# \(\beta\)-Caryophyllene: A Sesquiterpene with Countless Biological Properties
## 2 Biological properties of \(\beta\)-caryophyllene
### \(\beta\)-Caryophyllene and Cancer  
Both BCP and BCPO have shown cytotoxic activity against various cancer cell lines. In particular, BCP has significantly decreased the proliferation of two colon cancer cell lines, HT-29 and HCT-116, and a pancreas cancer cell line, PANC-1. Moreover, it has been quite successful on other types of cancer cells [45]. In the intestinal cancer cell line CaCo-2 [46], for example, BCP has not been able to exert a significant effect on cell growth, unlike the isomer \(\alpha\)-humulene [13]. In human breast cancer cells MCF-7, BCP amplifies the cytotoxicity of the isomers isocaryophyllene and \(\alpha\)-humulene [47]. A study realized on obese mice C57 BL/6N, injected with melanoma cells, has shown that the phytocannabinoid is able to decrease the precancerous effect caused by a high-fat diet [48]. BCP, which is more than 25% of the essential oil from _Pamburus missionis_, has synergistic effect with two other important components of the essential oil, phytol (**8**) and aromadendrene oxide (**9**) (Figure 3), resulting in antitumor activity against A431 and HaCaT cell lines, by blocking the cell in phase G0/G1 or sub-G1. The mechanism of action is associated to ROS production [69] and the mitochondrial membrane potential loss, by increasing Bax expression and decreasing Bcl-2 expression. Bax and Bak oligomers form pores, which increase the permeability of the external mitochondrial membrane, releasing cytochrome c in the cytoplasm, which is an apoptosis characterizing event [70; 71; 72]. The release of cytochrome c from mitochondria to cytosol leads to the formation of apoptosomes, and consequently, the activation of caspase-9, which activates the cascade of the effector caspases [49; 73; 74]. It has been shown that BCP causes the activation of caspase-3 and determines nucleolus fragmentation and the consequent apoptosis in two different cell lines, BS-24-1 (murine cell line of lymphoma) and MoFir (human T cell transformed through Epstein-Barr virus) [49]. BCP, one of the compounds in the essential oil, of _Comniophora gileadensis_, is responsible for antiproliferative exhibited by 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolzolium Bromide (MTT) assay [75; 76; 77; 78; 79; 80] and proapoptotic effects (exhibited via DNA \"ladder\" and caspase-3 activation) in tumor cell lines, while there was no apoptosis induction in normal cell lines (FB) [13; 50]. Figure 3: Structures of the phytol (**8**) and aromadendrene oxide (**9**). Anyhow, numerous studies have revealed that BCP enhances the effectiveness of antitumor drugs. In particular, a research has shown that it increases the activity of paclitaxel in lots of cell lines: MCF-7 (breast cancer), L-929 (mouse fibroblasts), DLD-1 (colon cancer) [47]. In detail, in the latter cell line, the BCP determines a rise of the intracellular concentrations in the drug, probably by increasing the permeability of the cell membrane [13]. BCP has been reported to exert anticancer and hypoglycemic effects in BALB/c mice transplanted with cells of the line CT26 exposed to high levels of glucose, to mimic a colorectal cancer. The sesquiterpene blocks ART1 effects, by inhibiting NF-kB. ART1 (arginine-specific mono-ADP-ribosyl transferase 1) is an enzyme, whose concentrations are higher in patients with type 2 diabetes, involved in the pathogenesis of colorectal cancer. The overexpression of ART1 probably increases glycolysis and energy metabolism, thus regulating the protein kinase B/mammalian target of rapamycin/c-Myc signaling pathway and the expression of glycolytic enzymes. This suggests that BCPO may be a potential treatment for this kind of carcinoma [51]. Further, BCPO is cytotoxic against various cell lines, including: HeLa (human cervical adenocarcinoma cells), HepG2 (human leukaemia cells), AGS (human lung cancer cells), SNU-1 and SNU-16 (human stomach cancer cells) and A-2780 (human ovarian cancer cells).