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ABSTRACT: NF-kappaB is a transcription factor that induces the expression of inflammatory cytokines and antiapoptotic proteins. Earlier we designed a new NF-kappaB inhibitor, (-)-DHMEQ, and showed that it had potent anticancer and anti-inflammatory activities in various animal models without any toxicity. In the present research, we studied whether (-)-DHMEQ could be efficiently taken by cultured cells and irreversibly inhibit NF-kappaB by short time application to cultured cells. Even after mouse monocytic leukaemia RAW264.7 cells had been washed free of (-)-DHMEQ, lipopolysacharide (LPS)-induced activation of NF-kappaB in these cells was still inhibited. Moreover, topical application for 15 min was found to induce dormancy of the cells against LPS for 2-8 h. When it was topically added to RAW264.7 cells in which NF-kappaB was activated by LPS, the inhibition lasted at least for 2 h. NF-kappaB derectly upregulates expression of iNOS that produces NO. Short time application of (-)-DHMEQ also inhibited the function of cells in terms of NO production and iNOS induction in RAW264.7 cells. Thus, the fast incorporation of (-)-DHMEQ into the cells and irreversible inhibition of NF-kappaB by it were demonstrated, and this observation would explain its effective inhibition of certain functions in cellular and animal disease models.
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 01/2010; 18(11-12):529-35. DOI:10.3727/096504010X12767359113721 · 1.06 Impact Factor