Figure 4

Identification of tivantinib and ABT-199 as a synergistic drug combination in AML cells. (a) Results of tivantinib combination drug screen in HL60 cells using a customized library of 240 targeted agents. Replicate correlations of cell viability following treatment with individual library compounds (2.5 μM) (left) and compounds in combination with tivantinib (0.25 μM) (middle) are displayed. Fold change corresponds to the ratio of inhibition of cell viability achieved by a drug combination with tivantinib (0.25 μM) compared to individual single library compounds (2.5 μM). Drugs passing fold change >1.5 cutoff are highlighted in red. Navitoclax and ABT-199 are labeled. (b) Dose response curves for inhibition of viability of HL60 cells of tivantinib and its combination with either ABT-199 (left) or cytarabine (Ara-C; right). Synergy is assessed by the Bliss model of independence (histograms in insets). Displayed in the histograms are the experimentally determined differences for each drug combination from the calculated Bliss additivity on a scale of +20% to −20% cell viability in order of increasing tivantinib concentrations. Vertical lines indicate increments of 10% cell viability. Bars pointing up from the blue baseline (additivity) indicate synergy, bars pointing down indicate antagonism. (c) Effects of tivantinib and ABT-199 combination (in μM) on PARP-1 and caspase 3 cleavage as well as pSer10 histone H3 levels after 24 h treatment. (d) Effects of tivantinib and ABT-199 combination on β-catenin stabilization and pGSK3α/β Y279/216 levels. (e) Effects of tivantinib and ABT-199 combination on MCL-1, BCL-XL, and Bak. V = vehicle (DMSO). Tivantinib, ABT-199, and BIO concentrations are in μM. NaCl and LiCl concentrations are in mM.