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

Uchini S. Kosgodage, Rhys Mould, Aine B. Henley, Alistair V. Nunn, Geoffrey W. Guy, E. L. Thomas, Jameel M. Inal, Jimmy D. Bell and Sigrun Lange

Frontiers in Pharmacology, 2018, Volume 9, Article 889

doi : 10.3389/fphar.2018.00889

 

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 mM) 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.

Keywords : exosomes, microvesicles (MVs), cannabidiol (CBD), peptidylarginine deiminase (PAD), cancer, inflammation, mitochondria, combinatory treatment

 

INTRODUCTION

Extracellular vesicles released from cells are classified into exosomes, microvesicles and apoptotic bodies (György et al., 2011). Exosomes and microvesicles (EMVs) are lipid-bilayer structures that carry molecules characteristic of their parental cells to recipient cells, mediating intercellular communication and affecting various physiological and pathological processes including cell migration, differentiation and angiogenesis (Ansa-Addo et al., 2010; Muralidharan-Chari et al., 2010; Turola et al., 2012; Colombo et al., 2014; Batrakova and Kim, 2015; Kholia et al., 2016).

Microvesicles (MVs) are phospholipid-rich cell-membrane derived vesicles (100–1000 nm) released as part of normal physiology as well as during apoptosis or upon stimulation (Piccin et al., 2007; Inal et al., 2013). The release of MVs can be mediated via calcium ion influx through stimulation of cation channels such as the ATP-gated P2X7, through pores created by sublytic complement, or via calcium released by the endoplasmic reticulum (Turola et al., 2012; Raposo and Stoorvogel, 2013; Stratton et al., 2015a,b). This increase in cytosolic calcium results in cytoskeletal reorganization and membrane asymmetry, followed by subsequent MV blebbing (Inal et al., 2012, 2013; Kholia et al., 2015; Kosgodage et al., 2017; Tricarico et al., 2017). MV formation can also be caused by mitochondrial stress, which leads to increased membrane permeability and leakage of reactive oxygen species (ROS), cytochrome C and apoptosis inducing factor into the cytoplasm. This results in the formation of the apoptosome – which, during pseudoapoptosis, can be formed into MVs for the export of hazardous agents (Inal et al., 2013).

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