Copper signaling axis as a target for prostate cancer therapeutics.
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.
Type
Journal articleSubject
AndrogensAnimals
Antineoplastic Agents
Apoptosis
Biological Transport
Cell Line, Tumor
Copper
Disulfiram
Gene Expression Regulation, Neoplastic
Homeostasis
Humans
Male
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Prostatic Neoplasms
Reactive Oxygen Species
Receptors, Androgen
Signal Transduction
Up-Regulation
Xenograft Model Antitumor Assays
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https://hdl.handle.net/10161/9192Published Version (Please cite this version)
10.1158/0008-5472.CAN-13-3527Publication Info
Safi, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Satish K. Chitneni
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
Katherine J. Franz
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
Daniel James George
Professor of Medicine
Donald Patrick McDonnell
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
Michael Rod Zalutsky
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
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