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. Attached Files Name Description MIMEType Size Downloads denoyer-copperasatarget-2016.pdf Published version application/pdf 7.22MB 62 Title Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution Author(s) Denoyer, Delphine orcid.org/0000-0001-8932-5116 Pearson, Helen B. Clatworthy, Sharnel Smith, Zoe Francis, Paul orcid.org/0000-0003-4165-6922 Llanos, Roxana Volitakis, Irene Phillips, Wayne A. Meggyesy, Peter 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 Persistent URL http://hdl.handle.net/10536/DRO/DU:30083561 Document type: Journal Article Collections: Faculty of Science, Engineering and Built Environment School of Life and Environmental Sciences Centre for Cellular and Molecular Biology Open Access Collection Related Links Link Description Connect to published version Go to link with your DU access privileges   Connect to Elements publication management system Go to link with your DU access privileges     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. 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. 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