Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer

Abstract

In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB₁ and CB₂. CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ⁹-THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa, since it contains only few levels of Δ⁹-THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ⁹-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ⁹-THC deprived hemp.

Figure 1

Chemical structures of main cannabinoids present in Cannabis sativa L. Abbreviation: Δ = heating; ox = oxidation; is = isomerization.

Figure 2

General representation of the signaling pathways involved in CBD anti-inflammatory effects. Cannabinoids reduce peripheral inflammation by acting at TRPV1, CB₂, and GPR55 receptors; these interactions lead to downregulation of enzymes involved in the production of prostaglandins, reactive oxygen species, and cytokines. MAPK inhibition and NF-kB downregulation, together with PPARγ-mediated reduction of lipid peroxidation, are also involved in the anti-inflammatory effects of cannabinoids in the CNS. Abbreviations: CBD, cannabidiol; CNS, central nervous system, CB₂, cannabinoid receptor 2; TRPV1, receptor potential channel subfamily V member 1; GPR55, orphan G-protein coupled receptor 55; Akt, protein kinase B; ERK, extracellular signal-regulated kinases; NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; COX2, cyclooxygenase 2; TNF-α, tumor necrosis factor alpha; PPARγ, peroxisome proliferator-activated receptor gamma.

Figure 3

General representation of the signaling pathways involved in CBD anticancer mediated effects. Cannabinoid-induced apoptosis relies on the stimulation of endoplasmic reticular (ER) stress and through stimulation of TRPV channel. The signaling route involving the arrest of cell proliferation is mediated by the antagonism mainly on GPR55, which causes an inhibition of the activation of ERK pathway; in addition, the block of ROCK activation might be responsible for the antimigratory effect elicited by cannabidiol. CBD, cannabidiol; CB₂, cannabinoid receptor 2; TRPV1/2, receptor potential channel subfamily V members 1 and 2; GPR55, orphan G-protein coupled receptor 55; ROS, reactive oxygen species; ER, endoplasmic reticulum; p8, protein p8 (Nuclear Protein 1, NUPR1); CHOP, CCAAT/-enhancer-binding protein homologous protein; ATF2, activating transcription factor 2; CREB, cAMP response element-binding protein; Akt, protein kinase B; ROCK Rho-associated protein kinase; NFAT, nuclear factor of activated T-cells; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PKC, protein kinase C; P38, mitogen-activated protein kinases.