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Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells.
MedLine Citation:
PMID:  22824846     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Despite recent advancements in therapeutic drugs, multiple myeloma remains an incurable disease. Therefore, a more effective treatment is urgently required. In this study, we show that isobavachalcone (IBC), a natural chalcone compound, induces apoptosis- and autophagy-related cell death in myeloma cells. The inhibition of autophagy by knocking down beclin-1 or by using autophagy inhibitors, such as 3-methyladenine, bafilomycin A and chloroquine significantly enhanced IBC-induced cell death, as demonstrated by the increased number of Annexin V-positive cells. Moreover, we demonstrate that the collapse of the mitochondrial membrane potential contributes to chloroquine and IBC-induced cell death, which is accompanied by the activation of caspase-9, and -3, the cleavage of poly (ADP-ribose) polymerase (PARP) and the proteolytic activation of protein kinase Cδ (PKCδ). Furthermore, the inhibition of the activation of PKCδ by rottlerin, an inhibitor of PKCδ, not only suppressed the activation of PKCδ, but also the apoptosis induced by the co-treatment of chloroquine and IBC, indicating the involvement of PKCδ in chloroquine plus IBC-induced cell death. Finally, the combination of chloroquine and IBC had little effect on the viability of normal peripheral blood mononuclear cells. As both chloroquine and IBC have been shown to be relatively specific for cancer cells, the combination of these two agents at non-toxic or sub-toxic concentrations represents an attractive novel regimen for myeloma treatment and warrants further investigation in preclinical and clinical studies.
Authors:
Shan Zhao; Chun-Min Ma; Chuan-Xu Liu; Wei Wei; Yun Sun; Hua Yan; Ying-Li Wu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-16
Journal Detail:
Title:  International journal of molecular medicine     Volume:  -     ISSN:  1791-244X     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9810955     Medline TA:  Int J Mol Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai 200025, P.R. China.
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