Analogues of Pyridoxal Isonicotinoyl Hydrazone (PIH) as Potential Iron Chelators for the Treatment of Neoplasia

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Abstract
Cancer cells have a high requirement for iron (Fe) as it plays a crucial role in a variety of metabolic processes including energy production and DNA synthesis. Studies in vitro and in vivo have demonstrated that the Fe chelator in current clinical use, desferrioxamine (DFO), can effectively inhibit the growth of some neoplasms, including leukemia and neuroblastoma. Unfortunately, DFO suffers from a number of serious disadvantages, including its high cost, the need for prolonged subcutaneous infusion (12-24 h/day, 5-6 nights/week), and its poor intestinal absorption precluding oral administration. Hence, the development of more effective Fe chelators is necessary. The Fe chelator, pyridoxal isonicotinoyl hydrazone (PIH), was initially identified as a ligand that showed high activity at mobilizing Fe from cells. More recently, a range of PIH analogues have been examined for their anti-proliferative effect, with several classes of these compounds showing high activity at inhibiting tumor growth in vitro. In fact, some of these hydrazones, particularly those derived from 2-hydroxy-1-naphthylaldehyde, showed comparable activity to the cytotoxic drugs cis-platin and bleomycin. In this review the role of Fe in cellular proliferation will be examined followed by a description of the most recent studies using the PIH analogues as effective anti-proliferative agents. Further studies in vivo with these Fe chelators are essential to determine their potential as chemotherapeutic agents.