Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-kappaB and p53 modulation

The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/ Akt and nuclear factor-KB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl(+) myeloid leukemia cells. The hop flavonoid xanthohumol inhibits tumor growth by targeting the nuclear factor-KB and Akt pathways and angiogenesis. Here, we show that xanthohumol has in vitro activity against Bcr-Abl(+) cells and clinical samples and retained its cytotoxicity when imatinib mesylate–resistant K562 cells were examined. Xanthohumol inhibition of K562 cell viability was associ-ated with induction of apoptosis, increased p21 and p53 expression, and decreased survivin levels. We show that xanthohumol strongly inhibited Bcr-Abl expression at both mRNA and protein levels and show that xantho-humol caused elevation of intracellular reactive oxygen species and that the antioxidant N-acetylcysteine blunted xanthohumol-induced events. Further, we observed that xanthohumol inhibits leukemia cell invasion, metallopro-tease production, and adhesion to endothelial cells, potentially preventing in vivo life-threatening complica-tions of leukostasis and tissue infiltration by leukemic cells. As structural mutations and/or gene amplification in Bcr-Abl can circumvent an otherwise potent anticancer drug such as imatinib, targeting Bcr-Abl expression as well as its kinase activity could be a novel additional therapeu-tic approach for the treatment of Bcr-Abl(+) myeloid leukemia. [Mol Cancer Ther 2008;7(9):2692–702