Potentiation of Hydroxyurea Cytotoxicity by Iron-Chelating Agent in Murine Tumor Models in vitro

Abstract

The biochemical modulation of tumor cell response to increase the cytotoxicity of Hydroxyurea (HU), directed at the ribonucleotide reductase enzyme, has been studied in in vitro. Mice bearing ascites tumor models such as L1210 leukemia, Sarcoma 180 (S180) and Ehrlich ascites tumor (EAT) were employed in this study. The cytotoxicity of HU alone at various concentrations was dose dependent and showed the following order of sensitivity; L1210 greater than EAT greater than S180. The hydrophobic iron-chelating agent 2,2-bipyridyl significantly potentiated the antitumor activity of HU in all the murine tumor models studied. In contrast, hydrophilic iron-chelator, Desferal, did not show any cytotoxicity when combined with HU. The present study demonstrated the factors influencing the amelioration of HU cytotoxicity and possible therapeutic use of iron-chelating agents alone and with HU for better therapeutic results in clinics.

Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes

“…For example, 2,2′-bpy appears to be a specific chelator of iron(II), being able to inhibit dopamine β-hydroxylase activity in rats and mice [ 79 ] and [ 3 H]-spiroperidol to bind to dopamine receptor 2 [ 80 ]. Additionally, this moiety can moderately induce DNA cleavage, as was shown for leukaemia and sarcoma cell lines [ 81 ].…”

1,10-Phenanthroline Potentiates Cytotoxicity of Hydroxyurea in Human Chronic Myeloid Leukemia Cells

“…We have previously analyzed the effect of various iron chelators and their effect on sensitization of P388 murine lymphocytic leukemia and other tumor cells to the nontoxic concentration of HU [5,15]. The present study describes the effect of the hydrophobic metal chelator 1,10-phenanthroline on the inhibition of pre cursor incorporation in the DNA of human CML cells, alone and in the presence of HU, to demonstrate the mechanism of action and the possible therapeutic use.…”

Bipyraloxifene – a modified raloxifene vector against triple-negative breast cancer

“… 42 Additionally, the 2,2′-bipy unit is able to induce DNA cleavage via intercalation. 43 Therefore, inspired by these interesting results we took 2,2′-bipy as a promising moiety to incorporate a dual therapeutic effect into the raloxifene molecule.…”