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

Pinchot, Scott N.; Adler, Joel T.; Luo, Yinggang; Ju, Jianhua; Li, Wenli; Shen, Ben; Kunnimalaiyaan, Muthusamy; Chen, Herbert

doi:10.1016/j.amjsurg.2008.10.007

« Previous Next »The American Journal of Surgery
Volume 197, Issue 3 , Pages 313-319, March 2009

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

Scott N. Pinchot, M.D.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, WI, USA
Joel T. Adler, B.A.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, WI, USA
Yinggang Luo, Ph.D.
- Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
Jianhua Ju, Ph.D.
- Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
Wenli Li, Ph.D.
- Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
Ben Shen, Ph.D.
- Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
- University of Wisconsin National Cooperative, Drug Discovery Group, Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
Muthusamy Kunnimalaiyaan, Ph.D.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, WI, USA
Herbert Chen, M.D., F.A.C.S
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, WI, USA
- Corresponding author. Tel.: +01-608-263-1387; fax: +01-608-263-7652

Received 1 October 2008; received in revised form 31 October 2008

Abstract

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 marker production in vitro. This new compound warrants further investigation in animal models of carcinoid cancer.

Keywords: Carcinoid tumor, Extracellular-regulated kinase pathway, Ref 1, Targeted therapies, Tautomycin