A novel PDE4A inhibitor suppresses hepatocellular carcinoma progression through activating the cAMP-induced PKA pathway

Hepatocellular carcinoma (HCC), a malignancy of the digestive system, presents limited therapeutic options at advanced stages. In this context, inhibitors of cyclic nucleotide phosphodiesterase 4 (PDE4) have emerged as promising novel agents for patients with advanced HCC. We synthesized a potent PDE4A inhibitor, designated as MG5b, derived from the natural bioactive compound alpha-mangostin, and evaluated its antitumor efficacy in HCC. To assess the impact of MG5b on the proliferation of HCC cells, we conducted MTT and colony formation assays. Flow cytometry was utilized to analyze cell cycle progression, apoptosis, and mitochondrial membrane potential in HCC cells. Intracellular reactive oxygen species (ROS) levels were quantified using a DCF-DA probe. Network pharmacology was employed to predict the associated signaling pathways. Furthermore, Western blotting and immunohistochemistry were utilized to determine the effects of MG5b on protein expression levels. The antitumor efficacy of MG5b was further evaluated in Huh7 xenograft models. MG5b demonstrated a significant inhibitory effect on the proliferation, migration, and invasion of HCC cells, induced cell cycle arrest at the G0/G1 phase, and promoted apoptosis. Mechanistically, MG5b activated the cyclic adenosine monophosphate (cAMP) induced protein kinase A (PKA) signaling pathway, resulting in increased intracellular ROS production and the subsequent suppression of the EGFR-PI3K-AKT pathway. In vivo studies indicated that MG5b markedly inhibited tumor growth while exhibiting minimal toxicity. These findings suggest that MG5b may function as a novel PDE4A inhibitor and hold potential as a promising drug candidate for the treatment of advanced HCC.