Synergistic effect of pasireotide and teriflunomide in carcinoids in vitro. Neuroendocrinology 2013;97(2):183-92
Date
09/12/2012Pubmed ID
22965070Pubmed Central ID
PMC3546174DOI
10.1159/000341810Scopus ID
2-s2.0-84876297619 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
BACKGROUND/AIM: Somatostatin (SST) analogs are mainstay for controlling tumor proliferation and hormone secretion in carcinoid patients. Recent data suggest that extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation may potentiate the anti-tumor effects of SST analogs in carcinoids. Additionally, ERK1/2 phosphorylating agents have been shown to suppress biomarker expression in carcinoids. Thus, Raf-1/MEK/ERK1/2 pathway activating drugs may be synergistic with SST analogs such as pasireotide (SOM230), which may be more effective than others in its class given its elevated receptor affinity and broader binding spectrum. Here, we investigate the effects of SOM230 in combination with teriflunomide (TFN), a Raf-1 activator, in a human carcinoid cell line.
METHODS: Human pancreatic carcinoid cells (BON) were incubated in TFN, SOM230 or a combination. Cell proliferation was measured using a rapid colorimetric assay. Western analysis was performed to analyze expression levels of achaete-scute complex-like 1 (ASCL1), chromogranin A (CgA), phosphorylated and total ERK1/2, and markers for apoptosis.
RESULTS: Combination treatment with SOM230 and TFN reduced cell growth beyond the additive effect of either drug alone. Combination indices (CI) fell below 1, thus quantifiably verifying synergy between both drugs as per the Chou-Talalay CI scale. Combined treatment also reduced ASCL1 and CgA expression beyond the additive effect of either drug alone. Furthermore, it increased levels of phosphorylated ERK1/2, cleaved poly(ADP)-ribose polymerase and caspase-3, and reduced levels of anti-apoptotic biomarkers. Elevated phosphorylated ERK1/2 expression following combination therapy may underlie the synergistic interaction between the two drugs.
CONCLUSION: Since efficacy is achieved at lower doses, combination therapy may palliate symptoms at low toxicity levels. Because each drug has already been evaluated in clinical trials, combinatorial drug trials are warranted.
Author List
Somnay Y, Chen H, Kunnimalaiyaan MMESH terms used to index this publication - Major topics in bold
Antineoplastic AgentsApoptosis
Basic Helix-Loop-Helix Transcription Factors
Carcinoma, Neuroendocrine
Cell Line, Tumor
Cell Proliferation
Chromogranin A
Crotonates
Dose-Response Relationship, Drug
Drug Synergism
Gastrointestinal Neoplasms
Humans
Hydroxybutyrates
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Nitriles
Pancreatic Neoplasms
Somatostatin
Toluidines
