c-Myc Inhibition Using 10058-F4 Increased the Sensitivity of Acute Promyelocytic Leukemia Cells to Arsenic Trioxide Via Blunting PI3K/NF-κB Axis.

ABSTRACT

BACKGROUNDS Although ATO is widely used to treat acute promelocytic leukemia (APL), the appropriate effects of the drug as a single agent are achieved in high doses which are not clinically achievable without the risk of side effects; highlighting the necessity of its application in a combined-modality. Herein, we aimed to investigate whether c-Myc inhibition could reinforce the anti-leukemic effect of ATO, while reducing its concentration in APL cells. METHODS: NB4 cells were treated with the relevant concentrations of 10058-F4 (c-Myc inhibitor) and ATO, and then the survival of the cells was evaluated using trypan blue, MTT and BrdU assays. Moreover, the mechanism of action of the agents were evaluated using Flow cytometry, qRT-PCR and western blot analysis. RESULTS: We found that the inhibition of c-Myc using 10058-F4 could enhance the anti-leukemic effect of ATO in APL cells through reducing the phosphorylation of IκB, decreasing the expression of the anti-apoptotic genes and in turn, inducing a caspase-3-dependent apoptotic cell death. Moreover, the combination of 10058-F4 and ATO abrogated the activation of the PI3K pathway, while neither agent had significant suppressive impact on this pathway; suggesting for the first time that probably the companionship of c-Myc inhibitor may be an appealing strategy for shifting the resistance condition toward a chemo-sensitive phenotype, without the necessity to elevate the effective dose of ATO. CONCLUSION: Given the efficacy of 10058-F4 in adjuvanting approaches, we suggest this small molecule inhibitor as an impressing agent to be used alongside ATO in the treatment of APL.