Handbook of Vitamin C Research

Pro-Oxidant vs. Antioxidant Effects of Vitamin C 167cell lines (Bran et al., 1980; Sestili et al., 1996; Chen et al., 2005), potentiates cytoxic agents(Song et al., 1995; Kurbacher et al., 1996; Kassouf et al., 2006; Grad et al., 2001; Abdel-Latifet al., 2005) and demonstrates anticancer activity alone and in combination with other agentsin tumor-bearing rodents (Sarna end Bhola 1993; Verrax et al., 2006; Taper et al., 2004).Simultaneously, theoretical interest has arisen in the potential of redox-active molecules tomodify cancer biology (Verrax et al., 2006) especially when administered together withcytotoxic drugs (Tetef et al., 1995; Diaz et al., 2005; Doroshow 2006).DNA mutation is likely a major contributor to the age-related development of cancer(Deng et al., 1998; Halliwell 2000). Attenuation of oxidative stress induced mutationsthrough vitamin C could provide a potential cancer prevention mechanism (Li and Schellhorn2007). Paradoxically, ascorbic acid may also function as a prooxidant, promoting oxidativedamage to DNA (Stich et al., 1976). This occurs in the presence of free transition metals,such as copper and iron, which are reduced by ascorbate and, in turn, react with hydrogenperoxide, leading to the formation of highly reactive and damaging hydroxyl radicals, via theFenton reaction (Stich et al., 1976). THowever, the relevance of such abnormal physiologicalconditions in vivo has been questioned, as most transition metals exist in inactive,proteinbound form in vivo (Halliwell and Gutteridge 1986). However, ascorbic acid may alsodisplay a pro-oxidant activity, which is more profound in cancer cells and causes cell death,when used at pharmacological concentrations (0.3–20 mmol/L), (Chen et al., 2005).Increased generation of hydrogen peroxide (by ascorbic acid autooxidation) in vivo may beexploited as a means for inducing tumor-specific cytotoxicity (Gonzales at al. 2005). Anexplanation for this quite specific anticancer activity of vitamin C is provided by recentresearch reporting highly increased levels of transition metals in malignant tumors (Ionescu etal., 2006; Ionescu 2007a; Yaman et al 2005) (Fig 79-911), leading to in situ auto-oxidation ofthe vitamin and generation of H 2 O 2 /HO • with apoptosis induction.Figure 7. Iron content of 20 breast cancer and 8 control human biopsies.