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Influence of ascorbic acid on the activity of the investigational anticancer drug KP1019

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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.

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Abbreviations

DCFH-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

D-PBS:

Dulbecco’s phosphate-buffered saline

ICP-MS:

Inductively coupled plasma mass spectrometry

KP1019:

Indazolium trans-[tetrachlorobis-(1H-indazole)ruthenate(III)]

MEM:

Eagle’s minimum essential medium

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

NAMI-A:

Imidazolium trans-[tetrachloro(dimethyl sulfoxide)(1H-imidazole)ruthenate(III)]

P-gp:

P-glycoprotein

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

TBS:

Tris(hydroxymethyl)aminomethane-buffered saline

Tris:

Tris(hydroxymethyl)aminomethane

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Acknowledgments

The authors acknowledge Daniel Schachner (Department of Pharmacognosy, University of Vienna) for performing fluorescence-activated cell sorting analyses. This work was supported by the Austrian Research Promotion Agency (FFG), project no. 811591 (B.K.), and the Fellinger Krebsforschungsverein (P.H.).

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Authors and Affiliations

  1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria

    Caroline Bartel, Alexander E. Egger, Michael A. Jakupec, Mathea Sophia Galanski & Bernhard K. Keppler

  2. Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria

    Petra Heffeter & Walter Berger

  3. Research Platform “Translational Cancer Therapy Research”, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria

    Michael A. Jakupec, Mathea Sophia Galanski & Bernhard K. Keppler

  4. Research Platform “Translational Cancer Therapy Research”, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria

    Petra Heffeter & Walter Berger

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  1. Caroline Bartel
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  2. Alexander E. Egger
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  3. Michael A. Jakupec
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  5. Mathea Sophia Galanski
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Correspondence to Michael A. Jakupec.

Additional information

C. Bartel and A.E. Egger contributed equally to this work.

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Bartel, C., Egger, A.E., Jakupec, M.A. et al. Influence of ascorbic acid on the activity of the investigational anticancer drug KP1019. J Biol Inorg Chem 16, 1205–1215 (2011). https://doi.org/10.1007/s00775-011-0809-4

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