Novel and clinically available iron chelators for cancer treatment: elucidation of molecular mechanisms underlying anti-tumour activity

Abstract

More potent and specific therapies are urgently required to help treat advanced and aggressive tumours. The potential for iron chelators to be utilised in cancer treatment has emerged in recent years, reflecting the fact that cancer cells require more iron than normal cells to mediate their rapid DNA synthesis and proliferation. Strategies for targeting iron in cancer through chelation could include the use of clinically approved chelators, such as deferasirox, or novel agents that demonstrate potent and selective anti-tumour effects in preclinical models, such as those of the di-2-pyridyl thiosemicarbazone (DpT) class that include di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). The studies presented herein have revealed novel insights into the potential for both clinically available and novel iron chelators to be utilised in cancer treatment. Important molecular mechanisms of these compounds have been identified through selective targeting of the AKT, ERK, TGF-beta and STAT3 pathways, which are deregulated in cancer. Further studies also revealed novel functions for the metastasis suppressor, NDRG1, in mediating the anti-tumour effects of iron chelators. Collectively, these studies will facilitate the development of these compounds for personalised cancer therapies.