Figure 5
BRB potentiates the cytotoxic activity of Venetoclax on CLL cells. (A) BRB and/or ABT-199 cytotoxicity (42 h) on activated CLL cultures of three CLL patients. Cells displayed increased sensitivity to drug combinations, if compared to either drug alone, as demonstrated by the statistically significant difference evaluated by a two- sided Wilcoxon signed rank test. *P ≤ 0.05;** P ≤ 0.01. (B) Combination index (CI) curves and isobolograms computed by the Chou–Talalay model (CalcuSyn software, Biosoft, Cambridge) from dose–effect profiles of activated leukemic cells treated for 42 h with increasing concentrations of BRB (1–10 μM), ABT-199 (10–100 nM) or BRB/ABT-199 at constant ratios. CI measures drug interaction effects: additive: 0.9 ≤ CI ≤ 1.1, synergism: CI < 0.9 and antagonism: CI > 1.1. Isobolograms: the x- and y-axes represent the doses of ABT-199 and BRB, respectively. The intercepts of the three lines on x- and y-axes represent the dose of the same efficacy when the two drugs are used alone, which are here expressed as half, 75% and 90% effective dose (i.e. ED50, ED75 and ED90). Additive: point on the line, synergism: point below the line, antagonism: point above the line. (C) CI values at the ‘fractional effect levels’ LC75 and LC90 (concentration lethal to 75% and 90% of CLL cells, respectively). Dotted lines indicate CI = 0.9 and CI = 1.1. (D) Dose Reduction Index (DRI) values at LC75 and LC90 computed for samples of three CLL patients.
