Interactions of Everolimus and Sorafenib in Pancreatic Cancer Cells
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Everolimus targets the mammalian target of rapamycin, a kinase that promotes cell growth and proliferation in pancreatic cancer. Sorafenib inhibits the Raf-mitogen-activated protein kinase, vascular endothelial growth factor, and platelet-derived growth factor pathways, thus inhibiting cell growth and angiogenesis. Combinations of these two agents are under evaluation for therapy of several cancers. This study examined the effects of everolimus and sorafenib on proliferation of the pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Cell growth inhibition was evaluated in vitro for a range of concentrations of the drugs alone and in combination. Maximum inhibition capacity (I max) and potency (IC50) were determined. The data were analyzed to characterize drug interactions using two mathematical analysis techniques. The Ariens noncompetitive interaction model and Earp model were modified to accommodate alterations in the inhibition parameters of one drug in the presence of another. Sorafenib alone inhibited growth of both cell lines completely (I max = 1), with an IC50 of 5–8 μM. Maximal inhibition by everolimus alone was only 40% (I max = 0.4) in both cell lines, with an IC50 of 5 nM. Slight antagonistic interaction occurred between the drugs; both analytic methods estimated the interaction term Ψ as greater than 1 for both cell lines. The in vitro data for two pancreatic cancer cell lines suggest that a combination of these two drugs would be no more efficacious than the individual drugs alone, consistent with the drug interaction analysis that indicated slight antagonism for growth inhibition.
KEY WORDSeverolimus MiaPaCa-2 modeling interactions Panc-1 sorafenib
This work was supported in part by NIH grant GM 57980 and by the pilot studies program of the University at Buffalo Clinical and Translational Research Center, and the Buffalo Translational Consortium. The authors thank Ninfa Straubinger, Xu Zhu, and Yang Qu for their assistance with cell culture.
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