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  • Innovative Therapies for Neuroblastoma: The Surprisingly Potent Role of Iron Chelation in Up-Regulating Metastasis and Tumor Suppressors and Down-Regulating the Key Oncogene, N-myc

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    Author(s)
    Wijesinghe, Tharushi P
    Dharmasivam, Mahendiran
    Dai, Charles C
    Richardson, Des R
    Griffith University Author(s)
    Richardson, Des R.
    Dharmasivam, Mahendiran
    Dai, Charles C.
    Year published
    2021
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    Abstract
    Iron is an indispensable requirement for essential biological processes in cancer cells. Due to the greater proliferation of neoplastic cells, their demand for iron is considerably higher relative to normal cells, making them highly susceptible to iron depletion. Understanding this sensitive relationship led to research exploring the effect of iron chelation therapy for cancer treatment. The classical iron-binding ligand, desferrioxamine (DFO), has demonstrated effective anti-proliferative activity against many cancer-types, particularly neuroblastoma tumors, and has the surprising activity of down-regulating the potent ...
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    Iron is an indispensable requirement for essential biological processes in cancer cells. Due to the greater proliferation of neoplastic cells, their demand for iron is considerably higher relative to normal cells, making them highly susceptible to iron depletion. Understanding this sensitive relationship led to research exploring the effect of iron chelation therapy for cancer treatment. The classical iron-binding ligand, desferrioxamine (DFO), has demonstrated effective anti-proliferative activity against many cancer-types, particularly neuroblastoma tumors, and has the surprising activity of down-regulating the potent oncogene, N-myc, which is a major oncogenic driver in neuroblastoma. Even more remarkable is the ability of DFO to simultaneously up-regulate the potent metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), which plays a plethora of roles in suppressing a variety of oncogenic signaling pathways. However, DFO suffers the disadvantage of demonstrating poor membrane permeability and short plasma half-life, requiring administration by prolonged subcutaneous or intravenous infusions. Considering this, the specifically designed di-2-pyridylketone thiosemicarbazone (DpT) series of metal-binding ligands was developed in our laboratory. The lead agent from the first generation DpT series, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), showed exceptional anti-cancer properties compared to DFO. However, it exhibited cardiotoxicity in mouse models at higher dosages. Therefore, a second generation of agents was developed with the lead compound being di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) that progressed to Phase I clinical trials. Importantly, DpC showed better anti-proliferative activity than Dp44mT and no cardiotoxicity, demonstrating effective anti-cancer activity against neuroblastoma tumors in vivo.
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    Journal Title
    Pharmacological Research
    DOI
    https://doi.org/10.1016/j.phrs.2021.105889
    Copyright Statement
    © 2021 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Bioinorganic chemistry
    Pharmacology and pharmaceutical sciences
    N-myc
    N-myc downstream-regulated gene-1
    Neuroblastoma
    di-2-pyridylketone thiosemicarbazone
    iron chelation
    Publication URI
    http://hdl.handle.net/10072/408327
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    • Journal articles

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