NHE1 inhibition resulted in sorafenib sensitivity induction. (A) TESC knockdown significantly potentiated the cytotoxic effect of sorafenib in (i) MOLM-13 and (ii) MV4-11. (B) HMA and sorafenib synergistically inhibited the growth of (i) MOLM-13 and (ii) MV4-11. (C) Combination of HMA and sorafenib also induced more apoptosis in (i) MOLM-13 and (ii) MV4-11 compared with single agent and vehicle control. The concentrations of sorafenib and HMA used in MOLM-13 (Bi and Ci) were 1 nM and 10 μM and in MV4-11 (Bii and Cii) were 1 nM and 1 μM. (Di) Effects of HMA and sorafenib-mediated percentage growth inhibition in MOLM-13. Each number represented the mean of triplicate experiments. (ii) Difference in percentage growth inhibition between combination treatment and either sorafenib or HMA alone, whichever had a stronger effect. HSA, highest single agent. (iii) Difference in percentage growth inhibition between combination treatment and the multiplication product of growth inhibition by each treatment alone (excess over Bliss additivism). The difference reflected the magnitude of the synergism as shown by the scale bar. (Ei-iii) The results obtained from MV4-11. (F) Combination of HMA and sorafenib enhanced the growth inhibitory and (G) apoptosis effects of primary FLT3-ITD⁺ AML samples. The average results of 5 primary samples were shown. (H) Pretreatment with HMA (10 μM) significantly upregulated the intracellular level of sorafenib in both (i) MOLM-13 and (ii) MV4-11. The count per minute (CPM) was normalized by the amount of protein in the samples.