Tautomycin suppresses growth and neuroendocrine hormone markers in carcinoid cells through activation of the Raf-1 pathway

BACKGROUND: Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Raf-1 pathway activation has been shown to suppress hormone production in carcinoid cells. We investigated a novel treatment for carcinoid cell growth based on pharmacologic Raf-1 activation using the compound tautomycin (TTY). METHODS: Human carcinoid cells were treated with TTY for 48 hours. Western blot analysis was used to demonstrate Raf-1 pathway activation by phosphorylation of ERK1/2 and to determine the effect on NE tumor markers. Cellular growth was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. RESULTS: Treatment with TTY resulted in dose-dependent activation of the Raf-1 pathway. Furthermore, a significant decrease in NE tumor markers was seen. Importantly, TTY inhibited carcinoid cellular growth and induced the cell-cycle inhibitors p21 and p27. CONCLUSION: TTY activates the Raf-1 pathway, limits carcinoid cell growth, and suppresses NE market production in vitro. This new Compound warrants further investigation in animal models of carcinoid cancer. (C) 2009 Published by Elsevier Inc.