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Open AccessArticle

The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells

Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(3), 129;
Received: 18 July 2019 / Revised: 28 August 2019 / Accepted: 29 August 2019 / Published: 2 September 2019
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
Ribonucleotide reductase (RR) is the rate-limiting enzyme that controls the deoxynucleotide triphosphate synthesis and it is an important target of cancer treatment, since it is expressed in tumor cells in proportion to their proliferation rate, their invasiveness and poor prognosis. Didox, a derivative of hydroxyurea (HU), is one of the most potent pharmaceutical inhibitors of this enzyme, with low in vivo side effects. It inhibits the activity of the subunit RRM2 and deoxyribonucleotides (dNTPs) synthesis, and it seems to show iron-chelating activity. In the present work, we mainly investigated the iron-chelating properties of didox using the HA22T/VGH cell line, as a model of hepatocellular carcinoma (HCC). We confirmed that didox induced cell death and that this effect was suppressed by iron supplementation. Interestingly, cell treatments with didox caused changes of cellular iron content, TfR1 and ferritin levels comparable to those caused by the iron chelators, deferoxamine (DFO) and deferiprone (DFP). Chemical studies showed that didox has an affinity binding to Fe3+ comparable to that of DFO and DFP, although with slower kinetic. Structural modeling indicated that didox is a bidentated iron chelator with two theoretical possible positions for the binding and among them that with the two hydroxyls of the catechol group acting as ligands is the more likely one. The iron chelating property of didox may contribute to its antitumor activity not only blocking the formation of the tyrosil radical on Tyr122 (such as HU) on RRM2 (essential for its activity) but also sequestering the iron needed by this enzyme and to the cell proliferation. View Full-Text
Keywords: didox; iron chelators; antitumor compound; iron metabolism; RRM2 didox; iron chelators; antitumor compound; iron metabolism; RRM2
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MDPI and ACS Style

Asperti, M.; Cantamessa, L.; Ghidinelli, S.; Gryzik, M.; Denardo, A.; Giacomini, A.; Longhi, G.; Fanzani, A.; Arosio, P.; Poli, M. The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells. Pharmaceuticals 2019, 12, 129.

AMA Style

Asperti M, Cantamessa L, Ghidinelli S, Gryzik M, Denardo A, Giacomini A, Longhi G, Fanzani A, Arosio P, Poli M. The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells. Pharmaceuticals. 2019; 12(3):129.

Chicago/Turabian Style

Asperti, Michela; Cantamessa, Luca; Ghidinelli, Simone; Gryzik, Magdalena; Denardo, Andrea; Giacomini, Arianna; Longhi, Giovanna; Fanzani, Alessandro; Arosio, Paolo; Poli, Maura. 2019. "The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells" Pharmaceuticals 12, no. 3: 129.

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