PT - JOURNAL ARTICLE AU - Nadia Lampiasi AU - Antonina Azzolina AU - Natale D'Alessandro AU - Kazuo Umezawa AU - James A. McCubrey AU - Giuseppe Montalto AU - Melchiorre Cervello TI - Antitumor Effects of Dehydroxymethylepoxyquinomicin, a Novel Nuclear Factor-κB Inhibitor, in Human Liver Cancer Cells Are Mediated through a Reactive Oxygen Species-Dependent Mechanism AID - 10.1124/mol.109.055418 DP - 2009 Aug 01 TA - Molecular Pharmacology PG - 290--300 VI - 76 IP - 2 4099 - http://molpharm.aspetjournals.org/content/76/2/290.short 4100 - http://molpharm.aspetjournals.org/content/76/2/290.full SO - Mol Pharmacol2009 Aug 01; 76 AB - Activation of the nuclear transcription factor-κB (NF-κB) has been implicated in liver tumorigenesis. We evaluated the effects of a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in two human liver cancer cell lines HA22T/VGH and HuH-6. DHMEQ treatment dose dependently decreased the DNA-binding capacity of the NF-κB p65 subunit, inhibited cell growth and proliferation, and increased apoptosis as shown by caspase activation, release of cytochrome c, poly(ADP-ribose) polymerase cleavage, and down-regulation of survivin. DHMEQ also induced a dose-dependent activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling, and inhibition of this pathway significantly reduced cell growth. It is noteworthy that we observed that DHMEQ stimulated reactive oxygen species (ROS) production in a dose-dependent manner and that pretreatment of the cells with the antioxidant N-acetyl-l-cysteine (NAC) significantly reduced DHMEQ-induced ROS generation. Accordingly, NAC completely reversed the DHMEQ-induced growth inhibition, caspase activation, and cell death. DHMEQ-treated cells exhibited DNA damage, as evaluated by accumulation in nuclear foci of phospho-H2AX, which was completely reversed by NAC. Moreover, DHMEQ induced the expression of genes involved in the endoplasmic reticulum stress response (GRP78, CHOP, TRB3) and promoted the splicing of XBP1 mRNA in a dose-dependent fashion in both cell lines, which was reversed in the presence of NAC. Knockdown of TRB3 mRNA expression by small interference RNA significantly decreased DHMEQ-induced cell growth inhibition. These data suggest that DHMEQ antitumor effects are primarily mediated through ROS generation. Thereby, considering that cancer cells are under increased ER stress and oxidative stress conditions, DHMEQ may greatly improve various anticancer strategies.