Combination of sorafenib with CI-1040 or CCI-779 induces synergistic pro-apoptotic effects and overcomes sorafenib resistance. A, The sorafenib-resistant and parental cells were treated with combinations of sorafenib with CI-1040 and/or CCI-779 at indicated ratios for 48 hours. DMSO served as a control. Apoptosis induction was determined as described in Fig. 1B. *p< 0.05; **p< 0.01; ***p< 0.001; NS, no significance. B, Isobologram and combination index (CI) analyses were performed using CalcuSyn software (Biosoft). C, The modulation of correlative proteins was determined using immunoblot analysis after 24 hours of single-agent/combination treatments. Bim-EL, extra-long; L, long; and S, short.