Abstract
BACKGROUND: The investigators' laboratory has demonstrated that the Notch1 signaling pathway acts as a tumor suppressor in carcinoid tumors. The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor. METHODS: A high-throughput drug screen revealed hesperetin as a Notch1 activator. Human gastrointestinal carcinoid (BON) cell growth after hesperetin treatment was assessed with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Western blots were used to measure neuroendocrine tumor markers, human achaete-scute complex-like 1, and chromogranin A. Notch1 expression was measured using western blot analysis and real-time polymerase chain reaction. RESULTS: Hesperetin induced cell death in a dose-dependent manner and reduced achaete-scute complex-like 1 and chromogranin A expression, with a concomitant rise in Notch1 levels. It also induced Notch1 messenger ribonucleic acid, indicating regulation at the transcriptional level. CONCLUSION: Hesperetin induces Notch1 expression in carcinoid cells, subsequently suppressing tumor cell proliferation and bioactive hormone production. This provides evidence for further study into hesperetin as a potential treatment for carcinoid cancer.