Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NF kappa B-TNF alpha feedback cycle which sustains persistent NF kappa B activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NF kappa B dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NF kappa B activation by disrupting the IR-induced NF kappa B-TNF alpha-NF kappa B feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NF kappa B-DNA binding activity/promoter activation and, maintained the NF kappa B repression by deterring NF kappa B-dependent TNF alpha transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK-PN-DW, MC-IXC and SK-N-MC) cell types. Further, EF24 completely suppressed IR-induced NF kappa B-TNF alpha cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NF kappa B dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NF kappa B and NF kappa B mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NF kappa B-dependent TNF alpha-NF kappa B cross-signaling maintained NF kappa B mediated survival advantage and clonal expansion.