title: 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.
authors: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors: Sheeja
authors: S
authors: Aravindan
authors: Mohan
authors: M
authors: Natarajan
authors: Vibhudutta
authors: V
authors: Awasthi
authors: Terence S
authors: TS
authors: Herman
authors: Natarajan
authors: N
authors: Aravindan
mesh_terms: D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002999:Clone Cells / Q000187:drug effects / Q000528:radiation effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D025461:Feedback, Physiological / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology*; D010881:Piperidones / Q000138:chemical synthesis / Q000494:pharmacology*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects*; D019098:Telomerase / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D001597:Benzylidene Compounds; D016328:NF-kappa B; D010881:Piperidones; D014409:Tumor Necrosis Factor-alpha; C509186:TERT protein, human; D019098:Telomerase
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