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Research Articles: Therapeutics

AGRO100 inhibits activation of nuclear factor-B (NF-B) by forming a complex with NF-B essential modulator (NEMO) and nucleolin

Departments of ¹ Biochemistry and Molecular Biology, ² Medicine, and ³ Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky

Requests for reprints: Paula J. Bates, University of Louisville, 580 South Preston Street, Delia Baxter Building 321, Louisville, KY 40202-1756. Phone: 502-852-2432; Fax: 502-852-2356. E-mail: paula.bates{at}louisville.edu

AGRO100, also known as AS1411, is an experimental anticancer drug that recently entered human clinical trials. It is a member of a novel class of antiproliferative agents known as G-rich oligonucleotides (GRO), which are non-antisense, guanosine-rich phosphodiester oligodeoxynucleotides that form stable G-quadruplex structures. The biological activity of GROs results from their binding to specific cellular proteins as aptamers. One important target protein of GROs has been previously identified as nucleolin, a multifunctional protein expressed at high levels by cancer cells. Here, we report that AGRO100 also associates with nuclear factor-B (NF-B) essential modulator (NEMO), which is a regulatory subunit of the inhibitor of B (IB) kinase (IKK) complex, and also called IKK. In the classic NF-B pathway, the IKK complex is required for phosphorylation of IB and subsequent activation of the transcription factor NF-B. We found that treatment of cancer cells with AGRO100 inhibits IKK activity and reduces phosphorylation of IB in response to tumor necrosis factor- stimulation. Using a reporter gene assay, we showed that AGRO100 blocks both tumor necrosis factor--induced and constitutive NF-B activity in human cancer cell lines derived from cervical, prostate, breast, and lung carcinomas. In addition, we showed that, in AGRO100-treated cancer cells, NEMO is coprecipitated by nucleolin, indicating that both proteins are present in the same complex. Our studies suggest that abrogation of NF-B activity may contribute to the anticancer effects of AGRO100 and that nucleolin may play a previously unknown role in regulating the NF-B pathway. [Mol Cancer Ther 2006;5(7):1790–9]

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⁴ P.J. Bates, A.C. Girvan, J.B. Klein, and W.M. Pierce, Jr., unpublished data.

⁵ http://www.physics.csbsju.edu/stats/t-test.html.

⁶ P.J. Bates, unpublished observation.

⁷ P.J. Bates, Y. Teng, L.K. Casson, and W.M. Pierce, Jr., unpublished observation.

Received 9/ 8/05; revised 5/ 4/06; accepted 5/16/06.

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