ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells. Mol Cancer Ther 2005 Jun;4(6):910-7
Date
06/16/2005Pubmed ID
15956248DOI
10.1158/1535-7163.MCT-04-0334Scopus ID
2-s2.0-21344443715 (requires institutional sign-in at Scopus site) 66 CitationsAbstract
Neuroendocrine tumors, such as carcinoids, are highly metastatic neoplasms that secrete bioactive hormones resulting in carcinoid syndrome. Few curative treatments exist outside of surgical resection. We have previously shown that activation of the Raf-1 signaling pathway can suppress hormone production in carcinoid tumor cells. In this study, we investigated a novel treatment for carcinoid tumor cell growth based on pharmacologic Raf-1 activation using the compound ZM336372. Treatment of carcinoid tumor cells with ZM336372 resulted in progressive phosphorylation of Raf-1, mitogen-activated protein kinase 1/2, and extracellular signal-regulated kinase 1/2. Importantly, exposure to ZM336372 resulted in a significant reduction of bioactive hormone levels as well as the transcription factor, human achaete-scute homologue-1 in carcinoid tumor cells. Furthermore, treatment with ZM336372 led to a marked suppression of cellular proliferation and induction of the cell cycle inhibitors p21 and p18. In summary, ZM336372 targets both proliferation and palliative issues associated with carcinoid tumor cells, and therefore, warrants further investigation as a possible therapeutic strategy for patients with carcinoid tumors.
Author List
Van Gompel JJ, Kunnimalaiyaan M, Holen K, Chen HMESH terms used to index this publication - Major topics in bold
BenzamidesCarcinoid Tumor
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Chromogranin A
Chromogranins
DNA-Binding Proteins
Dose-Response Relationship, Drug
Enzyme Activation
Histone-Lysine N-Methyltransferase
Hormones
Humans
MAP Kinase Signaling System
Molecular Structure
Proto-Oncogene Proteins c-raf
Transcription Factors
