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Copper signaling axis as a target for prostate cancer therapeutics.

Publication ,  Journal Article
Safi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; McDonnell, DP
Published in: Cancer Res
October 15, 2014

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

October 15, 2014

Volume

74

Issue

20

Start / End Page

5819 / 5831

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Signal Transduction
  • Receptors, Androgen
  • Reactive Oxygen Species
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Molecular Targeted Therapy
  • Mice, SCID
  • Mice, Inbred NOD
 

Citation

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Safi, R., Nelson, E. R., Chitneni, S. K., Franz, K. J., George, D. J., Zalutsky, M. R., & McDonnell, D. P. (2014). Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res, 74(20), 5819–5831. https://doi.org/10.1158/0008-5472.CAN-13-3527
Safi, Rachid, Erik R. Nelson, Satish K. Chitneni, Katherine J. Franz, Daniel J. George, Michael R. Zalutsky, and Donald P. McDonnell. “Copper signaling axis as a target for prostate cancer therapeutics.Cancer Res 74, no. 20 (October 15, 2014): 5819–31. https://doi.org/10.1158/0008-5472.CAN-13-3527.
Safi R, Nelson ER, Chitneni SK, Franz KJ, George DJ, Zalutsky MR, et al. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 2014 Oct 15;74(20):5819–31.
Safi, Rachid, et al. “Copper signaling axis as a target for prostate cancer therapeutics.Cancer Res, vol. 74, no. 20, Oct. 2014, pp. 5819–31. Pubmed, doi:10.1158/0008-5472.CAN-13-3527.
Safi R, Nelson ER, Chitneni SK, Franz KJ, George DJ, Zalutsky MR, McDonnell DP. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 2014 Oct 15;74(20):5819–5831.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

October 15, 2014

Volume

74

Issue

20

Start / End Page

5819 / 5831

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Signal Transduction
  • Receptors, Androgen
  • Reactive Oxygen Species
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Molecular Targeted Therapy
  • Mice, SCID
  • Mice, Inbred NOD