We previously designed and synthesized an NF-B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), that showed anti-inflammatory activity in vivo. In the present study we looked into its mechanism of inhibi-

We previously designed and synthesized the new nuclear factor κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-κB is constitutively activated. The addition of DHMEQ (10 μg/mL) completely inhibited the activated NF-κB for at least 8 hours. On the other hand, NF-κB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-α-induced activation of NF-κB. DHMEQ did not inhibit the degradation of IκB but inhibited the nuclear translocation of NF-κB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-α, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-κB activity.