Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics

Danuta S Kalinowski; Christian Stefani; Shinya Toyokuni; Tomas Ganz; Gregory J Anderson; Nathan V Subramaniam; Debbie Trinder; John K Olynyk; Anita Chua; Patric J Jansson; Sumit Sahni; Darius J R Lane; Angelica M Merlot; Zaklina Kovacevic; Michael L H Huang; C Soon Lee; Des R Richardson

doi:10.1016/j.bbamcr.2016.01.026

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics

Biochim Biophys Acta. 2016 Apr;1863(4):727-48. doi: 10.1016/j.bbamcr.2016.01.026. Epub 2016 Feb 2.

Authors

Danuta S Kalinowski¹, Christian Stefani², Shinya Toyokuni³, Tomas Ganz⁴, Gregory J Anderson⁵, Nathan V Subramaniam⁶, Debbie Trinder⁷, John K Olynyk⁸, Anita Chua⁷, Patric J Jansson², Sumit Sahni², Darius J R Lane², Angelica M Merlot², Zaklina Kovacevic², Michael L H Huang², C Soon Lee⁹, Des R Richardson¹⁰

Affiliations

¹ 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.
² Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
³ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
⁴ Department of Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA.
⁵ Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
⁶ Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
⁷ School of Medicine and Pharmacology, Harry Perkins Institute of Medical Research, The University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, 6150, Australia.
⁸ 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.
⁹ 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.
¹⁰ 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.

PMID: 26844773
DOI: 10.1016/j.bbamcr.2016.01.026

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.

Keywords: Bis(thiosemicarbazones); Cancer; Copper; Dp44mT; DpC; Iron; Thiosemicarbazones.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Antineoplastic Agents* / therapeutic use
Chelating Agents* / therapeutic use
Copper / metabolism*
Drug Discovery* / methods
Drug Discovery* / trends
Humans
Iron / metabolism*
Metals / metabolism*
Neoplasms / drug therapy
Neoplasms / metabolism
Neoplasms / pathology
Oxidation-Reduction
Reactive Oxygen Species / metabolism

Substances

Antineoplastic Agents
Chelating Agents
Metals
Reactive Oxygen Species
Copper
Iron