Reference - Detail
RRC ID | 77026 |
---|---|
Author | Ii H, Yoshiya T, Nakata S, Taniguchi K, Hidaka K, Tsuda S, Mochizuki M, Nishiuchi Y, Tsuda Y, Ito K, Kageyama S, Yoshiki T. |
Title | A Novel Prodrug of a γ-Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer. |
Journal | ChemMedChem |
Abstract |
γ-Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester-type cell-permeable prodrug, pro-GA, was developed based on the structure of N-glutaryl-l-alanine (GA), by structure optimization using temporary fluorophore-tagged prodrug candidates. The antiproliferative activity of pro-GA was demonstrated using GGCT-overexpressing NIH-3T3 cells and human cancer cells including MCF7, HL-60, and PC3 cells. By contrast, normal cells were not significantly affected by pro-GA treatment. Moreover, pro-GA administration exhibited anticancer effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the enzymatic activity of GGCT accelerates tumor growth and that GGCT inhibition is a promising therapeutic strategy for the treatment of GGCT-overexpressing tumors. |
Volume | 13(2) |
Pages | 155-163 |
Published | 2018-1-22 |
DOI | 10.1002/cmdc.201700660 |
PMID | 29316360 |
MeSH | Alanine / analogs & derivatives Alanine / chemistry Alanine / pharmacology Alanine / therapeutic use Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Cell Line Cell Line, Tumor Cell Proliferation / drug effects* Dipeptides / chemistry Dipeptides / pharmacology* Dipeptides / therapeutic use Glutarates / chemistry Glutarates / pharmacology Glutarates / therapeutic use Heterografts Humans Male Mice, SCID Prodrugs / chemistry Prodrugs / pharmacology* Prodrugs / therapeutic use Prostatic Neoplasms / drug therapy* Structure-Activity Relationship gamma-Glutamylcyclotransferase / antagonists & inhibitors* gamma-Glutamylcyclotransferase / metabolism |
IF | 3.124 |
Resource | |
Human and Animal Cells | PC-3(RCB2145) |