Abstract 5125: Muscadine grape extract inhibits breast cancer brain metastatic cells by multiple mechanisms

Abstract

Abstract Tumor metastasis to the brain is a common complication of cancer, affecting 500,000 patients each year. Due to poor penetration of most chemotherapeutics into the brain, brain metastasis may occur even while systemic disease in under control. Despite aggressive treatments including radiation therapy, survival at 12 months following diagnosis is only 20%, underscoring the need for better means to prevent and/or treat brain metastases. Natural products have historically been a very successful source of new drugs. We are investigating the anti-cancer potential of a proprietary muscadine grape extract (MGE; from Piedmont Research & Development Corp.) on breast cancer cell lines that are metastatic to the brain. In a colony formation assay, MGE (10 μg/mL) decreased clonogenic survival of 4T1.luc2.Br5 cells by 50% (n=3, p<0.0001). The Eo771.luc.Br5 cells were more sensitive to MGE, showing 33% inhibition at 5 μg/mL (n=3, p<0.001) and 91% inhibition at 7.5 μg/mL (n=3, p<0.0001). We also assessed response to the combined treatment of MGE and ionizing radiation (IR). While MGE did not sensitize cells to IR, combined administration of MGE and IR resulted in decreased clonogenic survival compared to either modality alone for both cell lines (n=3-4 experiments, p<0.01), suggesting an additive effect. Mechanistically, acute exposure (24 h) to 10 μg/mL MGE induced apoptosis in 4T1.luc2.Br5 cells as evidenced by PARP cleavage and detection of activated cleaved caspase 3. Further, ERK1/2 activation was decreased 68% at this time point (n=3, p<0.05). In contrast, although Eo771.luc.Br5 cells are more sensitive to clonogenic inhibition, no PARP cleavage, caspase 3 cleavage, or ERK1/2 inhibition was observed. Analysis of cyclin D1, a major regulator of cell cycle progression, identified >80% decrease following MGE treatment (24 h, 10 μg/mL) in both cell lines. Together these data suggest that MGE inhibits breast cancer brain metastatic cell proliferation by multiple mechanisms, including inhibition of clonogenic growth through induction of apoptosis and/or decreased cell cycle progression, suggesting that MGE may have utility in the treatment of breast cancer brain metastasis. Citation Format: Wenhong Chen, Patricia Gallagher, Ann Tallant, Linda J. Metheny-Barlow. Muscadine grape extract inhibits breast cancer brain metastatic cells by multiple mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5125. doi:10.1158/1538-7445.AM2017-5125