Sensitization of P388 murine leukemia cells to hydroxyurea cytotoxicity by hydrophobic iron-chelating agents

The potentiation in the cytotoxic effect of antineoplastic agent hydroxyurea (HU) from the non-toxic concentration on P388 murine lymphocytic leukemia cells is observed with the hydrophobic iron-chelating agents, 2,2-bipyridine (bipyridyl) and 1,10-phenanthroline in a concentration and time dependent manner. However EDTA, EGTA, 2,3-dihydroxybenzoic acid (2,3-DBA), Rhodotorulic acid, 8-hydroxyquinoline (8-Hq), catechin and Desferal, and other chelators failed to show sensitization of these tumor cells towards HU. The potentiation in the cytotoxic activity of HU in combination with the bipyridyl was found to be reversible but was maintained when the drug exposed cells were washed and retreated with the non-toxic concentrations of HU or bipyridyl. The presence of Fe++ blocked completely the cytotoxic action of HU alone and a combination with iron-chelator, and partially reversed the inhibition induced by HU and bipyridyl. These findings suggest that the hydrophobic iron-chelators affect the membrane-mediated transfer, localisation and transient intracellular chelatable iron pools. As a consequence of this, the regulatory role mediated by iron on the overall activity of ribonucleotide reductase enzyme is disturbed leading to a conclusive imbalance in DNA biosynthesis.