity against cancer cells [19-24] and the ability to reduce tumor growth in vivo [25-34]. Clinical trials to date [35-40] indicate that high dose (on the order of ten to 100 grams) intravenous ascorbate therapy can enhance anti-cancer effects of chemotherapy and improve quality of life in cancer patients. Recent studies indicate that vitamin C may have important effects on gene expression. For example, hypoxia inducible factor 1 (HIF-1) may induce the expression of more than sixty genes, including those coding for vascular endothelial growth factor (VEGF), erythropoietin (Epo), and nitric oxide synthase-2 (NOS-2); transcription and translation of these genes yields proteins that play key roles in angiogenesis, regulation of glucose metabolism, cell survival, and cell proliferation [41-44]. Decreased HIF-1 activation is associated with increased disease free survival in patients with cancer. The HIF-1a subunit regulates expression of Bcl-2 family proteins, which in turn protect cells from reactive oxygen species (ROS) induced apoptosis [45-50]. Since the induction of HIFs may be mediated by ROS, antioxidants such as vitamin C may inhibit HIF-1 and HIF-1a expression; this is supported by experimental studies [45-51]. Vitamin C may also act on HIF-1 expression by inhibiting the expression of Nuclear Factor kB (NF-kB) genes. NF-kB is involved in inflammation and tumor development [52-55]. Ascorbate has been shown to inhibit the expression of NF-kB [52,55-58]. The anticancer effect of ascorbate may be in part due to its ability to suppress specificity protein (SP) transcription factors (such as Sp1, Sp3, and Sp4) [59]. Sp-regulated genes are involved in cancer proliferation (via hepatocyte growth factor receptor, epidermal growth factor receptor, and cyclin D1), survival (via survivin and Bcl-2) and angiogenesis (via VEGF and its receptors) [59-62]. Ascorbate may also suppress tumor growth through modulation of p53 [63-65]. The gene for p53 is particularly important in regulating cell proliferation, cell cycle progression, DNA repair, senescence and apoptosis in tumor cells [66-70]. Other genes of importance to cancer that are possibly affected by millimolar levels of ascorbate include: DNA methyltransferase (DNMT1), which is responsible for maintaining DNA methylation and in silencing tumor susceptibility genes [71-76]; human telomerase Correspondence to: Nina Mikirova, Riordan Clinic, 3100 North Hillside, Wichita, KS, USA; E-mail: nmikirova@riordanclinic.org

Gene expression response to ascorbic acid in mice implanted with sarcoma S180 cells