Figure 1.

APR-246 synergistically enhanced the cytotoxic effect of CDDP in a p53-mutant background under both normoxic and hypoxic conditions. (A1–A3) To determine possible synergism, cells were simultaneously treated for 72 h with a CDDP (cisplatin) dose range of 0, 0.5, 1, 2, 5, 10 μM (A549^wt) or 0, 0.5, 1, 2, 5, 10, 20 μM (NCI-H2228^Q331* and NCI-H1975^R273H) and fixed concentrations of APR-246, based on the drug sensitivity of each cell line (Table S1). Cell confluence was determined using the SRB-assay and IC₅₀ values were calculated using WinNonlin. IC₅₀ values for CDDP monotherapy or combined with APR-246 are presented as mean ± SD of at least 3 independent experiments. (B1–B3) The corresponding combination index was calculated using the ‘Additive Model’ for each concentration presented, in correlation with the affected fraction (FA) of the cells. CI = 1.0 ± 0.2 indicates an additive effect, <0.8 indicates moderate synergism, <0.5 strong synergism, and <0.2 very strong synergism (** p < 0.05 compared to CDDP monotherapy). The corresponding values are presented in Table S1. Nx: normoxia; Hx: hypoxia.