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Leveraging γ‐Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells
Author(s) -
Bakthavatsalam Subha,
Sleeper Mark L.,
Dharani Azim,
George Daniel J.,
Zhang Tian,
Franz Katherine J.
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201807582
Subject(s) - cytotoxicity , prostate cancer , lncap , chemistry , prodrug , cancer cell , pharmacophore , chelation , cancer research , biochemistry , copper , prostate , in vitro , cancer , pharmacology , medicine , biology , organic chemistry
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 n m in prostate cancer lines 22Rv1 and LNCaP to over 15 μ m 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.