Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells

Federica Mannino; Giovanni Pallio; Roberta Corsaro; Letteria Minutoli; Domenica Altavilla; Giovanna Vermiglio; Alessandro Allegra; Ali H Eid; Alessandra Bitto; Francesco Squadrito; Natasha Irrera

doi:10.3390/cancers13225741

Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells

Cancers (Basel). 2021 Nov 16;13(22):5741. doi: 10.3390/cancers13225741.

Affiliations

¹ Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria Gazzi, 98125 Messina, Italy.
² Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria Gazzi, 98125 Messina, Italy.
³ Department of Human Pathology in Adulthood and Childhood, University of Messina, Via C. Valeria Gazzi, 98125 Messina, Italy.
⁴ Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, 2713 Doha, Qatar.
⁵ Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, 2713 Doha, Qatar.

Abstract

Cannabinoid receptors, which are widely distributed in the body, have been considered as possible pharmacological targets for the management of several tumors. Cannabinoid type 2 receptors (CB2Rs) belong to the G protein-coupled receptor family and are mainly expressed in hematopoietic and immune cells, such as B-cells, T-cells, and macrophages; thus, CB2R activation might be useful for treating cancers affecting plasma cells, such as multiple myeloma (MM). Previous studies have shown that CB2R stimulation may have anti-proliferative effects; therefore, the purpose of the present study was to explore the antitumor effect of beta-caryophyllene (BCP), a CB2R agonist, in an in vitro model of MM. Dexamethasone-resistant (MM.1R) and sensitive (MM.1S) human multiple myeloma cell lines were used in this study. Cells were treated with different concentrations of BCP for 24 h, and a group of cells was pre-incubated with AM630, a specific CB2R antagonist. BCP treatment reduced cell proliferation through CB2R stimulation; notably, BCP considerably increased the pro-apoptotic protein Bax and decreased the anti-apoptotic molecule Bcl-2. Furthermore, an increase in caspase 3 protein levels was detected following BCP incubation, thus demonstrating its anti-proliferative effect through apoptosis activation. In addition, BCP regulated AKT, Wnt1, and beta-catenin expression, showing that CB2R stimulation may decrease cancer cell proliferation by modulating Wnt/β-catenin signaling. These effects were counteracted by AM630 co-incubation, thus confirming that BCP's mechanism of action is mainly related to CB2R modulation. A decrease in β-catenin regulated the impaired cell cycle and especially promoted cyclin D1 and CDK 4/6 reduction. Taken together, these data revealed that BCP might have significant and effective anti-cancer and anti-proliferative effects in MM cells by activating apoptosis, modulating different molecular pathways, and downregulating the cell cycle.

Keywords: Wnt/β-catenin; apoptosis; beta-caryophyllene; cannabinoid receptor 2; multiple myeloma.