Cannabidiol Enhances the Therapeutic Effects of TRAIL by Upregulating DR5 in Colorectal Cancer, Jung Lim Kim et al., 2019

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

Jung Lim Kim, Bo Ram Kim, Dae Yeong Kim, Yoon A. Jeong, Soyeon Jeong, Yoo Jin Na, Seong Hye Park, Hye Kyeong Yun, Min Jee Jo, Bu Gyeom Kim, Han Do Kim, Dae Hyun Kim, Sang Cheul Oh, Sun Il Lee and Dae-Hee Lee

Cancers, 2019, 11, 642

DOI : 10.3390/cancers11050642

Abstract : 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 e ects in vitro. However, this synergistic e ect 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 e ect 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.

Keywords : cannabidiol; TNF-related apoptosis-inducing ligand; death receptor 5; endoplasmic reticulum stress

1. Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide, with nearly 1.4 million new cases diagnosed in 2017 [1]. Treatment of colorectal cancer most commonly involves a combination of three classic strategies of oncology: surgery, radiation, and chemotherapy. Many chemotherapeutic regimens have been used clinically for the treatment of colorectal cancer, but it is necessary to continue to develop new therapeutic agents for its successful treatment.

TNF-related apoptosis-inducing ligand (TRAIL) is a type 2 membrane protein belonging to the TNF superfamily. TRAIL induces apoptosis via interaction with its corresponding death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) [2]. TRAIL is one of the few tumor-selective agents that selectively kill cancer cells by activating signaling pathways used by the innate immune system, and it is not toxic to normal cells [3]. TRAIL has therapeutic potential for the treatment of cancer and is currently undergoing clinical phase Iand IItrials [4,5]. Nevertheless, recombinant TRAIL has limitations, such as its short plasma half-life and cellular resistance to its apoptotic e ects [6]. The mechanisms of TRAIL resistance that have been reported include downregulation of death receptors, loss of apoptotic proteins, and activation of the NF-B and PI3K/AKT pathways [7–9]. Therefore, it is necessary to understand the underlying mechanisms of the resistance to TRAIL and to overcome this resistance. It is possible to increase the sensitivity to TRAIL by combining it with other anticancer agents.

Cannabidiol (Figure 1A), a major non-psychotomimetic compound derived from Cannabis sativa, is a potential therapeutic agent for a variety of diseases such as inflammatory diseases, chronic neuro-degenerative diseases, and cancers. In particular, cannabidiol is being tested as a potential anticancer agent for a variety of cancers, including breast cancer, neuroblastoma, glioma, prostate cancer, and colorectal cancer [10–13]. Cannabidiol is already undergoing clinical trials for the treatment of brain tumors such as gliomas. In colorectal cancer cell lines, cannabidiol reduced cell proliferation through antagonism of cannabinoid receptor type 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1), protected DNA from oxidative damage, and increased endocannabinoid levels [14]. However, the underlying mechanism of the antitumor function of cannabidiol in solid tumor cells is not fully understood. Thus, there is interest in investigating the possible TRAIL-sensitization of cancer cells by the combined treatment of cannabidiol and TRAIL, which could enhance cell death.

The endoplasmic reticulum (ER) plays an essential role in protein synthesis, maturation, lipid synthesis, calcium homeostasis, and protein folding [10]. Intermediate ER stress acts as a defense mechanism for cell survival, but severe or prolonged ER stress may lead to the initiation of apoptosis [11,12]. Recent studies have found that anticancer agents, reactive oxygen species, hypoxia, and radiation aggravate ER-stress responses and activate ER stress-mediated apoptosis pathways in cancer [13,14]. Therefore, we hypothesized that cannabidiol activates ER stress-related apoptosis via exacerbating reactive oxygen species generation and aggravating ER-stress responses.

In the present study, we investigated whether the combination of cannabidiol and TRAIL could induce apoptosis in colorectal cancer cells. We found that cannabidiol enhanced TRAIL-induced apoptosis by increasing the expression of DR5 through ER-stress in colorectal cancer cells. Collectively, our results suggest that cannabidiol is a new agent for increasing the sensitivity to TRAIL.