Am J Transl Res 1(2):178-183;2009

Original Article
Sodium butyrate activates Notch1 signaling, reduces tumor markers,
and induces cell cycle arrest and apoptosis in pheochromocytoma

Max A. Cayo, Ashley K. Cayo, Sarah M. Jarjour, Herbert Chen

Departments of Epidemiology and Radiation Oncology, The University of Texas M. D. Anderson Cancer Center,
1515 Holcombe Blvd, Houston, TX 77030, USA

Received January 26, 2009; accepted January, 2009; available online January, 2009

Abstract: Background: Pheochromocytoma is a neuroendocrine (NE) tumor of the adrenal medulla for which
surgical resection is the only therapy.  However, 10-46% of tumors are metastatic or have malignant features, and
are often inoperable. Our lab has demonstrated the importance of the Notch1 signaling pathway in NE neoplasia,
indicating that this pathway could be a target for emergent treatments in pheochromocytoma. It has recently
become clear that histone deacetylase (HDAC) inhibitors influence Notch1 signaling. We hypothesized that the
HDAC inhibitor Sodium Butyrate (NaB) might activate Notch1 in pheochromocytoma resulting in altered tumor cell
proliferation. Methods: Pheochromocytoma (PC-12) cells were treated with increasing concentrations of NaB.  
MTT cellular proliferation assay was used to determine the effect of NaB on PC-12 cell growth. Expression of
Notch1, NE markers, and cell cycle proteins was studied using Western analysis. Results: Untreated PC-12 cells
lack Notch1 activity. Treatment with NaB led to a dose-dependent induction of Notch1 signaling, reduction of NE
markers ASCL1 and CgA, and a significant reduction in cellular proliferation. Levels of expression of cyclin D1,
p21, cleaved PARP, and cleaved caspase 3 proteins indicated the presence of cell cycle arrest and apoptosis
following NaB treatment. Conclusion: NaB activated Notch1 signaling, inhibited cellular proliferation, reduced NE
markers, and induced cell cycle arrest and apoptosis in pheochromocytoma cells. This data indicates that
activation of Notch1 signaling using NaB is a pr¬omising potential therapy or palliative measure for
pheochromocytoma that warrants further investigation.(AJTR901009).

Key Words: Sodium butyrate, pheochromocytoma, PC-12, Notch1, neuroendocrine, HDAC inhibitor

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Herbert Chen, M.D., FACS
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