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Acetogenins from Annona coriacea Target TNFR1-Mediated Cell Death in Head and Neck Cancer
Gilvânia Aparecida Rabelo Cordeiro1, Ana Gabriela Silva Oliveira1,2, João Gabriel Morais Junqueira3
1Universidade Federal de Sao Joao Del-Rei - Campus Centro-Oeste Dona Lindu, Divinópolis, Minas Gerais 35501-296, Brazil.
Abstract:
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.
Insights
Acetogenins from Annona coriacea show selective antitumor effects against head and neck cancer (HNC) cells. These natural compounds induce cell death and inhibit tumor growth, offering a promising new avenue for HNC treatment.
Area of Science:
- Pharmacology
- Natural Products Chemistry
- Oncology
Background:
- Head and neck cancer (HNC) presents significant therapeutic challenges due to its heterogeneity and resistance to current treatments.
- There is a critical need for novel, less toxic therapeutic strategies for HNC.
- Annona coriacea, a plant from the Brazilian Cerrado, is a known source of bioactive acetogenins.
Purpose of the Study:
- To evaluate the antitumor potential of acetogenin-enriched fractions from Annona coriacea against head and neck cancer.
- To investigate the mechanisms of action, including cell death pathways and anti-angiogenic effects.
- To assess the safety and efficacy of these fractions in preclinical models.
Main Methods:
- In vitro cytotoxicity assays using HNC cell lines (FaDu, HN13) and non-tumor cells.
- Mechanistic studies involving apoptosis and necroptosis pathway analysis.
- Molecular docking simulations to predict interactions with TNFR1.
- In vivo studies using the CAM model to assess tumor growth and angiogenesis.
- HET-CAM assay to evaluate vascular irritation.
Main Results:
- Annona coriacea fractions demonstrated significant cytotoxic activity against HNC cells with low toxicity to normal cells.
- Cell death mechanisms involved mitochondrial-associated apoptosis-like and necroptosis pathways.
- Molecular docking suggested acetogenins may interact with tumor necrosis factor receptor 1 (TNFR1).
- The ACL3 fraction reduced tumor growth and angiogenesis in vivo without causing vascular irritation.
Conclusions:
- Acetogenin-rich fractions from Annona coriacea possess selective antitumor properties against HNC.
- These fractions induce programmed cell death and inhibit tumor angiogenesis.
- Annona coriacea acetogenins represent promising candidates for further preclinical development in head and neck cancer therapy.
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