title: Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics.
abstract: Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia. Electronic address: danutak@med.usyd.edu.au.
authors: Danuta S
authors: DS
authors: Kalinowski
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Christian
authors: C
authors: Stefani
authors: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors: Shinya
authors: S
authors: Toyokuni
authors: Department of Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA.
authors: Tomas
authors: T
authors: Ganz
authors: Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
authors: Gregory J
authors: GJ
authors: Anderson
authors: Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
authors: Nathan V
authors: NV
authors: Subramaniam
authors: School of Medicine and Pharmacology, Harry Perkins Institute of Medical Research, The University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, 6150, Australia.
authors: Debbie
authors: D
authors: Trinder
authors: Department of Gastroenterology, Fiona Stanley Hospital, Bull Creek, WA, 6149, Australia; School of Veterinary Sciences, Murdoch University, Murdoch, WA, 6150, Australia; Curtin Health Innovation Research Institute and School of Biomedical Sciences, Curtin University, Perth, WA, 6102, Australia.
authors: John K
authors: JK
authors: Olynyk
authors: School of Medicine and Pharmacology, Harry Perkins Institute of Medical Research, The University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, 6150, Australia.
authors: Anita
authors: A
authors: Chua
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Patric J
authors: PJ
authors: Jansson
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Sumit
authors: S
authors: Sahni
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Darius J R
authors: DJ
authors: Lane
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Angelica M
authors: AM
authors: Merlot
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Zaklina
authors: Z
authors: Kovacevic
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
authors: Michael L H
authors: ML
authors: Huang
authors: Ingham Institute for Applied Medical Research, Sydney, NSW, Australia; Discipline of Pathology and Molecular Medicine Research Group, School of Medicine, University of Western Sydney, Sydney, NSW, Australia; Department of Anatomical Pathology, Liverpool Hospital, Sydney, NSW, Australia.
authors: C Soon
authors: CS
authors: Lee
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au.
authors: Des R
authors: DR
authors: Richardson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002614:Chelating Agents / Q000627:therapeutic use; D003300:Copper / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods / Q000639:trends; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008670:Metals / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D008670:Metals; D017382:Reactive Oxygen Species; D003300:Copper; D007501:Iron
keywords: Bis(thiosemicarbazones); Cancer; Copper; Dp44mT; DpC; Iron; Thiosemicarbazones