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Abstract Title:

Xanthohumol activates the proapoptotic arm of the unfolded protein response in chronic lymphocytic leukemia.

Abstract Source:

Anticancer Res. 2009 Oct;29(10):3797-805. PMID: 19846911

Abstract Author(s):

Sofie Lust, Barbara Vanhoecke, Mireille VAN Gele, Jerina Boelens, Heleen VAN Melckebeke, Mary Kaileh, Wim Vanden Berghe, Guy Haegeman, Jan Philippé, Marc Bracke, Fritz Offner

Abstract:

BACKGROUND: 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). PATIENTS AND METHODS: The involvement of the unfolded protein response (UPR) in the cell killing effect of xanthohumol (X) was examined in 18 patient samples. RESULTS: 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. CONCLUSION: 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.

Study Type : In Vitro Study

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Sayer Ji
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