Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer

Abstract

Exosomes and microvesicles (EMV) are lipid bilayer-enclosed structures, released by cells and involved in intercellular communication through transfer of proteins and genetic material. EMV release is also associated with various pathologies, including cancer, where increased EMV release is amongst other associated with chemo-resistance and active transfer of pro-oncogenic factors. Recent studies show that EMV-inhibiting agents can sensitize cancer cells to chemotherapeutic agents and reduce cancer growth in vivo. Cannabidiol (CBD), a phytocannabinoid derived from Cannabis sativa, has anti-inflammatory and anti-oxidant properties, and displays anti-proliferative activity. Here we report a novel role for CBD as a potent inhibitor of EMV release from three cancer cell lines: prostate cancer (PC3), hepatocellular carcinoma (HEPG2) and breast adenocarcinoma (MDA-MB-231). CBD significantly reduced exosome release in all three cancer cell lines, and also significantly, albeit more variably, inhibited microvesicle release. The EMV modulating effects of CBD were found to be dose dependent (1 and 5 μM) and cancer cell type specific. Moreover, we provide evidence that this may be associated with changes in mitochondrial function, including modulation of STAT3 and prohibitin expression, and that CBD can be used to sensitize cancer cells to chemotherapy. We suggest that the known anti-cancer effects of CBD may partly be due to the regulatory effects on EMV biogenesis, and thus CBD poses as a novel and safe modulator of EMV-mediated pathological events.

Peptidylarginine Deiminase inhibition abolishes the production of large extracellular vesicles fromGiardia intestinalis, affecting host-pathogen interactions by hindering adhesion to host cells

“…Previous work has also suggested that PAD-inhibitors can be strategically used to sensitize cancer cells to chemotherapy (Kholia et al, 2015; Kosgodage et al, 2017). The EV-modulatory functions of CBD were recently revealed, and it has been found to be a more potent EV inhibitor than Cl-amidine in some cancers, also to have chemosensiting effects and shows selective inhibition on smaller or larger EVs according to cancer type (Kosgodage et al, 2018b).…”

“…In addition, cannabidiol (CBD), a phytocannabinoid derived from Cannabis sativa (Mechoulam et al, 2002) was recently identified as a potent EV-inhibitor in cancer cells (Kosgodage et al, 2018b, Kosgodage et al, 2019). As cannabinoids have previously been associated with anti-parasitic functions (Nok et al, 1994, Croxford et al, 2005; Roulette et al, 2016) and immunoregulatory roles during infectious disease (reviewed in Hernández-Cervantes et al, 2017) we sought to identify whether EV release from Giardia may be affected by CBD, thus elucidating a novel aspect of CBD function on Giardia -host interaction.…”

Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma—An Overview

“…As mentioned before, the development of inhibitory techniques limiting cancer-derived EV release is an important area of research. Recently, Kosgodage et al [68] reported that cannabidiol (CBD) plays a role in inhibiting the release of EVs from an HCC cell line (HepG2). CBD, which is a phytocannabinoid extracted from Cannabis sativa, possesses antioxidant, anti-inflammatory, and antiproliferative properties.…”

A Novel, Tumor-Induced Osteoclastogenesis Pathway Insensitive to Denosumab but Interfered by Cannabidiol

“…We then investigated whether agents that inhibit the secretion of exosomes affected tumor-induced osteoclastogenesis. We selected two drugs, CBD and dimethyl amiloride (DMA) as candidates, both of which have been shown to suppress the secretion of exosomes [19,20]. In contrast to the ineffectiveness of the administration of denosumab, CBD and DMA both significantly inhibited osteoclastogenesis induced by 3A cells.…”

“…Each medium was changed after two days of culture, and osteoclastogenesis was evaluated on day four of the culture, as described above. The optimum concentration of CBD and DMA was evaluated by the application of different concentrations of CBD or DMA to the cocultures, as described previously [19,38].…”