benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and xanthohumol

Chronic lymphocytic leukemia (CLL) is an incurable disease with a natural history of increasing resistance to chemotherapy. A novel approach to overcome chemotherapy resistance may be targeting the endoplasmic reticulum (ER).. The involvement of the unfolded protein response (UPR) in the cell killing effect of xanthohumol (X) was examined in 18 patient samples.. X-induced apoptosis of CLL cells was accompanied by the induction of glucose-regulated protein of 78 kDa (GRP78) and heat-shock protein of 70 kDa (Hsp70) protein levels and by sustained phosphorylation of the eukaryotic translation initiation factor 2 (eIF2alpha), suggesting the involvement of the ER stress transducer, the double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK). The X-box-binding protein 1 (XBP1) mRNA was spliced but no clear activation of activating transcription factor 6 (ATF6) was observed. The proapoptotic outcome was further demonstrated by the up-regulation of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), down-regulation of myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2), cleavage of poly-(ADP)-ribose polymerase (PARP) and processing of caspase-3, -4 and -9. Furthermore, X showed proteasome inhibitory activity.. X stimulates the proapoptotic arm of the UPR in ex vivo CLL cells, suggesting that ER stress may play an important role during X-induced apoptosis.

Topics: Activating Transcription Factor 6; Amino Acid Chloromethyl Ketones; Apoptosis; Caspase Inhibitors; Caspases; Cysteine Proteinase Inhibitors; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoribonucleases; Flavonoids; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Membrane Proteins; NF-kappa B; Propiophenones; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Serine-Threonine Kinases; Unfolded Protein Response

Xanthohumol (X), isoxanthohumol (IX), 8-prenylnaringenin (8PN) and 6-prenylnaringenin (6PN), prenylflavonoids from hop (Humulus lupulus L.), were investigated for their cytotoxicity and the mechanism by which they exert cell death when incubated with prostate cancer cell lines PC-3 and DU145. All compounds induced cell death in the absence of caspase-3 activation and typical apoptotic morphological features. The general pan-caspase inhibitor zVAD-fmk could not protect this form of cell death. In addition, the formation of vacuoles was observed in PC-3 cells treated with IX and 6PN, and in DU145 treated with IX, 8PN and 6PN, which could suggest the induction of autophagy and consequent cell death. The results indicate that hop-derived prenylflavanones (IX, 8PN, 6PN), but not prenylchalcones (X) induce a caspase-independent form of cell death, suggested to be autophagy. Therefore, IX, 8PN and 6PN appear to be promising candidates for further investigation in prostate anticancer therapy.

Topics: Amino Acid Chloromethyl Ketones; Caspase 3; Caspase Inhibitors; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Flavanones; Flavonoids; Humans; Humulus; Male; Molecular Structure; Plant Extracts; Propiophenones; Prostatic Neoplasms; Xanthones