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

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.

• Authors: Ashley Kappes, Abram Vaccaro, Muthusamy Kunnimalaiyaan, Herbert Chen
• Journal: The Journal of surgical research (J Surg Res) Vol. 133 Issue 1 Pg. 42-5 (Jun 01 2006) ISSN: 0022-4804 [Print] United States
• PMID: 16603190 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Chromogranin A
• Chromogranins
• N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Benzamides (therapeutic use)
• Cell Proliferation (drug effects)
• Chromogranin A
• Chromogranins (metabolism)
• MAP Kinase Signaling System (physiology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• PC12 Cells
• Pheochromocytoma (drug therapy, metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Rats