title: Dioxonaphthoimidazoliums AB1 and YM155 disrupt phosphorylation of p50 in the NF-κB pathway.
abstract: The NF-κB pathway is overexpressed in non-small cell lung cancers (NSCLC) and contributes to the poor prognosis and high mortality characterizing this malignancy. Silencing the p50 and p65 NF-κB subunits in the NSCLC H1299 cell line led to profound loss in cell viability and downregulated anti-apoptotic proteins survivin and Mcl1. We also showed that a survivin suppressant, the dioxonaphthoimidazolium YM155, and its structural analog AB1 arrested the growth of H1299 cells at nanomolar concentrations. Both compounds were apoptogenic and suppressed survivin and other anti-apoptotic proteins (Mcl1, Bcl-2, Bcl-xl) in a dose- and/or time-dependent manner. YM155 and AB1 did not affect the expression of key proteins (IκBα, p65, p50) involved in NF-κB signaling. Stable IκBα levels suggest that the NF-κB/IκB complex and proteins upstream of IκBα, were not targeted. Neither did the compounds intercept the nuclear translocation of the p50 and p65 subunits. On the other hand, YM155 and AB1 suppressed the phosphorylation of the p50 subunit at Ser337 which is critical in promoting the binding of NF-κB dimers to DNA. Both compounds duly impeded the binding of NF-κB dimers to DNA and attenuated transcriptional activity of luciferase-transfected HEK293 cells controlled by NF-κB response elements. We propose that the "silencing" the NF-κB pathway effected by these compounds contributed to their potent apoptogenic effects on H1299. Notwithstanding, the mechanism(s) involved in their ability to abolish phosphorylation of p50 remains to be elucidated. Taken together, these results disclose a novel facet of functionalized dioxonaphthoimidazoliums that could account for their potent cell killing property.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Si Han Sherman
authors.initials: SH
authors.lastname: Ho
authors.affiliation: Cancer Science Institute, Yong Loo Lin School of Medicine, Singapore.
authors.forename: Azhar
authors.initials: A
authors.lastname: Ali
authors.affiliation: Cancer Science Institute, Yong Loo Lin School of Medicine, Singapore.
authors.forename: Tan Min
authors.initials: TM
authors.lastname: Chin
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Mei Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D007093:Imidazoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D052002:NF-kappa B p50 Subunit; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; C501107:chlorambucil-N-(2-(4-(4-bis(2-chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2-furancarboxamide hydrochloride; D002699:Chlorambucil; C523798:sepantronium
keywords: NF-κB signaling; YM155; non-small cell lung cancer; p50 phosphorylation; survivin suppressant