title: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.affiliation: Department of Radiology, Duke University, Durham, North Carolina.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Chitneni
authors.affiliation: Department of Chemistry, Duke University, Durham, North Carolina.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Franz
authors.affiliation: Divisions of Medical Oncology and Urology, Duke University, Durham, North Carolina.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.affiliation: Department of Radiology, Duke University, Durham, North Carolina.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina. Donald.McDonnell@duke.edu.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000728:Androgens / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D003300:Copper; D004221:Disulfiram