title: Autophagy inhibition enhances isobavachalcone-induced cell death in             multiple myeloma cells.
abstract: 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: 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, PR China.
authors: Shan
authors: S
authors: Zhao
authors: Chun-Min
authors: CM
authors: Ma
authors: Chuan-Xu
authors: CX
authors: Liu
authors: Wei
authors: W
authors: Wei
authors: Yun
authors: Y
authors: Sun
authors: Hua
authors: H
authors: Yan
authors: Ying-Li
authors: YL
authors: Wu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics; D051745:Protein Kinase C-delta / Q000378:metabolism; D059748:Proteolysis
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D047188:Chalcones; D018942:Macrolides; D008565:Membrane Proteins; C057620:bafilomycin A; C468754:isobavachalcone; C025946:3-methyladenine; D002738:Chloroquine; D051745:Protein Kinase C-delta; D000225:Adenine