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Mol Carcinog. 2015 Dec;54(12):1796-806. doi: 10.1002/mc.22251. Epub 2015 Jan 16.

Targeting cannabinoid receptor-2 pathway by phenylacetylamide suppresses the proliferation of human myeloma cells through mitotic dysregulation and cytoskeleton disruption.

Author information

1
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.
2
Department of Computational Biology, Joint Pitt/CMU Computational Biology Program, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Division of Hematology/Oncology, Columbia University, New York.
4
Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana.

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.

KEYWORDS:

apoptosis; cannabinoid receptor-2; cell cycle; cytoskeleton; multiple myeloma

PMID:
25640641
PMCID:
PMC4504841
DOI:
10.1002/mc.22251
[Indexed for MEDLINE]
Free PMC Article

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