ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells.
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.


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.
Kappes
Ashley
A
Endocrine Surgery Research Laboratories, Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, Madison, WI 53792, USA.
Vaccaro
Abram
A
Kunnimalaiyaan
Muthusamy
M
Chen
Herbert
H
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats
D001549:Benzamides; D053379:Chromogranin A; D002864:Chromogranins; C121825:N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3