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

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.

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

“…Recently, it has been reported that the downregulation of GGCT elicits an anti-proliferative effect in some cancer cell lines, such as breast cancer cell lines MCF-7, MCF-7/ADR, and MDA-MB-231 [44][45][46]. Interestingly, ChaC1 was suggested as a novel biomarker because the overexpression of mammalian ChaC1 and its related transcript variants has been previously found to promote cell proliferation in breast cancer cell lines Hs578T and BT-20 [18,47,48].…”

Mechanisms of Tumor Growth Inhibition by Depletion of γ-Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy

“…Recently, the first cell membrane permeable GGCT inhibitor has been developed by Ii et al [ 32 ]. As the structure of an inhibitor of enzymatic activity often resembles the structure of the natural substrate of the enzyme, 18 compounds structurally similar to γ-glutamyl- l -amino acid were selected as candidates for GGCT inhibition.…”

GGCT promotes colorectal cancer migration and invasion via epithelial‑mesenchymal transition

“…In the present study, GGCT was revealed to be increased in CRC tissues compared with normal colon tissues, and patients with CRC that had higher GGCT expression exhibited a worse prognosis compared with patients with a lower expression of GGCT, indicating the prognostic value of GGCT. The dysregulation of GGCT has been reported in certain cancer types, for example Li et al ( 13 ) demonstrated that GGCT suppressed the progression of prostate cancer, indicating that GGCT may serve as a tumor suppressor gene. However, Zhang et al ( 30 ) indicated that the disruption of GGCT inhibited proliferation and induced late apoptosis in human gastric cancer, demonstrating that GGCT may serve as an oncogene.…”

“…GGCT has been reported to accumulate in a variety of cancer types, including breast, ovarian, cervical, lung, bladder, prostate, colon, osteosarcoma and glioma, indicating that it may serve as an oncogene in these tumor types ( 7 – 12 ). The depletion of GGCT has been indicated to inhibit the proliferation of bladder cancer cells and induce the cytotoxicity of McF-7/ADR cells in vitro and in vivo ( 13 ). In previous years, one study has identified the suppression of cancer cell proliferation by disrupting GGCT, highlighting the potential for treatment of malignant tumor types through inhibiting GGCT ( 14 ).…”

“…The depletion of GGCT has been indicated to inhibit the proliferation of bladder cancer cells and induce the cytotoxicity of McF-7/ADR cells in vitro and in vivo ( 13 ). In previous years, one study has identified the suppression of cancer cell proliferation by disrupting GGCT, highlighting the potential for treatment of malignant tumor types through inhibiting GGCT ( 14 ). However, the underlying mechanism as to how GGCT regulates CRC progression remains yet to be determined.…”