Article
Synergistic antiproliferative action of HER1/EGFR, RAC1 and SMO inhibition in erlotinib-sensitive human glioblastoma multiforme cells
Search Medline for
Authors
Published: | April 28, 2011 |
---|
Outline
Text
Objective: Several candidate genes for resistance of human glioblastoma multiforme cell lines towards erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, have recently been proposed. In the current study, we sought to examine the antiproliferative effect of additionally inhibiting two of these candidate resistance gene products, i.e., RAC1 and SMO, on glioblastoma cell lines with erlotinib-sensitive, somewhat responsive and resistant phenotypes.
Methods: Glioblastoma cell lines selected to represent the erlotinib-sensitive, somewhat responsive and resistant phenotypes, respectively, were grown in 96-well plates and exposed to erlotinib, HhAntag (an inhibitor of SMO) and NSC23766 (an inhibitor of RAC1) in various combinations and concentrations. After 10 days of continuous exposure, inhibitory concentration 50 (IC50) values were determined using a cytotoxicity assay and drug combination effects (i.e., synergism, additivity, or antagonism) were calculated using the Bliss equation.
Results: Antiproliferative synergism among erlotinib, HhAntag and NSC23766 was observed for the combination of erlotinib with either HhAntag or NSC23766 as well as for the combination of all three agents in both the erlotinb-sensitive and – to a lesser extent – in the somewhat responsive cell line. It was significant that combinations of erlotinib plus HhAntag or NSC23766 or both acted antagonistically in the erlotinib-resistant cell line.
Conclusions: In a system of human glioblastoma cell lines with sensitive, somewhat responsive and resistant phenotypes, this study is the first to identify erlotinib combined with inhibitors of RAC1 and SMO to synergistically inhibit proliferation in a priori erlotinib-sensitive and somewhat responsive cell lines. These results strengthen the role of multi-targeting approaches in the development of more effective therapies for glioblastoma. The antagonistic action of erlotinib, HhAntag and NSC23766 in the erlotinib-resistant cell line is counterintuitive and requires further clarification. Taken together, combinations of targeted agents may act differentially depending on the glioblastoma cell phenotype.