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

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 ce...

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Autores principales:	Federica Mannino, Giovanni Pallio, Roberta Corsaro, Letteria Minutoli, Domenica Altavilla, Giovanna Vermiglio, Alessandro Allegra, Ali H. Eid, Alessandra Bitto, Francesco Squadrito, Natasha Irrera
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	beta-caryophyllene cannabinoid receptor 2 multiple myeloma apoptosis Wnt/β-catenin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b386869567b346e3803739868b25df20
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spelling	oai:doaj.org-article:b386869567b346e3803739868b25df202021-11-25T17:03:28ZBeta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells10.3390/cancers132257412072-6694https://doaj.org/article/b386869567b346e3803739868b25df202021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5741https://doaj.org/toc/2072-6694Cannabinoid 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.Federica ManninoGiovanni PallioRoberta CorsaroLetteria MinutoliDomenica AltavillaGiovanna VermiglioAlessandro AllegraAli H. EidAlessandra BittoFrancesco SquadritoNatasha IrreraMDPI AGarticlebeta-caryophyllenecannabinoid receptor 2multiple myelomaapoptosisWnt/β-cateninNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5741, p 5741 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	beta-caryophyllene cannabinoid receptor 2 multiple myeloma apoptosis Wnt/β-catenin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	beta-caryophyllene cannabinoid receptor 2 multiple myeloma apoptosis Wnt/β-catenin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Federica Mannino Giovanni Pallio Roberta Corsaro Letteria Minutoli Domenica Altavilla Giovanna Vermiglio Alessandro Allegra Ali H. Eid Alessandra Bitto Francesco Squadrito Natasha Irrera Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells
description	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.
format	article
author	Federica Mannino Giovanni Pallio Roberta Corsaro Letteria Minutoli Domenica Altavilla Giovanna Vermiglio Alessandro Allegra Ali H. Eid Alessandra Bitto Francesco Squadrito Natasha Irrera
author_facet	Federica Mannino Giovanni Pallio Roberta Corsaro Letteria Minutoli Domenica Altavilla Giovanna Vermiglio Alessandro Allegra Ali H. Eid Alessandra Bitto Francesco Squadrito Natasha Irrera
author_sort	Federica Mannino
title	Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells
title_short	Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells
title_full	Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells
title_fullStr	Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells
title_full_unstemmed	Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells
title_sort	beta-caryophyllene exhibits anti-proliferative effects through apoptosis induction and cell cycle modulation in multiple myeloma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b386869567b346e3803739868b25df20
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Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells

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