Interactions of everolimus and sorafenib in pancreatic cancer cells

Dipti K. Pawaskar, Robert M. Straubinger, Gerald J. Fetterly, Wen Wee Ma, William J. Jusko

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)78-84
Number of pages7
JournalAAPS Journal
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Cell Line
Inhibitory Concentration 50
Growth
Drug Interactions
Pharmaceutical Preparations
Platelet-Derived Growth Factor
Drug Combinations
Sirolimus
Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Phosphotransferases
Cell Proliferation
sorafenib
Everolimus
Neoplasms
In Vitro Techniques
Therapeutics

Keywords

  • everolimus
  • MiaPaCa-2
  • modeling interactions
  • Panc-1
  • sorafenib

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Pawaskar, D. K., Straubinger, R. M., Fetterly, G. J., Ma, W. W., & Jusko, W. J. (2013). Interactions of everolimus and sorafenib in pancreatic cancer cells. AAPS Journal, 15(1), 78-84. https://doi.org/10.1208/s12248-012-9417-7

Interactions of everolimus and sorafenib in pancreatic cancer cells. / Pawaskar, Dipti K.; Straubinger, Robert M.; Fetterly, Gerald J.; Ma, Wen Wee; Jusko, William J.

In: AAPS Journal, Vol. 15, No. 1, 01.01.2013, p. 78-84.

Research output: Contribution to journalArticle

Pawaskar, DK, Straubinger, RM, Fetterly, GJ, Ma, WW & Jusko, WJ 2013, 'Interactions of everolimus and sorafenib in pancreatic cancer cells', AAPS Journal, vol. 15, no. 1, pp. 78-84. https://doi.org/10.1208/s12248-012-9417-7
Pawaskar, Dipti K. ; Straubinger, Robert M. ; Fetterly, Gerald J. ; Ma, Wen Wee ; Jusko, William J. / Interactions of everolimus and sorafenib in pancreatic cancer cells. In: AAPS Journal. 2013 ; Vol. 15, No. 1. pp. 78-84.
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