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  • Title: Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells.
    Author: Karacay B, Sanlioglu S, Griffith TS, Sandler A, Bonthius DJ.
    Journal: Cancer Gene Ther; 2004 Oct; 11(10):681-90. PubMed ID: 15332116.
    Abstract:
    Neuroblastoma is the most common solid extracranial neoplasm in children and causes many deaths. Despite treatment advances, prognosis for neuroblastoma remains poor, and a critical need exists for the development of new treatment regimens. TNF-related apoptosis-inducing-ligand (TRAIL) induces cell death in a variety of tumors, but not in normal tissues. Moreover, TRAIL is nontoxic, making it a strong antitumor therapeutic candidate. We demonstrate that introduction of the TRAIL gene into neuroblastoma cell lines using an adenoviral vector leads to apoptotic cell death. RT-PCR and flow-cytometric analyses demonstrated that TRAIL's effect is mediated primarily via the TRAIL R2 receptor. As TRAIL can activate the nuclear factor-kappaB (NF-kappaB) signaling pathway, which can exert an antiapoptotic effect, we hypothesized that inhibition of NF-kappaB signaling may augment TRAIL's killing effects. TRAIL-mediated cell death was enhanced when neuroblastoma cells were simultaneously infected with a dominant-negative mutant of IkappaB kinase, a kinase essential for NF-kappaB activation. The combination of blockade of NF-kappaB signaling and expression of TRAIL induced apoptotic death in a greater proportion of SKNSH cells than did either treatment alone. Thus, concurrent inhibition of the NF-kappaB pathway and the induction of TRAIL-mediated apoptosis may become a useful approach for the treatment of neuroblastoma.
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