Assessment of Three-Drug Combination Pharmacodynamic Interactions in Pancreatic Cancer Cells

The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term. TFP fully inhibited growth of cells (I_max = 1) with an IC₅₀ = 9887 nM. Near-maximum inhibition was achieved for GEM (I_max = 0.825) and PTX (I_max= 0.844) with an IC₅₀ = 17.4 nM for GEM and IC₅₀ = 7.08 nM for PTX. Estimates of an interaction term ψ revealed that the combination of TFP-GEM was apparently synergistic; close to additivity, the combination TFP-PTX was antagonistic. The interaction of GEM-PTX was additive, and TFP-GEM-PTX was synergistic but close to additive. The combination of TFP IC₆₀-GEM IC₆₀-PTX IC₆₀ seemed optimal in producing inhibition of PANC-1 cells with an inhibitory effect of 82.1-90.2%. The addition of ψ terms to traditional interaction equations allows assessment of the degree of perturbation of assumed mechanisms.