Abstract
Over the last few years, much attention has been paid to phytocannabinoids derived from Cannabis for their therapeutic potential. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant compounds of the Cannabis sativa L. plant. Recently, novel phytocannabinoids, such as cannabidibutol (CBDB) and cannabidiphorol (CBDP), have been discovered. These new molecules exhibit the same terpenophenolic core of CBD and differ only for the length of the alkyl side chain. Roles of CBD homologs in physiological and pathological processes are emerging but the exact molecular mechanisms remain to be fully elucidated. Here, we investigated the biological effects of the newly discovered CBDB or CBDP, compared to the well-known natural and synthetic CBD (nat CBD and syn CBD) in human breast carcinoma cells that express CB receptors. In detail, our data demonstrated that the treatment of cells with the novel phytocannabinoids affects cell viability, increases the production of reactive oxygen species (ROS) and activates cellular pathways related to ROS signaling, as already demonstrated for natural CBD. Moreover, we observed that the biological activity is significantly increased upon combining CBD homologs with drugs that inhibit the activity of enzymes involved in the metabolism of endocannabinoids, such as the monoacylglycerol lipase (MAGL) inhibitor, or with drugs that induces the activation of cellular stress pathways, such as the phorbol ester 12-myristate 13-acetate (PMA).
Highlights
Cannabinoids include a wide group of organic molecules, including those that are physiologically produced in the human body, called endocannabinoids, those extracted primarily from the Cannabis sativa L. plant, named phytocannabinoids, and synthetic cannabinoids [1]
High-performance liquid chromatography coupled to high-resolution mass spectrometry (HPLC-HRMS) analyses has recently shown that nat CBD contains small amounts (0.1–0.5%, w/w) of two impurities corresponding to CBD propyl and butyl homologs, cannabidivarin (CBDV) and CBDB respectively [4]
The length of the alkyl side chain could dramatically affect the affinity for the biological targets as it has been demonstrated for THC, a CBD isomer [22]
Summary
Cannabinoids include a wide group of organic molecules, including those that are physiologically produced in the human body, called endocannabinoids, those extracted primarily from the Cannabis sativa L. plant, named phytocannabinoids, and synthetic cannabinoids [1]. In the last few years, the homologous series of CBD has been expanded by the isolation in a medicinal cannabis variety of novel phytocannabinoids such as cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN) and cannabidivarin (CBDV) [3,4,5,6,7,8] These compounds have similar chemical structures, they can elicit different biological actions. We investigated the biological effects of two novel CBD homologs in breast cancer cells and reported, for the first time, the activation of catastrophic processes after the combination of CBDB or CBDP with drugs that modulate the metabolism of endocannabinoids or regulate the activation of specific protein kinases
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