Modulating factors of radical intensity and cytotoxic activity of ascorbate (review).

Ascorbate acts both as an antioxidant and as an oxidant, depending upon the environment in which the molecule is present. We have reported that millimolar concentrations of ascorbate induced apoptotic cell death, characterized by cell shrinkage, nuclear fragmentation and internucleosomal DNA cleavage, in human myelogenous leukemic cell lines. Ascorbate derivatives, which can induce the apoptosis, produced the radical(s), elevated the oxidation potential and stimulated the methionine oxidation in the culture medium, whereas inactive derivatives did not. This suggests that the ascorbate induce the apoptosis by its prooxidant action. The effects of various factors, such as temperature, pH, metal, metal antagonist, redox agent, serum protein, polyphenol and (natural, chemically modified) polysaccharide on the radical intensity and apoptosis-inducing activity of ascorbate are reviewed. Gallate and benzo[a]phenothiazine derivatives, which can induce apoptosis or monocytic differentiation in human myelogenous leukemic cell lines, also produced radicals. These data suggest the significant role of radicals in the initiation of diverse biological activities.