title: Influence of ascorbic acid on the activity of the investigational anticancer drug KP1019.
abstract: 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.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Austria.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bartel
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Egger
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Mathea Sophia
authors.initials: MS
authors.lastname: Galanski
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D015507:Drugs, Investigational; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D007624:KB Cells / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012428:Ruthenium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017975:Ruthenium Compounds; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D007191:Indazoles; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D017975:Ruthenium Compounds; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D012428:Ruthenium; D004247:DNA; D001205:Ascorbic Acid