Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted.
These findings suggest that specific pathway genes were further targeted by adding chemotherapy and support the rationale of combination therapy. Treatment with short hairpin RNAs targeting either CCND1 or c-Mos further sensitized MV4-11 cells to ABT-869. CCND1 and c-Mos were the most significantly inhibited targets on both transcriptional and translational levels. Low-density array analysis revealed the synergistic interaction involved in downregulation of cell cycle and mitogen-activated protein kinase pathway genes. The optimal combination was validated in MV4-11 xenografts. ABT-869 demonstrates significant sequence-dependent synergism with cytarabine and doxorubicin in cell lines and primary leukemia samples. We also evaluate the combinations of ABT-869 and chemotherapy. ABT-869 induces apoptosis through downregulation of Bcl-xL and upregulation of BAK, BID and BAD. Here, we provide further evidence that ABT-869 treatment significantly downregulates cyclins D and E but increases the expression of p21 and p27. ABT-869 has demonstrated potent effects in AML cells with FLT3-ITDs. Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of acute myeloid leukemia (AML) and represent an attractive therapeutic target.