Molecular Target Therapy of AKT and NF-kB Signaling Pathways and Multidrug Resistance by Specific Cell Penetrating Inhibitor Peptides in HL-60 Cells

Background: PI3/AKT and NF-kB signaling pathways are constitutively active in acute myeloid leukemia andcross-talk between the two has been shown in various cancers. However, their role in acute myeloid leukemia hasnot been completely explored. We therefore used cell penetrating inhibitor peptides to define the contributions ofAKT and NF-kB to survival and multi drug resistance (MDR) in HL-60 cells. Materials and
Methods: Inhibitionof AKT and NF-kB activity by AKT inhibitor peptide and NBD inhibitor peptide, respectively, resulted indecreased expression of mRNA for the MDR1 gene as assessed by real time PCR. In addition, treatment of HL-60cells with AKT and NBD inhibitor peptides led to inhibition of cell viability and induction of apoptosis in a dosedependent manner as detected by flow cytometer.
Results: Finally, co-treatment of HL-60 cells with sub-optimaldoses of AKT and NBD inhibitor peptides led to synergistic apoptotic responses in AML cells.
Conclusions: Thesedata support a strong biological link between NF-kB and PI3-kinase/AKT pathways in the modulation of antiapoptoticand multi drug resistant effects in AML cells. Synergistic targeting of these pathways using NF-kB andPI3-kinase/AK inhibitor peptides may have a therapeutic potential for AML and possibly other malignancieswith constitutive activation of these pathways.