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Modification of the cysteine residues in I B kinase and NF-B ( p 65 ) by xanthohumol leads to suppression of NF-B – regulated gene products and potentiation of apoptosis in leukemia cells

Xanthohumol (XN), a prenylated chalcone isolated from hop plant, exhibits antiinflammatory, antiproliferative, and antiangiogenic properties through an undefined mechanism. Whether examined by intracellular esterase activity, phosphatidylserine externalization, DNA strand breaks, or caspase activation, we found that XN potentiated tumor necrosis factor– induced apoptosis in leukemia and myeloma cells. This enhancement of apoptosis correlated with down-regulation of nuclear factorB (NFB) survivin, bclxL, XIAP, cIAP1, cIAP2, cylin D1, and c-myc. XN down-regulated both constitutive and inducible NFB activation, inhibition of phosphorylation and degradation of I B , suppression of p65 nuclear translocation, and NFB–dependent reporter gene transcription. XN directly inhibited tumor necrosis factor-induced I B kinase (IKK) activation and a reducing agent abolished this inhibition, indicating the role of cysteine residue. XN had no effect on the IKK activity when cysteine residue 179 of IKK was mutated to alanine. XN also directly inhibited binding of p65 to DNA, a reducing agent reversed this effect, and mutation of cysteine residue 38 to serine of p65 abolished this effect. Thus, our results show that modification of cysteine residues of IKK and p65 by XN leads to inhibition of the NFB activation pathway, suppression of antiapoptotic gene products, and potentiation of apoptosis in leukemia cells. (Blood. 2009;113:2003-2013)