%0 Journal Article
%T Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells
%A Eva Juengel
%A Johanna Engler
%A Iyad Natsheh
%A Jon Jones
%A Ausra Mickuckyte
%A Lukasz Hudak
%A Dietger Jonas
%A Roman A Blaheta
%J BMC Cancer
%D 2009
%I BioMed Central
%R 10.1186/1471-2407-9-161
%X RCC cell lines Caki-1, KTC-26 or A498 were treated with various concentrations of RAD001 or AEE788 and tumor cell proliferation, tumor cell adhesion to vascular endothelial cells or to immobilized extracellular matrix proteins (laminin, collagen, fibronectin) evaluated. The anti-tumoral potential of RAD001 combined with AEE788 was also investigated. Both, asynchronous and synchronized cell cultures were used to subsequently analyze drug induced cell cycle manipulation. Analysis of cell cycle regulating proteins was done by western blotting.RAD001 or AEE788 reduced adhesion of RCC cell lines to vascular endothelium and diminished RCC cell binding to immobilized laminin or collagen. Both drugs blocked RCC cell growth, impaired cell cycle progression and altered the expression level of the cell cycle regulating proteins cdk2, cdk4, cyclin D1, cyclin E and p27. The combination of AEE788 and RAD001 resulted in more pronounced RCC growth inhibition, greater rates of G0/G1 cells and lower rates of S-phase cells than either agent alone. Cell cycle proteins were much more strongly altered when both drugs were used in combination than with single drug application. The synergistic effects were observed in an asynchronous cell culture model, but were more pronounced in synchronous RCC cell cultures.Potent anti-tumoral activitites of the multikinase inhibitors AEE788 or RAD001 have been demonstrated. Most importantly, the simultaneous use of both AEE788 and RAD001 offered a distinct combinatorial benefit and thus may provide a therapeutic advantage over either agent employed as a monotherapy for RCC treatment.Renal cell carcinoma (RCC) has an extremely poor prognosis with a third of patients presenting with metastatic disease at primary diagnosis and approximately 40% experiencing tumor recurrence after surgical treatment for localized disease. Treatment regimens for metastatic disease included surgical tumor size reduction, followed by immunotherapy. However, the response rate
%U http://www.biomedcentral.com/1471-2407/9/161