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

Subha Bakthavatsalam, Mark L. Sleeper, Azim Dharani, Daniel J. George, Tian Zhang, Katherine J. Franz

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12780-12784
Number of pages5
JournalAngewandte Chemie - International Edition
Volume57
Issue number39
DOIs
StatePublished - Sep 24 2018
Externally publishedYes

Keywords

  • cancer
  • copper
  • dithiocarbamate
  • prochelators
  • γ-glutamyl transpeptidase

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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