| Popis: |
Tumor necrosis factor α (TNFα) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IκBα kinase (IKK), which in turn activates nuclear factor-κB (NF-κB) to help cancer cells survive. Therefore, inhibition of TNFα-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 IKKα and IKKβ, which effectively blocked TNFα-mediated IKK activation and subsequent NF-κB activity. Using gene profiling analysis, we show that IKI-1 blocked most of the TNFα-mediated mRNA expression, including many genes that play important roles in cell survival. We further show that in vitro and in vivo combination of TNFα 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 TNFα and IKI-1. Additionally, IKKβ small interfering RNA transfected cells were more sensitive to the treatment of TNFα. The study suggests that the limited efficacy of TNFα in cancer treatment was due in part to the activation of NF-κB, allowing tumor cells to escape apoptosis. Therefore, the combination of IKI-1 with TNFα may improve the efficacy of TNFα for certain tumor types. [Cancer Res 2008;68(22):9519–24] |
