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Inhibition of Nuclear Factor-B Activity by Temozolomide Involves O⁶-Methylguanine–Induced Inhibition of p65 DNA Binding

¹ Section of Neurosurgery, Department of Surgery, ² Section of Hematology/Oncology, Department of Medicine, and ³ Department of Radiation and Cellular Oncology, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois and ⁴ Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts

Requests for reprints: Bakhtiar Yamini, MC 4066, Section of Neurosurgery, University of Chicago Hospitals, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: 773-702-2475; Fax: 773-702-5234; E-mail: byamini{at}surgery.bsd.uchicago.edu.

The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O⁶-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-B (NF-B). Temozolomide inhibits basal and tumor necrosis factor (TNF)–induced NF-B transcriptional activity without altering phosphorylation or degradation of inhibitor of B-. Inhibition of NF-B is secondary to attenuation of p65 DNA binding, not nuclear translocation. Inhibition of DNA binding is shown both in vitro, with gel shift studies and DNA binding assays, and in vivo at B sites. Consistent with inhibition of NF-B activity, temozolomide reduces basal and TNF-induced B-dependent gene expression. Temozolomide also inhibits NF-B activated by inducers other than TNF, including lipopolysaccharide, doxorubicin, and phorbol 12-myristate 13-acetate. The inhibitory action of temozolomide on NF-B is observed to be maximal following pretreatment of cells with temozolomide for 16 h and is also seen with the S_N1-type methylating agent methylnitrosourea. The ability of temozolomide to form O⁶-methylguanine adducts is important for inhibition of NF-B as is the presence of a functioning mismatch repair system. Activation of NF-B with TNF before administration of temozolomide reduces the cytotoxicity of temozolomide, whereas 16-h pretreatment with temozolomide resensitizes cells to killing. This work shows a mechanism whereby O⁶-methylguanine adducts formed by temozolomide lead to inhibition of NF-B activity and illustrates a link between mismatch repair processing of alkylator-induced DNA damage and cell death. [Cancer Res 2007;67(14):6889–98]

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				Correction: Article on Inhibition of NF-{kappa}B by Temozolomide Cancer Res., February 15, 2009; 69(4): 1695 - 1695. [Full Text] [PDF]

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