Expanding horizons in iron chelation and the treatment of cancer: role of iron in the regulation of ER stress and the epithelial-mesenchymal transition.
Cancer is a major public health issue and, despite recent advances, effective clinical management remains elusive due to intra-tumoural heterogeneity and therapeutic resistance. Iron is a trace element integral to a multitude of metabolic processes, including DNA synthesis and energy transduction. Due to their generally heightened proliferative potential, cancer cells have a greater metabolic demand for iron than normal cells. As such, iron metabolism represents an important "Achilles' heel" for cancer that can be targeted by ligands that bind and sequester intracellular iron. Indeed, novel thiosemicarbazone chelators that act by a "double punch" mechanism to both bind intracellular iron and promote redox cycling reactions demonstrate marked potency and selectivity in vitro and in vivo against a range of tumours. The general mechanisms by which iron chelators selectively target tumour cells through the sequestration of intracellular iron fall into the following categories: (1) inhibition of cellular iron uptake/promotion of iron mobilisation; (2) inhibition of ribonucleotide reductase, the rate-limiting, iron-containing enzyme for DNA synthesis; (3) induction of cell cycle arrest; (4) promotion of localised and cytotoxic reactive oxygen species production by copper and iron complexes of thiosemicarbazones (e.g., Triapine(®) and Dp44mT); and (5) induction of metastasis and tumour suppressors (e.g., NDRG1 and p53, respectively). Emerging evidence indicates that chelators can further undermine the cancer phenotype via inhibiting the epithelial-mesenchymal transition that is critical for metastasis and by modulating ER stress. This review explores the "expanding horizons" for iron chelators in selectively targeting cancer cells.
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Darius J R
DJ
Lane
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Thomas M
TM
Mills
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Nurul H
NH
Shafie
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Angelica M
AM
Merlot
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Rayan
R
Saleh Moussa
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Danuta S
DS
Kalinowski
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia.
Zaklina
Z
Kovacevic
Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au.
Des R
DR
Richardson
D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004273:DNA, Neoplasm; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D007501:Iron; D012264:Ribonucleotide Reductases
EMT; ER stress; Epithelial–mesenchymal transition; Iron chelation; PERK; Thiosemicarbazone