Faculty Collaboration Database

Identification of a novel Raf-1 pathway activator that inhibits gastrointestinal carcinoid cell growth. Mol Cancer Ther 2010 Feb;9(2):429-37

Date

01/28/2010

Pubmed ID

20103603

Pubmed Central ID

PMC2820603

DOI

10.1158/1535-7163.MCT-09-0718

Scopus ID

2-s2.0-76649101419 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration-approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G(2)-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal-regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation.

Author List

Cook MR, Pinchot SN, Jaskula-Sztul R, Luo J, Kunnimalaiyaan M, Chen H

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Chromogranin A
Crotonates
Enzyme Activation
Gastrointestinal Neoplasms
Humans
Hydroxybutyrates
Isoxazoles
Mice
Neoplasm Transplantation
Nitriles
Proto-Oncogene Proteins c-raf
Serotonin
Toluidines