title: Targeting cannabinoid receptor-2 pathway by phenylacetylamide suppresses the proliferation of human myeloma cells through mitotic dysregulation and cytoskeleton disruption.
abstract: Cannabinoid receptor-2 (CB2) is expressed dominantly in the immune system, especially on plasma cells. Cannabinergic ligands with CB2 selectivity emerge as a class of promising agents to treat CB2-expressing malignancies without psychotropic concerns. In this study, we found that CB2 but not CB1 was highly expressed in human multiple myeloma (MM) and primary CD138+ cells. A novel inverse agonist of CB2, phenylacetylamide but not CB1 inverse agonist SR141716, inhibited the proliferation of human MM cells (IC50 : 0.62 ∼ 2.5 μM) mediated by apoptosis induction, but exhibited minor cytotoxic effects on human normal mononuclear cells. CB2 gene silencing or pharmacological antagonism markedly attenuated phenylacetylamide's anti-MM effects. Phenylacetylamide triggered the expression of C/EBP homologous protein at the early treatment stage, followed by death receptor-5 upregulation, caspase activation, and β-actin/tubulin degradation. Cell cycle related protein cdc25C and mitotic regulator Aurora A kinase were inactivated by phenylacetylamide treatment, leading to an increase in the ratio inactive/active cdc2 kinase. As a result, phosphorylation of CDK substrates was decreased, and the MM cell mitotic division was largely blocked by treatment. Importantly, phenylacetylamide could overcome the chemoresistance of MM cells against dexamethasone or melphalan. Thus, targeting CB2 may represent an attractive approach to treat cancers of immune origin.
authors: Department of Pharmaceutical Sciences and Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy, and NIH NIDA Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Rentian
authors: R
authors: Feng
authors: Department of Pharmaceutical Sciences and Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy, and NIH NIDA Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Qin
authors: Q
authors: Tong
authors: Department of Pharmaceutical Sciences and Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy, and NIH NIDA Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Zhaojun
authors: Z
authors: Xie
authors: Department of Pharmaceutical Sciences and Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy, and NIH NIDA Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Haizi
authors: H
authors: Cheng
authors: Department of Pharmaceutical Sciences and Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy, and NIH NIDA Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Computational Biology, Joint Pitt/CMU Computational Biology Program, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Lirong
authors: L
authors: Wang
authors: Division of Hematology/Oncology, Columbia University, New York.
authors: Suzanne
authors: S
authors: Lentzsch
authors: Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana.
authors: G David
authors: GD
authors: Roodman
authors: Department of Pharmaceutical Sciences and Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy, and NIH NIDA Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Computational Biology, Joint Pitt/CMU Computational Biology Program, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Xiang-Qun
authors: XQ
authors: Xie
mesh_terms: D000199:Actins / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000235:genetics; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D020169:Caspases / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D003599:Cytoskeleton / Q000187:drug effects* / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D053668:Syndecan-1 / Q000235:genetics; D014404:Tubulin / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000199:Actins; C588309:CNR2 protein, human; D063386:Cannabinoid Receptor Agonists; D018797:Cell Cycle Proteins; D043885:Receptor, Cannabinoid, CB2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C508241:SDC1 protein, human; D053668:Syndecan-1; D014404:Tubulin; D016203:CDC2 Protein Kinase; D020169:Caspases
keywords: apoptosis; cannabinoid receptor-2; cell cycle; cytoskeleton; multiple myeloma
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