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  • Title: IkappaBalpha kinase inhibitor IKI-1 conferred tumor necrosis factor alpha sensitivity to pancreatic cancer cells and a xenograft tumor model.
    Author: Zhang Y, Gavriil M, Lucas J, Mandiyan S, Follettie M, Diesl V, Sum FW, Powell D, Haney S, Abraham R, Arndt K.
    Journal: Cancer Res; 2008 Nov 15; 68(22):9519-24. PubMed ID: 19010928.
    Abstract:
    Tumor necrosis factor alpha (TNFalpha) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IkappaBalpha kinase (IKK), which in turn activates nuclear factor-kappaB (NF-kappaB) to help cancer cells survive. Therefore, inhibition of TNFalpha-induced IKK activity with specific IKK inhibitor represents an attractive strategy to treat cancer patients. This study reveals IKI-1 as a potent small molecule inhibitor of IKKalpha and IKKbeta, which effectively blocked TNFalpha-mediated IKK activation and subsequent NF-kappaB activity. Using gene profiling analysis, we show that IKI-1 blocked most of the TNFalpha-mediated mRNA expression, including many genes that play important roles in cell survival. We further show that in vitro and in vivo combination of TNFalpha with IKI-1 had superior potency than either agent alone. This increased potency was due primarily to the increased apoptosis in the presence of both TNFalpha and IKI-1. Additionally, IKKbeta small interfering RNA transfected cells were more sensitive to the treatment of TNFalpha. The study suggests that the limited efficacy of TNFalpha in cancer treatment was due in part to the activation of NF-kappaB, allowing tumor cells to escape apoptosis. Therefore, the combination of IKI-1 with TNFalpha may improve the efficacy of TNFalpha for certain tumor types.
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