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Copper signaling axis as a target for prostate cancer therapeutics.

dc.contributor.author Chitneni, SK
dc.contributor.author Franz, KJ
dc.contributor.author George, Daniel J
dc.contributor.author McDonnell, Donald Patrick
dc.contributor.author Nelson, ER
dc.contributor.author Safi, R
dc.contributor.author Zalutsky, Michael Rod
dc.coverage.spatial United States
dc.date.accessioned 2014-10-17T15:45:43Z
dc.date.issued 2014-10-15
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/25320179
dc.identifier 74/20/5819
dc.identifier.uri https://hdl.handle.net/10161/9192
dc.description.abstract Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.
dc.language eng
dc.relation.ispartof Cancer Res
dc.relation.isversionof 10.1158/0008-5472.CAN-13-3527
dc.subject Androgens
dc.subject Animals
dc.subject Antineoplastic Agents
dc.subject Apoptosis
dc.subject Biological Transport
dc.subject Cell Line, Tumor
dc.subject Copper
dc.subject Disulfiram
dc.subject Gene Expression Regulation, Neoplastic
dc.subject Homeostasis
dc.subject Humans
dc.subject Male
dc.subject Mice, Inbred NOD
dc.subject Mice, SCID
dc.subject Molecular Targeted Therapy
dc.subject Prostatic Neoplasms
dc.subject Reactive Oxygen Species
dc.subject Receptors, Androgen
dc.subject Signal Transduction
dc.subject Up-Regulation
dc.subject Xenograft Model Antitumor Assays
dc.title Copper signaling axis as a target for prostate cancer therapeutics.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/25320179
pubs.begin-page 5819
pubs.end-page 5831
pubs.issue 20
pubs.organisational-group Basic Science Departments
pubs.organisational-group Chemistry
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Endocrinology, Metabolism, and Nutrition
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group Pathology
pubs.organisational-group Pharmacology & Cancer Biology
pubs.organisational-group Radiation Oncology
pubs.organisational-group Radiology
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 74
dc.identifier.eissn 1538-7445


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