Cannabidiol (CBD) as a Promising Anti-Cancer Drug

Abstract

Recently, cannabinoids, such as cannabidiol (CBD) and Δ⁹ -tetrahydrocannabinol (THC), have been the subject of intensive research and heavy scrutiny. Cannabinoids encompass a wide array of organic molecules, including those that are physiologically produced in humans, synthesized in laboratories, and extracted primarily from the Cannabis sativa plant. These organic molecules share similarities in their chemical structures as well as in their protein binding profiles. However, pronounced differences do exist in their mechanisms of action and clinical applications, which will be briefly compared and contrasted in this review. The mechanism of action of CBD and its potential applications in cancer therapy will be the major focus of this review article.

Keywords: CBD; Cannabidiol; Cannbinoids; anti-cancer drug.

Figure 1

Endocannabinoid system. (A) Chemical structures of two endogenous cannabinoids, 2-arachidonylglycerol (i, 2-AG) and N-arachidonylethanolamine (ii, AEA), and two representative exogenous cannabinoids from Cannabis sativa, cannabidiol (iii, CBD) and Δ⁹-tetrahydrocannabinol (iv, Δ⁹-THC). (B) Schematic diagrams of the signaling transduction pathways of the endocannabinoid system. 2-AG and AEA are agonists of CB₁ and CB₂. Some of the downstream effects include: (1) upregulation of p42/p44 mitogen-activated protein kinases (MAPKs) by direct inhibition of adenylyl cyclase (AC) and direct activation of phospholipase C (PLC), leading to the induction of neuronal growth, interleukin production, and inflammation. PKA: protein kinase A. PKC: protein kinase C. (2) Activation of p38 MAPK, which induces inflammation and apoptosis. (3) Activation of the phosphatidylinositol-3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) signaling pathways. Under certain conditions, these endocannabinoids can also induce transcription, cell survival, proliferation, and differentiation through similar pathways. Additionally, the cannabinoid receptors can also modulate ion channels including G protein-coupled inwardly-rectifying potassium channels (GIRKs) and voltage (V)-gated calcium channels.

Figure 2

Origins and effects of cellular reactive oxygen species (ROS). ROS are generated by complex I and III of the electron transport chain in the mitochondria and by NADPH oxidase (NOX) enzymes located at the cytoplasmic membrane (PM). ROS disrupt cellular processes by oxidizing the cysteine (Cys) residues of various proteins and damaging nucleic acids. Oxidation by ROS could cause the inactivation of phosphatases, activation of kinases and transcription factors (TF), and genomic alterations, leading to enhanced cellular proliferation and survival. ROS production is counteracted by the generation of antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), peroxiredoxin (PRX), thioredoxin (TRX), and catalase. In cancers, redox homeostasis is modified to favor ROS tolerance. OM: outer mitochondrial membrane. IM: inner mitochondrial membrane. NM: nuclear membrane.

Figure 3

Endoplasmic reticulum (ER) homeostasis, stress, and the unfolded protein response (UPR). (A) ER homeostasis is mediated by 78-kDa glucose-regulated protein (GRP78). Under stress conditions, GRP78 dissociates from pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzymes 1α (IRE1α), as well as the activating transcription factor 6 (ATF6), leading to activation of their downstream signaling cascades in order to restore ER homeostasis. (B) When ER homeostasis fails to be restored, excessive UPR could lead to apoptosis, primarily via upregulation of C/EBP homologous protein (CHOP). PM: cytoplasmic membrane; eIF2α: eukaryotic initiation factor 2α; ATF4: activating transcription factor 4; GADD34: DNA damage inducible protein 34; XPB1: X-box-binding protein (XBP1s: spliced form); ERO1α: endoplasmic reticulum oxidoreductase 1α; PDI: protein disulfide isomerase; DR5: death receptor 5; TRAIL: TNF related apoptosis-inducing ligand; IP3R: inositol 1,4,5-triphosphate receptor; BAP31: B cell receptor-associated protein 31; Bid: BH3 Interacting Domain Death Agonist; TRAF2: tumor necrosis factor receptor-associated factor 2; RIDD: regulated IRE1-dependent decay; ASK1: apoptosis signal-regulating kinase 1; JNK: JUN N-terminal kinase; E2F7: E2F transcription factor 7; E2F1: E2F transcription factor 1.

Figure 4

The interplays between tumor cells and inflammatory cells during tumorigenesis. (A) The effect of tumor cells on inflammatory cells. Tumor cells secrete many cytokines to alter the microenvironment to promote tumor growth and invasion and to blunt the anti-tumorigenic immune response. (B) Inflammatory cells affect the genomic stability of tumor cells. AID: activation-induced cytidine deaminase; DNMT1: DNA methyltransferase 1. (C) Inflammatory cells enhance tumor cell proliferation and survival through autocrine and paracrine signaling. (D) Inflammatory cells promote tumor cell migration, invasion, and metastasis through cytokine and chemokine production. COX-2: cyclooxygenase 2; MMP: matrix metalloproteinase; E-cad: E-cadherin; EMT: epithelial-mesenchymal transition; sLex: sialyl Lewis X; CXCR: CXC chemokine receptor; BV: blood vessel.

Figure 5

CBD’s effects on cancer cells and infiltrating immune cells. (A) Through its interactions with the CB₁, CB₂, and TRPV1 receptors, CBD induces cell cycle arrest and apoptosis in cancer cells. (B) CBD also binds the CB₁ and CB₂ receptors on the infiltrating inflammatory cells and disrupts the pro-tumorigenic cytokine production, thus leading to ineffective immunosuppression and promoting tumor cell death. ROS production by phagocytic cells disrupts the ER and mitochondrial homeostasis in tumor cells leading to apoptosis. UPR: unfolded protein response.