Anti-proliferative and apoptosis-inducing properties of Xanthohumol, a prenylated chalcone from hops (Humulus lupulus L.)

Xanthohumol (XN)* is a prenylated chalcone found at high concentrations in hop cones (Humulus lupulus L.). XN has been characterized as a promising cancer chemopreventive lead structure that acts via a broad spectrum of bioactivities. This chapter summarizes the anti-proliferative and apoptosis-inducing potential of XN and gives a detailed overview of underlying mechanisms and pathways targeted by XN to induced programmed cell death. XN is a potent inhibitor of NFB and inhibits activation of the death-receptor pathway by tumor necrosis factor (TNF). In various cell lines, XN treatment results in an immediate transient increase in mitochondria-derived reactive oxygen species (ROS) that is considered as the initial trigger of apoptosis induction via the intrinsic pathway by breakdown of the mitochondrial membrane potential, release of cytochrome c and activation of the caspase cascade. Oxidative stress may also contribute to the activation of endoplasmatic reticulum (ER) stress and unfolded protein response recently identified as a novel mechanisms underlying XN-mediated apoptosis induction. *Abbreviations: AML, acute myelocytic leukemia; A-SMase, acid sphingomyelinase; ATF, activating transcription factor; ATP, adenosine triphosphate; BiP, immunoglobulin-heavy-chain binding protein; BPH, benign prostate hyperplasia; CHOP, CAAT/enhancer-binding protein (C/EBP) homologous protein; CLL, chronic lymphocytic leukemia; Cox, cyclooxygenase; CYP, cytochrome P450; DC, dendritic cells; DCF-DA, dichlorofluorescein-diacetate; DHE, dihydroethidium; DISC, death-inducing signaling complex; DMBA, dimethylbenz-[a]-anthracene; DMSO, dimethylsulfoxide; DR, death receptor; ER, endoplasmatic reticulum; FADD, Fas-associated death domain; FITC, fluorescein isothiocyanate; Gadd153, growth arrest and DNA damage 153; GRP78, glucose-regulated protein 78; GSH, glutathione; H2O2, hydrogen peroxide; HUVEC, human umbilical vein endothelial cells; IC50, half-maximal inhibitory concentration; IKK, I-B kinase; IL, interleukin; Ire1α, inositol-requiring 1α; LDH, lactate dehydrogenase; MMP, matrix metalloprotease; MnTMPyP, manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin; MTT, 3(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazoliumbromide; NAC, N-acetyl cysteine; NAD(P)H, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor κB; O2, superoxide anion radicals; OH, hydroxyl radicals; PARP, poly(ADP-ribose)polymerase; PERK, double stranded RNA-dependent protein kinase (PKR)-like ER kinase; RIP, receptor interacting kinase; ROS, reactive oxygen species; SCID, severe combined immuno-deficient; SM, sphingomyelin; SOD, superoxide dismutase; SRB, sulforhodamine B; TNF, tumor necrosis factor; TNFR1, TNF-receptor 1; TRAF, TNF receptor-associated factor; TRAIL, TNF-related apoptosisinducing ligand; Trb3, Tribble homolog 3; TUNEL, TdT-mediated dUTP-biotin nick end labeling; UPR, unfolded protein response; XBP1, X-box-binding protein 1; XN, Xanthohumol; Ψm, mitochondrial membrane potential; ρ, rho zero