Copper signaling axis as a target for prostate cancer therapeutics.
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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.
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Mice, Inbred NOD
Molecular Targeted Therapy
Reactive Oxygen Species
Xenograft Model Antitumor Assays
Published Version (Please cite this version)10.1158/0008-5472.CAN-13-3527
Publication InfoSafi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; & McDonnell, DP (2014). Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res, 74(20). pp. 5819-5831. 10.1158/0008-5472.CAN-13-3527. Retrieved from https://hdl.handle.net/10161/9192.
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Associate Professor in Radiology
The major focus of our research has been on the design, development and evaluation of novel radiotracers based on small molecules for imaging specific molecular targets using positron emission tomography (PET). The imaging targets are usually enzymes, cell surface receptors or transporters that are strongly implicated in or markers of diseases. Fluorine-18, which has a half-life of about 110 min, is ideally suited for radiolabeling of small molecules, and permits PET imaging studies for
Chair of the Department of Chemistry
Research in the Franz group is involved in elucidating the structural and functional consequences of metal ion coordination in biological systems. We are particularly interested in understanding the coordination chemistry utilized by biology to manage essential yet toxic species like copper and iron. Understanding these principles further guides our development of new chemical tools to manipulate biological metal ion location, speciation, and reactivity for potential therapeutic benefit. We use
Professor of Medicine
Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, in the School of Medicine
The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of severa
Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School of Medicine
The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living huma
Alphabetical list of authors with Scholars@Duke profiles.