Valproic acid activates Notch1 signaling and induces apoptosis in medullary thyroid cancer cells

Ann Surg. 2008 Jun;247(6):1036-40. doi: 10.1097/SLA.0b013e3181758d0e.


Objective: To examine the effects of valproic acid (VPA) on Notch1 expression and cancer cell proliferation in medullary thyroid cancer (MTC) cells.

Background: Other than surgery, there are no effective treatments for MTC, a neuroendocrine malignancy that frequently metastasizes. We have previously shown that over-expression of Notch1 in MTC cells inhibits cell growth and hormone production. VPA, a drug long used for the treatment of epilepsy, has recently been identified as a potential Notch1 activator. We hypothesized that VPA might activate Notch1 signaling in MTC cells, with antiproliferative effects.

Methods: Human MTC cells were treated with VPA (0-5 mM) and Western blotting was performed to measure levels of Notch1 pathway proteins and neuroendocrine tumor markers. After confirming that VPA is a Notch1 activator in MTC cells, we performed cell proliferation assay. Finally, to determine the mechanism of growth inhibition, we measured protein levels of various markers of apoptosis.

Results: Notch1 was absent in MTC cells at baseline. VPA treatment resulted in an increase in both full-length and active Notch1 protein. Notch1 activation with VPA suppressed 2 neuroendocrine tumor markers, ASCL1 and chromogranin A. Importantly, VPA inhibited the growth of MTC cells in a dose-dependent manner. Immunoblot analysis demonstrated caspase activation and poly(ADP-ribose) polymerase cleavage, indicating the induction of apoptosis.

Conclusions: VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis. As the safety of VPA in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC could be initiated in the near future.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Medullary / drug therapy*
  • Carcinoma, Medullary / metabolism
  • Carcinoma, Medullary / physiopathology
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Receptor, Notch1 / metabolism*
  • Signal Transduction
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / physiopathology
  • Tumor Cells, Cultured
  • Valproic Acid / pharmacology*


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Valproic Acid