NF-κB-dependent Mechanism of Action of c-Myc Inhibitor10058-F4: Highlighting a Promising Effect of c-Myc Inhibition inLeukemia Cells, Irrespective of p53 Status

Due to the frequent contribution in the pathogenesis of different human malignancies, c-mycis among those transcription factors that are believed to be pharmacologically targeted for cancertherapeutic approaches. in the present study, we examined the anti-leukemic effect of a well-knownc-myc inhibitor 10058-f4 on a panel of hematologic malignant cells harboring either mutant orwild-type p53. notably, we found that the suppression of c-myc was coupled with the reduction inthe survival of all the tested leukemic cells; however, as far as we are aware, this study suggests forthe first time that the cytotoxic effect of 10058-f4 was not significantly affected by the molecularstatus of p53. delving into the molecular mechanisms of the inhibitor in the most sensitive cellline revealed that 10058-f4 could induce apoptotic cell death in mutant p53-expressing nb4 cellsthrough the suppression of nf-κb pathway coupled with a significant induction of intracellularreactive oxygen species (ros). in addition, we found that the anti-leukemic effect of 10058-f4 wasovershadowed, at least partially, through the compensatory activation of the pi3k signaling pathway;highlighting a plausible attenuating role of this axis on 10058-f4 cytotoxicity. in conclusion, theresults of the present study shed light on the favorable anti-leukemic effect of 10058-f4, especially incombination with pi3k inhibitors in acute promyelocytic leukemia; however, further investigationsshould be accomplished to determine the efficacy of the inhibitor, either as a single agent or in acombined-modal strategy, in leukemia treatment.