| BMS-754807, a Small Molecule Inhibitor of Insulin-like Growth Factor-1 Receptor / Insulin Receptor, Enhances Gemcitabine Response in Pancreatic Cancer. | |
| | |
MedLine Citation:
|
PMID: 23047891 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor (IGF) signaling proteins are frequently over-expressed in PDAC. The therapeutic potential of BMS-754807, a small molecule inhibitor of IGF-type 1 receptor (IGF-1R) and insulin receptor (IR), and gemcitabine was evaluated in experimental PDAC. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in murine xenografts. PDAC cells expressed phospho-IGF-1R protein. BMS-754807 and gemcitabine inhibited cell proliferation of PDAC cells; the combination of BMS-754807 with gemcitabine had additive effects. Addition of BMS-754807 decreased gemcitabine IC50 from 9.7 μM to 75 nM for AsPC-1, from 3 μM to 70 nM for Panc-1, from 72 nM to 16 nM for MIA PaCa-2, and from 28 nM to 16 nM for BxPC-3 cells. BMS-754807 caused a decrease in phospho-IGF-1R and phospho-AKT proteins in AsPC-1 and Panc-1 cells. BMS-754807 and gemcitabine caused an increase in PARP-1 and caspase-3 cleavage. Net tumor growth inhibition in BMS-754807, gemcitabine and BMS-754807+gemcitabine groups was 59, 35 and 94 percent compared to controls. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BMS-754807 also caused a decrease in phospho-IGF-1R and phospho-AKT in tumor tissue lysates. Median animal survival (controls: 21 days) with BMS-754807 was 27 days (p=0.03), with gemcitabine 28 days (p=0.05) and in the BMS-754807+gemcitabine combination group 41 days (p=0.007). The strong antitumor activity of BMS-754807 in experimental PDAC supports the potential of BMS-754807-induced mechanisms for clinical PDAC therapy. |
| | |
Authors:
|
Niranjan Awasthi; Changhua Zhang; Winston Ruan; Margaret A Schwarz; Roderich E Schwarz |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2012-10-9 |
Journal Detail:
|
Title: Molecular cancer therapeutics Volume: - ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2012 Oct |
Date Detail:
|
Created Date: 2012-10-10 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
|
1Surgery, UTSW. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Tobacco control advocacy in the age of social media: using Facebook, Twitter and Change.
Next Document: Feedback-Controlled Parallel Point Process Filter for Estimation of Goal-Directed Movements from Neu...