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.

The tamoxifen derivative ridaifen-B is a high affinity selective CB 2 receptor inverse agonist exhibiting anti-inflammatory and anti-osteoclastogenic effects

“…The present study identifies RID-B as the first high affinity, selective, CB 2 inverse agonist derived from a SERM scaffold. Furthermore, similar to that reported for other selective CB 2 inverse agonists (Idris et al, 2008; Yang et al, 2013; Reiner et al, 2014; Feng et al, 2015; Presley et al, 2015a), RID-B exhibits anti-inflammatory, anti-osteoclastogenic and cytotoxic effects that are mediated in part by CB 2 and/or CB 1 receptors. RID-B is a first generation pseudo-symmetrical derivative of tamoxifen with reduced ER affinity (Shiina et al, 2008; Guo et al, 2013b), while exhibiting increased affinity for cannabinoid receptors (this study).…”

“…In addition to development as anti-inflammatory agents, CB 2 inverse agonists may represent a novel approach to treat certain forms of cancer (Feng et al, 2015). In support of this suggestion, there is significant overlap between the mechanisms by which RID-B and cannabinoids produce cytotoxicity in cancers of immune origin.…”

Cannabinoid derivatives exert a potent anti-myeloma activity bothin vitroandin vivo

“…Given that U266 and RPMI cell lines do not express the receptor TRPV2, we suggest that the effect of WIN‐55 on myelomatous cells would not be mediated by this vanilloid receptor. For their part, Feng et al . studied the effect of a cannabinoid receptor antagonist, namely phenylacetylamide, and they showed that this drug induces cell cycle arrest in MM cell lines.…”

The influence of biomechanical properties and cannabinoids on tumor invasion

“…In myeloma cell lines a reduction of b-actin und b-tubulin protein levels were found after inhibition of CB2. 26 A reorganization of cytoskeletal components was observed in various cell types treated with cannabinoids without reporting precise measurements of changes of biomechanical parameters. [27][28][29][30] Here, we have shown that stimulation with cannabinoid receptor agonists can have a (non-)receptor specific impact on cell stiffness.…”