3-Phenethyl-2-phenylquinazolin-4(3H)-one Inhibits Breast Cancer Cell Motility, Energy Metabolism, and Proliferation by Inactivating Phosphoinositide 3-Kinase/Protein Kinase B and Epidermal Growth Factor Receptor Pathways

Marine-derived compounds hold great promise for cancer therapy, targeting various essential processes in cancer progression, such as apoptosis, metastasis, proliferation, and drug resistance. 3-Phenethyl-2-phenylquinazolin-4(3H)-one (1) is a natural quinazolinone derivative extracted from the marine sediment-derived genus Acremonium sp. CNQ-049. This study explores the therapeutic effects and underlying mechanisms of 1 in breast cancer. Compound 1 significantly inhibited epithelial–mesenchymal transition by downregulating EMT-related transcription factors as well as cancer metabolism by reducing the expression of glycolytic enzymes. By targeting protein kinase B (AKT1) and epidermal growth factor receptor (EGFR), compound 1 decreased the expression of p-AKT, p-EGFR, p-STAT3, p-NF-κB, β-catenin, and estrogen receptor, along with their downstream targets c-Myc and cyclin-D1, thereby inhibiting breast cancer cell motility, proliferation, and energy metabolism. In an orthotopic mouse model of breast cancer, treatment with 1 effectively inhibited tumor growth and downregulated associated target genes in vivo. Compound 1 exerted potent anticancer activity against breast cancer (BC) cells in vitro and effectively inhibited tumor growth in an orthotopic mouse model. Overall, suppression of both EMT and reprogramming of cancer metabolism metabolic pathways by inactivating phosphoinositide 3-kinase (PI3K)/AKT and EGFR pathways suggested that 1 could be a potential therapeutic agent for BCs. Notably, 1 represents a promising therapeutic effect against hormone-dependent (ER-positive) BCs.