New insights in the antitumor effects of β-caryophyllene in breast cancer cells: The role of cannabinoid and adrenergic systems

Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive disease, with poor therapeutic alternatives, whose incidence and mortality seem to be increased by smoking habit. In line with our previous evidence (Di Giacomo et al. Food Chem Toxicol 2018,111:393), we evaluated the antitumor properties of the natural sesquiterpene bcaryophyllene (CRY) in triple negative breast cancer as a possible novel targeted therapeutic strategy. Particularly, its effect on the molecular pathways of STAT3 and IL-8, and the involvement of cannabinoid and b2-adrenergic systems, whose control on cell proliferation has been reported, were studied. Methods: Cytotoxicity of CRY was evaluated in triple negative MDA-MB-468 breast cancer cells, also after pre-treatment with CB1-, CB2- and b2-adrenergic receptor antagonists (AM281, AM630 and ICI 118.551). To study the ability of CRY to interfere with the pro-carcinogenic effects of tobacco smoke, cells were treated with a condensed sample of cigarette smoke (CSC). The levels of STAT3/ERP57, IL-8 and ROS were measured. At last, we looked at the expression of BIRC5, MMP2 and TPX2 genes, known to regulate cancer progression and metastatization. Results: CRY was found able to significantly inhibit the growth of MDA-MB-468 cells: the effect was slightly reduced by AM630, while a remarkable inhibition by ICI 118.551 was displayed. CRY also inhibited the activation of STAT3 pathway and the pro-oxidant effects of CSC. IL-8 level resulted significantly reduced by CSC, while the basal level was restored by CRY. Furthermore, a remarkable inhibition of CSC-induced cell migration and BIRC5, MMP2 and TPX2 gene expression was found. Conclusions: Data obtained highlight antiproliferative properties of CRY in triple negative breast cancer, with a possible b2-adrenergic systemcontribution. CRY acts partly by a CB2- activation, although other CB1/CB2 independent mechanisms appear involved. CRY also interferes with smoking-induced progression and metastatization of breast cancer cells: this effect can be approached as a chemopreventive strategy in breast oncologic patients. Present results encourage further studies on CRY as chemopreventive agent or in targeted supporting therapies for breast cancer.