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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Bakthavatsalam, S; Sleeper, ML; Dharani, A; George, DJ; Zhang, T; Franz, KJ

Published Date

  • September 2018

Published In

Volume / Issue

  • 57 / 39

Start / End Page

  • 12780 - 12784

PubMed ID

  • 30025197

Pubmed Central ID

  • 30025197

Electronic International Standard Serial Number (EISSN)

  • 1521-3773

International Standard Serial Number (ISSN)

  • 1433-7851

Digital Object Identifier (DOI)

  • 10.1002/anie.201807582

Language

  • eng