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  • Copper and conquer: copper complexes of di-2-pyridylketone thiosemicarbazones as novel anti-cancer therapeutics

    Author(s)
    Park, Kyung Chan
    Fouani, Leyla
    Jansson, Patric J
    Wooi, Danson
    Sahni, Sumit
    Lane, Darius JR
    Palanimuthu, Duraippandi
    Lok, Hiu Chuen
    Kovacevic, Zaklina
    Huang, Michael LH
    Kalinowski, Danuta S
    Richardson, Des R
    Griffith University Author(s)
    Richardson, Des R.
    Year published
    2016
    Metadata
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    Abstract
    Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth ...
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    Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed.
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    Journal Title
    Metallomics
    Volume
    8
    Issue
    9
    DOI
    https://doi.org/10.1039/c6mt00105j
    Subject
    Chemical sciences
    Science & Technology
    Life Sciences & Biomedicine
    Biochemistry & Molecular Biology
    Downstream-Regulated Gene-1
    Epithelial-Mesenchymal Transition
    Publication URI
    http://hdl.handle.net/10072/408203
    Collection
    • Journal articles

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