Sydney Cancer Center - Cancer Cell Iron Metabolism and Chelation

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Cancer Iron metabolism and chelation program

Group Leader:

Members:

Dr David Lovejoy
Research Fellow, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 9666; Fax: 9351 3429; dlovejoy@med.usyd.edu

Dr Erika Becker Research Fellow, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 6547; Fax: 9351 3429; ebecker@med.usyd.edu.au

Dr Robert Sutak
Research Fellow, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 6547; Fax: 9351 3429; rsutak@med.usyd.edu.au

Dr Patric Jansson
Research Fellow, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 7120; Fax: 9351 3429; pjansson@med.usyd.edu.au

Dr Maggie Lok
Research Fellow, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 6547; Fax: 9351 3429; mlok@med.usyd.edu.au

Ms Megan Whitnall
Research assistant and PhD candidate, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 6547; Fax:+61 2 9351 3429; mwhitnall@med.usyd.edu.au

Ms Rosei Siafakas
Research assistant, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 9666; Fax: 9351 3429; asiafakas@med.usyd.edu.au

Ms Danuta Kalinowski
Research assistant and PhD candidate, Iron Metabolism and Chelation Program, Level 5, Blackburn Building, USYD; Ph: 9036 6547; Fax: 9351 3429; dkalinowski@med.usyd.edu.au

Research Overview
This program of research is based at the Sydney University Blackburn Building and is involved in the design of novel drugs against cancer known as iron chelators. These studies are based on the knowledge that iron is critical for DNA synthesis and cell cycle progression.

We have designed novel agents that markedly inhibit the growth of a range of solid tumours in vivo and are covered by a suite of national patents. Discussions are on-going with several biotechnology and pharmaceutical companies regarding commercialisation and clinical trials.

Our work also focuses on investigating the mechanisms involved in the role of iron in proliferation and cell cycle regulation and the function of the melanoma tumour antigen p97 (melanotransferrin) in the pathogenesis of this cancer.

In another project we are investigating the effects on cellular iron metabolism of the widely used anthracycline class of anti-cancer drugs which cause cardiotoxic effects by their interaction with iron. We hope to combat the cardiotoxicity caused by these agents by using iron chelators to limit the potential for toxic interaction.

2006/2007 Highlights
Discovery of the mechanism of action of our chelators involves down-regulation of p21CIP1/WAF1 that could be involved in the induction of apoptosis. (Published: Fu, D. and Richardson, D.R. (2007) Iron chelation and regulation of the cell cycle: Two mechanisms of post-transcriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron-depletion. Blood. 110, 752-761.
Featured Article in an “Inside Blood” Editorial Commentary).

Discovery that our novel anti-tumour agents have multiple mechanisms of action on cell cycle regulation which includes down-regulation of cyclin D1 which is necessary for G1 progression. (Published in: Nurtjahja-Tjendraputra, E., Fu, D., Phang, J. and Richardson, D.R. (2007) Iron chelation regulates cyclin D1 expression via the proteasome: A link to iron-deficiency mediated growth suppression. Blood. 109:4045-4054).

Discovery of new compounds that mediate marked selectivity and anti-tumour activity (Published: Kalinowski, D.S., Yu, Y., Sharpe,P.S., Mohammad Islam, M., Liao, Y-T., Lovejoy, D.B., Kumar, N., Bernhardt, P.V. and Richardson, D.R. (2007) Design, synthesis and characterization of novel iron chelators: Structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogs as potent anti-tumor agents. J. Med. Chem. 50(15):3716-3729.

Discovery of a group of novel anti-tumour agents that show marked anti-tumour activity and overcome resistance to established chemotherapeutics (Published: Whitnall, J., Howard, J., Ponka, P. and Richardson, D.R. (2006) A novel class of iron chelators with a wide spectrum of potent anti-tumor activity that overcome resistance to chemotherapeutics.Proc. Natl. Acad. Sci. USA 103:14901-6.

Discovery of a mechanism of activity of the cytotoxic macrophage effector molecule nitric oxide that depends upon its interaction with tumour cell iron (Published: Watts, R.N., Hawkins, C., Ponka, P. and
Richardson, D.R. 2006) Nitrogen monoxide (NO)-mediated iron mobilization from cells is linked to NO-induced glutathione efflux via MRP1. Proc. Natl. Acad. Sci. USA103(20):7670-7675)

Discovery of structure-activity relationships of novel iron chelators and their Fe complexes that show marked anti-tumour activity (Published: Richardson, D.R., Sharpe, P.C., Lovejoy, D.B., Senaratne, D., Kalinowski, D.S., Islam, M., Bernhardt, P.V. (2006) Dipyridyl thiosemicarbazone chelators with potent and selective anti-tumor activity form iron complexes with marked redox activity. J. Med. Chem. 49(22):6510-6521).

Publication of article in Blood as a Plenary Paper (defined by this journal as “Papers of Exceptional Scientific Importance”) describing the generation of a knockout mouse for the melanoma tumour antigen, melanotransferrin (Published: Sekyere, E.O., Dunn, L.L., Suryo Rahmanto, Y.and Richardson, D.R. (2006) The function of melanotransferrin in iron metabolism: Studies using targeted gene disruption in vivo. Blood 107:2599-2601).

Publications 2006/2007
(1) Sekyere, E.O., Dunn, L.L., Suryo Rahmanto, Y. and Richardson, D.R. (2006) The function of melanotransferrin in iron metabolism: Studies using targeted gene disruption in vivo. Blood 107:2599-2601. Selected by the Editors of Blood as a Plenary Paper which this journal describes as “papers of exceptional scientific importance”

(2) Davies, N., Suryo Rahmanto, Y., Chitambar, C.R. and Richardson, D.R. (2006) Resistance to the anti-neoplastic agent gallium nitrate results in marked alternations in intracellular iron trafficking: Identification of novel intermediates involved in Fe transport. J. Pharmacol. Exp. Ther. 317(1):153-162.

(3) Whitnall, M. and Richardson, D.R. (2006) Novel chelators of iron in brain: Potential treatment for neurological disorders. Semin. Pediatric Neurology 13(3):186-97. Invited Review

(4) Bernhardt, P.V, Mattsson, J and Richardson, D.R. (2006) Complexes of cytotoxic chelators from the dipyridylketone isonicotinoyl hydrazone (HPKIH) analogues. Inorg. Chem. 45(2):752-760.

(5) Dunn, L.L., Sekyere, E., Rahmanto, Y. and Richardson, D.R. (2006) The function of melanotransferrin: A role in proliferation and tumorigenesis. Carcinogenesis 27(11):2157-69.

(6) Watts, R.N., Hawkins, C., Ponka, P. and Richardson, D.R. (2006) Nitrogen monoxide (NO)-mediated iron mobilization from cells is linked to NO-induced glutathione efflux via MRP1. Proc. Natl. Acad. Sci. USA 103(20):7670-7675.

(7) Kovacevic, Z. and Richardson, D.R. (2006) The Metastasis Suppressor, Ndrg-1: A New Ally in the Fight Against Cancer. Carcinogenesis 27(12):2355-66

(8) Richardson, D.R. and Lovejoy, D.B. (2006) “Iron mining” to inhibit tumor growth. Blood 108(7):2140. Invited Inside Blood Editorial Commentary.

(9) Richardson, D.R., Sharpe, P.C., Lovejoy, D.B., Senaratne, D., Kalinowski, D.S., Islam, M., Bernhardt, P.V. (2006) Dipyridyl thiosemicarbazone chelators with potent and selective anti-tumor activity form iron complexes with marked redox activity. J. Med. Chem. 49(22):6510-6521.

(10) Whitnall, M., Howard, J. Ponka, P. and Richardson, D.R. (2006) A class of iron chelators with a wide spectrum of potent anti-tumor activity that overcome resistance to chemotherapeutics. Proc. Natl. Acad. Sci. USA 103:14901-6.

(11) Yu, Y., Chan, J., Kalinowski, D., Lovejoy, D.B. and Richardson, D.R. (2006) Chelators at the cancer coalface: Desferrioxamine to Triapine and beyond. Clin. Cancer Res. 12(23): 6876-6883.

(12) Mrkvicková, Z., Kovaríková, P., Klimeš, J., Kalinowski, D. and Richardson, D.R. (2006) Development and validation of HPLC-DAD methods for the analysis of two novel iron chelators with potent anti-cancer activity. J. Pharmac. Biomed. Anal. 43(4):1343-51.

(13) Richardson, D.R. (2007) DNIC and intracellular iron. In: Radicals for Life: The Various Forms of Nitric Oxide, Elsevier Press, van Faasen, E and Vanin, A. Eds. Invited Book Chapter

(14) Musiol R, Jampilek J, Kralova K, Richardson DR, Kalinowski D, Podeszwa B, Finster J, Niedbala H, Palka A, Polanski J. (2007) Investigating biological activity spectrum for novel quinoline analogues. Bioorg. Med. Chem. 15(3):1280-8

(15) Dunn, L.L., Suryo-Rahmanto, Y. and Richardson, D.R. (2007) Iron Uptake and Metabolism in the New Millennium. Trends Cell Biol. 17(2):93-100.

(16) Richardson, D.R. and Suryo-Rahmanto, Y.(2007) Differential Regulation of the Menkes and Wilson Disease Copper Transporters by Hormones: An Integrated Model of Metal Transport in the Placenta. Biochem. J. 402, e1-3. (Invited Commentary).

(17) Nurtjahja-Tjendraputra, E., Fu, D., Phang, J. and Richardson, D.R. (2007) Iron chelation regulates cyclin D1 expression via the proteasome: A link to iron-deficiency mediated growth suppression. Blood. 109:4045-4054.

(18) Lovejoy, D., YuYu and Richardson, D.R. (2007) Chelators as anti-cancer drugs. In: Cancer Encyclopedia, 2nd Ed., Schwab, M. (in press) Invited Chapter

(19) Rahmanto, Y., Sekyere, E., Dunn, L. and Richardson, D.R. (2007) The Function of the Membrane-Bound Transferrin Homologue, Melanotransferrin (Melanoma Tumour Antigen p97). In: Iron Metabolism and Disease., Ed. H. Fuchs, Chapter 9, Transworld Research Network Publishers. Invited Book Chapter.

(20) Suryo-Rahmanto, Y., Dunn, L. and Richardson, D.R. (2007) The melanoma tumor antigen, melanotransferrin (p97): A 25-year hallmark from iron metabolism to tumorigenesis. Oncogene Apr 23; [Epub ahead of print]

(21) Kalinowski, D.S. and Richardson, D.R. (2007) Iron chelators and differing modes of action and toxicity: The changing face of iron chelation therapy. Chem Res. Toxicol. 20:715-20. Invited Perspective and Issue Cover

(22) Suryo-Rahmanto, Y., Dunn, L., L. and Richardson, D.R. (2007) Identification of distinct changes in gene expression after modulation of melanoma tumour antigen p97 (melanotransferrin) in multiple models in vitro and in vivo. Carcinogenesis (In Press Apr 21; [Epub Ahead of Print]).

(23) Fu, D. and Richardson, D.R. (2007) Iron chelation and regulation of the cell cycle: Two mechanisms of post-transcriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron-depletion. Blood. 110, 752-761. Featured Article in an “Inside Blood” Editorial Commentary.

(24) Debebe, Z., Kurantsin-Mills, J., Ammosova, T., Niu, X., Richardson, D.R., Jerebtsova, M., Ray, P.E., Gordeuk, V.R., and Nekhai, S. (2007) Iron Chelators ICL670 and 311 Inhibit HIV-1 Transcription. Virology (In Press, June 7th).

(25) Yu, Y., Kovacevic, Z. and Richardson, D.R. (2007) Tuning cell cycle regulation with an iron key. Cell Cycle. In Press, June 19th.. Invited Review

(26) Richardson, D.R. (2007) Cellular and molecular biology of iron-binding proteins. In: Cellular and Molecular Biology of Metals, Zalups, R.K. and Koropatnick, J. Eds. Invited Book Chapter.

(27) Bernhardt, P.V., Chin, P., Sharpe, P.C. and Richardson, D.R. (2007) Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity. Dalton Trans. (In Press; May 22nd ). Selected by the Editors as a “Hot Article” and also Invited Cover of the Journal.

(28) Kalinowski, D.S., Yu, Y., Sharpe,P.S., Mohammad Islam, M., Liao, Y-T., Lovejoy, D.B., Kumar, N., Bernhardt, P.V. and Richardson, D.R. (2007) Design, synthesis and characterization of novel iron chelators: Structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogs as potent anti-tumor agents. J. Med. Chem. 50(15):3716-3729

(29) Bernhardt, P.V., Wilson, G.J. , Sharpe, P.C., Kalinowski, D. and Richardson, D.R. (2007) Tuning the anti-proliferative activity of biologically active iron chelators: Characterisation of the coordination chemistry and biological efficacy of 2-acetylpyridine and 2-benzoylpyridine hydrazone ligands. J. Biol. Inorg. Chem. (In Press July)