ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells.
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.
Van Gompel
Jamie J
JJ
Department of Surgery, University of Wisconsin Medical School, Madison, 53792, USA.
Kunnimalaiyaan
Muthusamy
M
Holen
Kyle
K
Chen
Herbert
H
D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015394:Molecular Structure; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics
D001549:Benzamides; D053379:Chromogranin A; D002864:Chromogranins; D004268:DNA-Binding Proteins; D006728:Hormones; C121825:N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide; D014157:Transcription Factors; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase; D019908:Proto-Oncogene Proteins c-raf