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Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

Denoyer, Delphine, Pearson, Helen B., Clatworthy, Sharnel, Smith, Zoe, Francis, Paul, Llanos, Roxana, Volitakis, Irene, Phillips, Wayne A., Meggyesy, Peter, Masaldan, Shashank and Cater, Michael 2016, Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution, Oncotarget, vol. 7, no. 24, pp. 37064-37080, doi: 10.18632/oncotarget.9245.

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Title Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution
Author(s) Denoyer, DelphineORCID iD for Denoyer, Delphine orcid.org/0000-0001-8932-5116
Pearson, Helen B.
Clatworthy, Sharnel
Smith, Zoe
Francis, PaulORCID iD for Francis, Paul orcid.org/0000-0003-4165-6922
Llanos, Roxana
Volitakis, Irene
Phillips, Wayne A.
Meggyesy, Peter
Masaldan, ShashankORCID iD for Masaldan, Shashank orcid.org/0000-0003-4960-4983
Cater, Michael
Journal name Oncotarget
Volume number 7
Issue number 24
Start page 37064
End page 37080
Total pages 17
Publisher Impact Journals LLC
Place of publication Albany, N.Y.
Publication date 2016-05-09
ISSN 1949-2553
Keyword(s) Atp7b
TRAMP
copper
ionophore
prostate cancer
Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
TOXIC MILK MOUSE
OXIDATIVE STRESS
ALZHEIMERS-DISEASE
TRANSGENIC MOUSE
CELL LINES
MODEL
MICE
GLUTATHIONE
PROTEIN
INHIBITION
Summary Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed.
Language eng
DOI 10.18632/oncotarget.9245
Field of Research 111204 Cancer Therapy (excl Chemotherapy and Radiation Therapy)
111201 Cancer Cell Biology
111207 Molecular Targets
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30083561

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Created: Fri, 20 May 2016, 08:10:47 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.