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IB Kinase Inhibitor IKI-1 Conferred Tumor Necrosis Factor Sensitivity to Pancreatic Cancer Cells and a Xenograft Tumor Model

Department of Oncology, Wyeth Research, Pearl River, New York

Requests for reprints: Yixian Zhang, Enzon Pharmaceutical, 20 Kingsbridge Road, Piscataway, NJ 08854. Phone: 732-980-4914; Fax: 732-885-2950; E-mail: yixian.zhang{at}enzon.com.

Key Words: IKK • TNF • pancreatic cancer • combination • inhibitor

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

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