Abstract:
:The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O(6)-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). Temozolomide inhibits basal and tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB transcriptional activity without altering phosphorylation or degradation of inhibitor of kappaB-alpha. Inhibition of NF-kappaB 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 kappaB sites. Consistent with inhibition of NF-kappaB activity, temozolomide reduces basal and TNFalpha-induced kappaB-dependent gene expression. Temozolomide also inhibits NF-kappaB activated by inducers other than TNFalpha, including lipopolysaccharide, doxorubicin, and phorbol 12-myristate 13-acetate. The inhibitory action of temozolomide on NF-kappaB is observed to be maximal following pretreatment of cells with temozolomide for 16 h and is also seen with the S(N)1-type methylating agent methylnitrosourea. The ability of temozolomide to form O(6)-methylguanine adducts is important for inhibition of NF-kappaB as is the presence of a functioning mismatch repair system. Activation of NF-kappaB with TNFalpha 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 O(6)-methylguanine adducts formed by temozolomide lead to inhibition of NF-kappaB activity and illustrates a link between mismatch repair processing of alkylator-induced DNA damage and cell death.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Yamini B,Yu X,Dolan ME,Wu MH,Darga TE,Kufe DW,Weichselbaum RRdoi
10.1158/0008-5472.CAN-06-4496subject
Has Abstractpub_date
2007-07-15 00:00:00pages
6889-98issue
14eissn
0008-5472issn
1538-7445pii
67/14/6889journal_volume
67pub_type
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