Acetogenins from Annona coriacea Target TNFR1-Mediated Cell Death in Head and Neck Cancer.

Head and neck cancer (HNC) remains a major therapeutic challenge due to its biological heterogeneity and limited response to current treatments, highlighting the need for more effective and less toxic therapeutic strategies. Annona coriacea Mart., a plant native to the Brazilian Cerrado, is a source of bioactive acetogenins. In this study, we evaluated the antitumor effects of acetogenin-enriched fractions from A. coriacea using in vitro and in vivo models of HNC. The fractions exhibited cytotoxic activity against FaDu and HN13 cells, with IC50 values ranging from 2.42 to 8.25 μg/mL and from 1.61 to 12.57 μg/mL, respectively, while showing lower toxicity toward nontumor cells. Mechanistic analyses suggested the involvement of mitochondrial-associated apoptotic-like and necroptotic cell death processes. Molecular docking analyses indicated a possible modulatory interaction between acetogenins and tumor necrosis factor receptor 1 (TNFR1). In vivo, the selected fraction ACL3 reduced tumor growth and angiogenesis in the CAM model without inducing vascular irritation, as confirmed by the HET-CAM assay. Together, these findings demonstrate that A. coriacea acetogenin-rich fractions exhibit selective antitumor activity, induce mitochondrial-mediated and necroptosis-related cell death mechanisms, and inhibit tumor-associated angiogenesis, supporting their potential as promising candidates for further preclinical investigation in HNC.