Cannabidiol Enhances the Therapeutic Effects of TRAIL by Upregulating DR5 in Colorectal Cancer

Cannabidiol, a major non-psychotomimetic compound derived from Cannabis sativa, is a potential therapeutic agent for a variety of diseases such as inflammatory diseases, chronic neurodegenerative diseases, and cancers. Here, we found that the combination of cannabidiol and TNF-related apoptosis-inducing ligand (TRAIL) produces synergistic antitumor effects in vitro. However, this synergistic effect was not observed in normal colonic cells. The levels of ER stress-related proteins, including C/EBP homologous protein (CHOP) and phosphorylated protein kinase RNA-like ER kinase (PERK) were increased in treatment of cannabidiol. Cannabidiol enhanced significantly DR5 expression by ER stress. Knockdown of DR5 decreased the combined effect of cannabidiol and TRAIL. Additionally, the combination of TRAIL and cannabidiol decreased tumor growth in xenograft models. Our studies demonstrate that cannabidiol enhances TRAIL-induced apoptosis by upregulating DR5 and suggests that cannabidiol is a novel agent for increasing sensitivity to TRAIL.