Ascorbic acid has been previously discussed to have antitumor potential through its interaction with transition
metal ions such as
iron and
copper. Furthermore,
ascorbic acid may act as a
reducing agent for Ru(III) compounds such as indazolium trans-[tetrachlorobis(1H-
indazole)ruthenate(III)] (
KP1019), an investigational anticancer
drug which is supposed to be activated by reduction, prior to binding to cellular target
proteins. Therefore, we investigated the influence of
ascorbic acid on the activity of this antitumor
metal complex in cell culture studies. We show that co-incubation of equicytotoxic, constant amounts of
KP1019 with high concentrations of
ascorbic acid (50-700 μM) increases cytotoxicity of the
ruthenium anticancer
drug in the human colon
carcinoma cell line SW480, human cervical
carcinoma KB-3-1 cells, and the multidrug-resistant subline KBC-1, whereas addition of low concentrations (2.7-50 μM) has a strong chemoprotective effect in the human colon
carcinoma cell line SW480, but not in multidrug-resistant KBC-1 cells. Although cellular uptake of
KP1019 is not altered,
ascorbic acid induce stronger interaction of the
ruthenium compound with
DNA both in SW480 cells and under cell-free conditions with plasmid
DNA. Even if
DNA interactions probably play a subordinate role in vivo given the extensive protein binding of the compound, our data exemplify that
ascorbic acid enhances the reactivity of
KP1019 with biomolecules. Moreover, we demonstrate that the levels of KP1019-generated
reactive oxygen species are markedly decreased by co-incubation with
ascorbic acid. Conclusively, our results indicate that application of high doses of
ascorbic acid might increase the anticancer effects of
KP1019.