Faculty Collaboration Database

ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells. J Surg Res 2006 Jun 01;133(1):42-5

Date

04/11/2006

Pubmed ID

16603190

DOI

10.1016/j.jss.2006.02.002

Scopus ID

2-s2.0-33646254621 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

BACKGROUND: Surgical resection is the only curative treatment for patients with pheochromocytomas, paragangliomas, and other catecholamine-producing tumors. Patients with metastatic disease can often have significant symptoms associated with catecholamine excess. Activation of the Raf-1/MEK/ERK1/2 pathway has been shown to inhibit growth and hormone production for neuroendocrine tumors (NE) such as carcinoid and medullary thyroid cancer. However, the role of the Raf-1/MEK/ERK1/2 signaling pathway in pheochromocytomas is unknown.

MATERIALS AND METHODS: Pheochromocytoma PC-12 cells were treated with varying concentrations of ZM336372, a pharmacologic Raf-1 activating drug. Levels of phosphorylated ERK1/2 and the NE marker Chromogranin A (CgA) were determined by Western blot. Cellular growth was measured by MTT cell-proliferation assay.

RESULTS: At baseline, PC-12 cells had very little phosphorylated ERK1/2, similar to other NE tumors. Treatment of PC-12 cells with increasing dosages of ZM336372 resulted in increased phosphorylated ERK1/2. Importantly, ZM336372 inhibited pheochromocytoma cellular proliferation. Furthermore, Raf-1 pathway activation by ZM336372 was associated with suppression of NE marker, CgA, by the tumor cells.

CONCLUSIONS: These data suggest that Raf-1/MEK/ERK1/2 pathway activation may be a novel strategy to treat pheochromocytoma and other catecholamine-producing tumors. In pheochromocytoma cells, ZM336372 blocks cellular proliferation and suppresses NE vasoactive peptide production. Thus, ZM336372 may be used for both therapeutic and palliative treatment for patients with pheochromocytomas.

Author List

Kappes A, Vaccaro A, Kunnimalaiyaan M, Chen H

MESH terms used to index this publication - Major topics in bold

Animals
Benzamides
Cell Proliferation
Chromogranin A
Chromogranins
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
PC12 Cells
Pheochromocytoma
Proto-Oncogene Proteins c-raf
Rats