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

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.