pyridoxal-isonicotinoyl-hydrazone and Neoplasms

The success of DFO at markedly inhibiting the growth of aggressive tumors such as neuroblastoma and leukemia justifies interest in the development of chelators as anti-neoplastic agents. This is emphasized by the fact that DFO has suboptimal properties, namely poor membrane permeability and a very short serum half-life. More recently, the thiosemicarbazone chelator, Triapine, has entered a phase I clinical trial again confirming the potential of these compounds. Further studies examining the effects of chelators on neoplastic cells will not only be valuable in terms of identifing novel anti-cancer agents, but will also provide new information on the role of Fe in cell cycle control.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Deferoxamine; Humans; Iron; Iron Chelating Agents; Isoniazid; Neoplasms; Pyridoxal; Thiosemicarbazones; Tumor Suppressor Protein p53

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.

Topics: Animals; Antineoplastic Agents; Biological Transport; Carrier Proteins; Cell Division; Humans; Iron Chelating Agents; Isoniazid; Membrane Proteins; Neoplasms; Pyridoxal

Topics: Aldehydes; Animals; Deferoxamine; Humans; Hydrazones; Iron Chelating Agents; Iron Overload; Isoniazid; Myocardial Reperfusion Injury; Neoplasms; Pyridines; Pyridoxal; Rats; Reactive Oxygen Species; Thiosemicarbazones

We have recently screened 36 analogues of the lipophilic iron (Fe) chelator, pyridoxal isonicotinoyl hydrazone (PIH), for their antiproliferative effect (Richardson et al, Blood 86:4295, 1995). Of these compounds, 1 chelator derived from salicylaldehyde benzoyl hydrazone (206) and 4 ligands derived from 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone (308, 309, 311, and 315) showed pronounced antiproliferative activity, being far more effective than desferrioxamine (DFO). The present study was designed to investigate in detail the mechanism of action of these PIH analogues in a variety of neoplastic cell lines. This investigation showed that the analogues were far more active than DFO at inhibiting cellular proliferation and 3H-thymidine, 3H-leucine, and 3H-uridine incorporation. Additional experiments showed that, in contrast to DFO, the 5 analogues were potent at preventing 59Fe uptake from transferrin (Tf) and increasing 59Fe release from cells at concentrations as low as 10 micromol/L. Examination of the distribution of 59Fe in neoplastic cells using native polyacrylamide gel electrophoresis (PAGE)/59Fe-autoradiography showed that most of the 59Fe taken up from Tf was incorporated into ferritin, although 3 other previously unrecognized components (bands A, B, and C) were also identified. Band C comigrated with 59Fe-citrate and was chelated on incubation of neuroblastoma cells with DFO, PIH, or the PIH analogues, with this compartment being the main intracellular target of these ligands. Further work showed that the effects of the chelators at inducing characteristics consistent with apoptosis or necrosis were cell line-specific, and while DFO increased the percentage of cells in the G0/G1 phases in all cell types, the effect of analogue 311 on the cell cycle was variable depending on the cell line. This study provides further evidence for the potential use of these Fe chelators as anticancer agents.

Topics: Antineoplastic Agents; Apoptosis; Benzaldehydes; Cell Cycle; Cell Division; Deferoxamine; DNA Fragmentation; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Ferritins; Growth Inhibitors; HL-60 Cells; Humans; Hydrazones; Iron; Iron Chelating Agents; Isoniazid; Ligands; Molecular Structure; Naphthols; Neoplasm Proteins; Neoplasms; Pyridoxal; Structure-Activity Relationship; Transferrin; Tumor Cells, Cultured

Suramin was used to analyze the growth-effects of blockade of iron uptake on two established human cell lines, U-937 (monocytoid) and K-562 (erythroleukemic). Suramin suppressed cell surface transferrin (Tf) binding and uptake of iron via inhibition of receptor-mediated endocytosis (RME). As a result, both lines accumulated in the S-phase. DNA synthesis and cell division were inhibited in the suramin-treated U-937, but not in K-562. Iron, supplied by a route alternative to Tf-to suramin-suppressed U-937 cells, reinitiated DNA synthesis and cell division, although at a lower level than in control cells. Multiple effects on iron-dependent enzymes and an inhibition of binding of undefined growth factors necessary for the transition through the cell cycle are suggested to be mechanisms by which suramin affects the U-937 cells. The results imply that clinically observed side effects of suramin may be caused by interference with cellular iron metabolism.

Topics: Cell Cycle; Cell Division; Cell Line; DNA; Humans; Intracellular Membranes; Iron; Iron Chelating Agents; Isoniazid; Neoplasms; Pyridoxal; Receptors, Transferrin; Suramin; Transferrin