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Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells.

Publication ,  Journal Article
Bakthavatsalam, S; Sleeper, ML; Dharani, A; George, DJ; Zhang, T; Franz, KJ
Published in: Angew Chem Int Ed Engl
September 24, 2018

A prodrug approach is presented to direct copper-dependent cytotoxicity to prostate cancer cells. The prochelator GGTDTC requires activation by γ-glutamyl transferase (GGT) to release the metal chelator diethyldithiocarbamate from a linker that masks its thiol reactivity and metal binding properties. In vitro studies demonstrated successful masking of copper binding as well as clean liberation of the chelator by GGT. GGTDTC was stable to non-specific degradation when incubated with a series of prostate cancer and normal cell lines, with selective release of diethyldithiocarbamate only occurring in cells with measurable GGT activity. The antiproliferative efficacy of the prochelator correlated with cellular GGT activity, with 24 h inhibitory concentrations ranging from 800 nm in prostate cancer lines 22Rv1 and LNCaP to over 15 μm in normal prostate PWR-1E cells. These findings underscore a new strategy to leverage the amplified copper metabolism of prostate cancer by conditional activation of a metal-binding pharmacophore.

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Published In

Angew Chem Int Ed Engl

DOI

EISSN

1521-3773

Publication Date

September 24, 2018

Volume

57

Issue

39

Start / End Page

12780 / 12784

Location

Germany

Related Subject Headings

  • gamma-Glutamyltransferase
  • Sulfhydryl Compounds
  • Prostatic Neoplasms
  • Organic Chemistry
  • Male
  • Humans
  • Copper
  • Cell Survival
  • Cell Line, Tumor
  • Carbamates
 

Citation

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Bakthavatsalam, S., Sleeper, M. L., Dharani, A., George, D. J., Zhang, T., & Franz, K. J. (2018). Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells. Angew Chem Int Ed Engl, 57(39), 12780–12784. https://doi.org/10.1002/anie.201807582
Bakthavatsalam, Subha, Mark L. Sleeper, Azim Dharani, Daniel J. George, Tian Zhang, and Katherine J. Franz. “Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells.Angew Chem Int Ed Engl 57, no. 39 (September 24, 2018): 12780–84. https://doi.org/10.1002/anie.201807582.
Bakthavatsalam S, Sleeper ML, Dharani A, George DJ, Zhang T, Franz KJ. Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells. Angew Chem Int Ed Engl. 2018 Sep 24;57(39):12780–4.
Bakthavatsalam, Subha, et al. “Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells.Angew Chem Int Ed Engl, vol. 57, no. 39, Sept. 2018, pp. 12780–84. Pubmed, doi:10.1002/anie.201807582.
Bakthavatsalam S, Sleeper ML, Dharani A, George DJ, Zhang T, Franz KJ. Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells. Angew Chem Int Ed Engl. 2018 Sep 24;57(39):12780–12784.
Journal cover image

Published In

Angew Chem Int Ed Engl

DOI

EISSN

1521-3773

Publication Date

September 24, 2018

Volume

57

Issue

39

Start / End Page

12780 / 12784

Location

Germany

Related Subject Headings

  • gamma-Glutamyltransferase
  • Sulfhydryl Compounds
  • Prostatic Neoplasms
  • Organic Chemistry
  • Male
  • Humans
  • Copper
  • Cell Survival
  • Cell Line, Tumor
  • Carbamates