Hesperetin, a potential therapy for carcinoid cancer

Am J Surg. 2011 Mar;201(3):329-32; discussion 333. doi: 10.1016/j.amjsurg.2010.08.018.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / blood
  • Blotting, Western
  • Carcinoid Tumor / drug therapy*
  • Carcinoid Tumor / genetics
  • Carcinoid Tumor / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hesperidin / pharmacology*
  • Humans
  • Polymerase Chain Reaction
  • Receptor, Notch1 / agonists*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Transcriptional Activation / drug effects*
  • Up-Regulation


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Hesperidin
  • hesperetin