Valproic Acid Activates Notch1 Signaling and Induces Apoptosis in Medullary Thyroid Cancer Cells

Abstract

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.

Valproic Acid Induces Notch1 Signaling in Small Cell Lung Cancer Cells

“…We subsequently treated human carcinoid tumor and medullary thyroid cancer cells with VPA, and found that Notch1 was also activated in these cell lines, with a resultant decrease in cell proliferation and NET marker expression (13,20). VPA is an attractive potential anticancer drug for neuroendocrine tumors because it is approved by the U.S. Food and Drug Administration (FDA) and has a favorable toxicity profile compared to most cytotoxic chemotherapeutic agents.…”

“…VPA has been shown to inhibit growth in several tumor cell lines (13,19,20,24). To date, the effect of VPA treatment on SCLC cell growth has not been characterized.…”

“…Given that VPA has been reported to activate Notch1 signaling in several NET cell lines (13,20), we were interested in determining the ability of VPA to activate Notch1 signaling in SCLC cells. To assess this, we measured protein levels of full-length Notch1 and NICD after treatment with various concentrations of VPA.…”

“…We have previously shown that Notch1 signaling is minimal or absent at baseline in several NET cell lines, and that expression of exogenous Notch1 via an inducible construct inhibits NET cell growth (6,14). Additionally, VPA has been reported to activate Notch1 signaling in neuroblastoma, carcinoid, and medullary thyroid cancer cells (13,19,20). We hypothesized, then, that VPA may also activate Notch1 signaling in SCLC cells with subsequent anti-tumor effects.…”

Histone Deacetylase Inhibitors: A Novel Therapeutic Weapon Αgainst Medullary Thyroid Cancer?

“…However, it is responsible for approximately 14% of all thyroid carcinoma-related deaths (5). Roughly half of all MTCs metastasize; lymph node metastases are frequent, but MTCs can also easily invade the jugular vein or the trachea and give metastases to more distant organs, such as the brain, the lungs, the liver and the bones (7)(8)(9). Additional symptoms of advanced and metastatic MTCs are airway obstruction and abdominal pain (3).…”