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BioMed Research International
Volume 2014, Article ID 568693, 13 pages
http://dx.doi.org/10.1155/2014/568693
Research Article

Biological and Molecular Effects of Small Molecule Kinase Inhibitors on Low-Passage Human Colorectal Cancer Cell Lines

1Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany
2Oscar Langendorff Institute of Physiology, Rostock University Medical Center, Gertrudenstraße 9, 18057 Rostock, Germany
3Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
4Institute of Pathology, Rostock University Medical Center, Strempelstraße 14, 18055 Rostock, Germany

Received 27 June 2014; Accepted 26 August 2014; Published 17 September 2014

Academic Editor: Raj Kumar

Copyright © 2014 Falko Lange et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC) patients, to evaluate effects of the small molecule kinase inhibitors (SMI) vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K) inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models.