The phosphodiesterase-4 inhibitor Zl-n-91 suppresses glioblastoma growth via EGR1/PTEN/AKT pathway.

in European journal of pharmacology by Yuyu Li, Xin He, Shiri Li, Shenjie Chen, Zhenggang Zhao, Yunping Mu, Allan Z Zhao, Sujin Zhou, Fanghong Li

TLDR

  • A novel PDE4 inhibitor, Zl-n-91, shows greater efficacy than Rolipram in treating GBM by suppressing cell proliferation and inducing apoptosis through the EGR1/PTEN/AKT signaling pathway.

Abstract

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor, which presents significant challenges for treatment in clinical settings. Phosphodiesterase 4 (PDE4) inhibitors can prevent the degradation of cAMP and have been used as a potential targeted therapeutic approach for different cancer types. However, its clinical use is restricted by the side effects such as nausea and vomiting. Herein, we investigated the efficacy and therapeutic mechanisms of a specific PDE4 inhibitor, Zl-n-91, on GBM cells. The results demonstrated that Zl-n-91 exhibited more effectiveness than the well-known PDE4 inhibitor Rolipram in treating GBM. It can notably suppress the proliferation of GBM cells by inducing G0/G1 phase arrest and apoptosis. Additionally, Zl-n-91 significantly inhibited the growth of subcutaneous glioma xenografts. Mechanistically, Zl-n-91 treatment increased the expression and nuclear transcription of Early growth response (EGR1), while knockdown EGR1 could decrease PTEN levels and increase p-AKT levels, restoring the inhibition of cell proliferation induced by Zl-n-91. Collectively, we revealed for the first time that PDE4 inhibitor Zl-n-91 could inhibit the growth of GBM cells through the EGR1/PTEN/AKT signaling pathway. Zl-n-91, a specific PDE4 inhibitor, may be a promising therapeutic candidate for GBM.

Overview

  • The study investigates the efficacy and therapeutic mechanisms of a specific PDE4 inhibitor, Zl-n-91, on Glioblastoma multiforme (GBM) cells.
  • The study aims to identify novel targeted therapeutic approaches for treating GBM by screening the effects of Zl-n-91 on GBM cells.
  • The primary objective is to elucidate the mechanisms underlying the efficacy of Zl-n-91 and its potential as a therapeutic agent for GBM.

Comparative Analysis & Findings

  • Zl-n-91 exhibited more effectiveness than the well-known PDE4 inhibitor Rolipram in treating GBM, as it could notably suppress the proliferation of GBM cells and induce apoptosis.
  • Zl-n-91 treatment significantly inhibited the growth of subcutaneous glioma xenografts, whereas Rolipram showed limited effects.
  • The study found that Zl-n-91 could inhibit the growth of GBM cells through the EGR1/PTEN/AKT signaling pathway, a novel mechanism for PDE4 inhibitors in GBM treatment.

Implications and Future Directions

  • Zl-n-91, as a specific PDE4 inhibitor, may be a promising therapeutic candidate for GBM treatment, offering a potential new approach for the management of this aggressive brain tumor.
  • Future studies should focus on mechanistic investigations to further elucidate the role of the EGR1/PTEN/AKT signaling pathway in the therapeutic efficacy of Zl-n-91 and other PDE4 inhibitors.
  • Additionally, investigations on the effects of Zl-n-91 on GBM stem cells and the development of delivery strategies to optimize its therapeutic efficacy will be crucial for future studies.