c-Abl/Arg inhibitors reverse doxorubicin resistance.

<p>(<b>A</b>) 435s/M14 melanoma and (<b>B</b>) BT-549 breast cancer cells were treated with doxorubicin/imatinib (72 h), and viability assessed by CellTiter-Glo. Mean±SEM for 3 independent experiments (left). Representative dose response curve (right). (<b>C,F</b>) Graphical representation of combination indices obtained with CalcuSyn software using dose response curves for each drug alone and in combination. >1-antagonism; = 1-additive; <1-synergism. Graphs are representative of 3 independent experiments. (<b>D</b>) Cells stably expressing imatinib-resistant mutant Arg (ArgT) were transiently transfected with imatinib-resistant c-Abl (c-AblT), treated with doxorubicin/imatinib (48 h), and viability assessed. Representative experiment (left). Mean±SEM of 3 independent experiments: imatinib alone (right, top) and imatinib+doxorubicin (right, bottom). (<b>E,F</b>) Parental (E) and acquired doxorubicin-resistant (F) cells were drug-treated (72 h), and viability assessed. Experiments were performed ≥3 times, and representative dose response curves are shown. Mean±SEM for 3 independent experiments is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055509#pone.0055509.s003" target="_blank">Figure S3B</a>. For all subfigures, some error bars are too small to visualize. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 (see methods).