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

Abstract

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB 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 NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα 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 NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB 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 NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

Acquired genetic alterations in tumor cells dictate the development of high-risk neuroblastoma and clinical outcomes

“…The subcutaneous administration of human SH-SY5Y cells resulted in the development of ~200 mm 3 xenografts in ~70 % of the animals within 30 days, as described previously [ 26 , 31 ], while the other 30 % of the mice were presented with multiple clinically-mimicking aggressive metastatic tumors in the mediastinum and retroperitoneal, pelvic, abdominal, and chest cavities as shown previously (27).

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Reorganization of metastamiRs in the evolution of metastatic aggressive neuroblastoma cells

“…Xenotransplantation of SH-SY5Y cells resulted in the development of ~200 mm 3 xenografts in ~70 % of the animals within 30 days (Fig. 1a ) [ 53 , 54 ]. About 30 % of the mice that received identical clones initially (within 10–20 days) showed xenograft development, then subsided to a residual tumor (Fig.…”

Bioactivities of EF24, a Novel Curcumin Analog: A Review

“…EF24 robustly conferred radiation-induced cell death mainly by inhibiting radiation-induced NF-κB signaling in breast cancer (43). In the same year, the same group found that EF24 can suppress the radiation-induced NF-κB-DNA binding activity/promoter activation in genetically varied human neuroblastoma (44). Inhibition of the NF-κB signaling extends the therapeutic application of EF24 to other NF-κB-dependent diseases, such as inflammatory diseases (described below).…”