Handbook of Vitamin C Research

368Neena PhilipsKeywords: Vitamin C, Cancer, Viability, Matrix-metalloproteinases, Tissue inhibitor ofmatrixmetalloproteinases, Transforming Growth Factor-beta, P. leucotomosAscorbic AcidAscorbic acid or vitamin C is essential for collagen formation and thereby extracellularmatrix (ECM) integrity, scurvy prevention and tumor encapsulation. Ascorbic acid is acofactor for prolyl hydroxylase, which hydroxylates proline residues for collagen structure,and also regulates the expression of collagen genes at the levels of transcription and mRNAstability [1-3].Ascorbic acid is a potent antioxidant physiologically via the scavenging of reactiveoxygen species (ROS), reactive nitrogen species and lipid hydroperoxides [4]. Radicalspecies are highly reactive and trigger lipid peroxidation and cellular damage [4]. Ascorbicacid also regenerates other cellular antioxidants such as vitamin E, glutathione (GSH) andbetacarotene from their radical species [4,5]. Ascorbate is depleted in biological fluids invivo under conditions of oxidative stress and inflammation [4].Cancer and Ascorbic AcidAscorbic acid is a major regulator of the ECM and regulates cancer biology. It inhibitsthe invasiveness of several cancers such as gastric, oral, pulmonary, fibrosarcoma andmelanoma [5-10]. It eliminates breast, oral, epidermoid and endometrial cancer cells [11-17].Ascorbic acid is preferentially cytotoxic to cancer cells, because of its rapid cell division,whereas nonmalignant cells are 10-20 times less sensitive [18].There are several mechanisms of ascorbate‘s anti-carcinogenic activity. The generationof reactive oxygen species is higher in gastric neoplasia than in nonplastic tissue and vitaminC retards gastric tumor growth by reducing the reactive oxygen species [12]. Oxidation ofestrogen to reactive metabolites induces renal tumors in syrian hamsters that are inhibited byvitamin C by the removal of reactive superoxide radicals [11]. Vitamin C inhibits the growthof human mammary tumor xenografts from its chemical structure (the lactone functionalgroup), depletion of bioavailability of lysine and cysteine, immune system improvement andadduct formation of its metabolites with cellular components [18].Ascorbic acid has synergistic effects in combination with other vitamins orchemotherapeutic drugs. In combination with vitamin K, vitamin C (100 M to 1mM)inhibits the growth of breast, endometrial and oral epidermoid cancer cells at 10-50 foldlower concentrations [19]. The growth inhibition is counteracted by catalase, indicating theinvolvement of hydrogen peroxide, and from the reactivation of nucleases that induce celltoxicity [19]. In addition, the combination of vitamin C, vitamin K, and diversechemotherapeutics synergistically inhibits endometrial adenocarcinoma cell growth [20].There is synergistic toxicity of the chemotherapeutics (adriamycin, mitomycin, bleomycin,methotrexate, vincristine, cyclophosphosphamide) and vitamins (C and K) from reducedprotein synthesis, reactive oxygen species, ATP depletion, and DNA single strand breaks