cbd and non hodgkin’s lymphoma

Cbd and non hodgkin's lymphoma

Together, these findings provide a novel mechanism underlying the anti-invasive action of CBD on human lung cancer cells and imply its use as a therapeutic option for the treatment of highly invasive cancers.

Endogenous ligands for the cannabinoid receptors were discovered soon after their characterization. The two major known endogenous ligands are anandamide (AEA) and 2-AG [3–6]. Both are arachidonic acid derivatives produced from phospholipid precursors through activity-dependent activation of specific phospholipase enzymes [7]. Later on, a number of other eCB ligands have been discovered, including N-arachidonoyldopamine, N-arachidonoylglycerolether and O-arachidonoylethanolamine [8].

Given the poor response of lung cancer to available therapy and its aggressive biological nature, a series of targets and new therapeutic strategies for their treatment are currently being investigated [47–50].

AEA and 2-AG do not share the same biosynthetic or metabolic pathways. Different pathways can produce AEA from the phospholipid precursor N-arachidonoyl-phosphatidylethanolamine, the most important being a direct conversion catalyzed by an N-acyl-phosphatidylethanolamine-selective phosphodiesterase. 2-AG is mainly synthesized through activation of phospholipase C and subsequent production of diacylglycerol, which is converted to 2-AG by diacylglycerol lipase. After its re-uptake, AEA is hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH), producing arachidonic acid and ethanolamine, while 2-AG is primarily metabolized by monoacylglycerol lipase, leading to the formation of arachidonic acid and glycerol [9]. Apart from their binding to CB1 and CB2 receptors, eCBs may bind to other receptors. For example, AEA may intracellularly activate the potential vanilloid receptor type 1 (TRPV1) [10]. Moreover, other putative cannabinoid receptors are the ‘orphan’ G protein-coupled receptor, GPR55 [11], and the peroxisome proliferator-activated receptor, PPAR [12, 13]. However, CB1 and CB2 receptors are certainly the most known targets for AEA and 2-AG, which activate them with different affinity. AEA has the highest affinity in both cases, whereas 2-AG has the highest efficacy in both cases [14].

CBD and colon cancer

Together, the results suggest that CBD, acting through CB2 receptors and ROS production, may represent a novel and highly selective treatment for leukaemia. Moreover, previous evidence indicated that human leukaemias and lymphomas expressed significantly higher levels of CB2 receptors compared with other tumour cell lines, suggesting that tumours of immune origin may be highly sensitive to the CB2-mediated effects of CBD [46].

However, the clinical use of Δ 9 -THC and additional synthetic agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive phytocannabinoids, such as CBD, has substantially increased in recent years. Interestingly CBD has no psychotropic activity and, although it has very low affinity for both CB1 and CB2 receptors, it has been recently reported to act with unexpectedly high potency in vitro as antagonist of CB1 receptors in the mouse vas deferens [28] and brain [29] tissues. Additionally, CBD displays inverse agonism at human CB2 receptors [29]. Moreover, other putative molecular targets of CBD are TRPV, 5-HT1A, GPR55 and PPARγ receptors (see Figure 2 ). Besides its beneficial effects in the treatment of pain and spasticity and other CNS pathologies, several reports demonstrated that CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion.

Physiological or pathological stimuli induce synthesis and release of endocannabinoids, which can subsequently activate cannabinoid receptors. Therefore eCBs are synthesized and released ‘on demand’ through the cleavage of membrane phospholipid precursors.

The endocannabinoid system: a brief overview

Surprisingly, so far no study has investigated the effect of CBD on angiogenesis. Our data currently awaiting publication [58] demonstrated that CBD potently inhibited HUVE cells proliferation, migration and invasion through the induction of endothelial cell cytostasis without triggering apoptosis. Interestingly, CBD also affected endothelial cell differentiation into tubular capillaries as well as the outgrowth of capillary-like structures from HUVEC spheroids in vitro. In addition, the anti-angiogenic properties of CBD were demonstrated also in vivo, using a matrigel sponge model. These effects were associated with down-modulation of several molecules associated with angiogenesis, including MMP2, MMP9, uPA, endothelin-1, PDGF-AA and CXCL16.

Among the cellular events involved in glioma cell death, CBD produced a time-dependent release of cytochrome C and activation of caspase-8, −9 and −3, suggesting the involvement of both the intrinsic and extrinsic apoptotic pathways [38]. Marcu et al. [39] later confirmed the efficacy of CBD in inhibiting the growth of multiple glioblastoma cell lines in a more potent way than Δ 9 -THC. Interestingly, combined treatment of Δ 9 -THC with CBD demonstrated that CBD enhanced the Δ 9 -THC inhibitory effect on glioblastoma cell growth, but not on invasiveness [39]. In line with this, more recently Torres et al. [40] confirmed that combined treatment with CBD and Δ 9 -THC greatly reduced human glioma cell viability enhancing both autophagy and apoptosis and triggering caspase-3 activation. Moreover, combined administration of submaximal doses of CBD and Δ 9 -THC reduced the growth of U87-MG cell-derived tumour xenografts in nude mice to a greater extent than treatment with the individual compounds, suggesting the potential use of combination therapy which would reduce the amount of the psychoactive Δ 9 -THC.

In the last two decades, Cannabinoids have been studied extensively for its potential use in various fields of medicine including oncology. Today some of the cannabinoids are FDA approved for the treatment of chemotherapy-induced side effects in cancer treatment however, studies are showing their effect against tumor growth as well. Aggressive B cell lymphoma or Non-Hodgkin lymphoma (NHL) is the fifth leading cause of human cancer death and is the second fastest-growing cancer with regard to mortality in people as 30% of patients develop resistance against chemotherapy. For this reason, it is essential to develop novel strategies to improve the outcome of patients suffering from aggressive or therapy-resistant lymphoma. The purpose of this study was to demonstrate the antitumor effects of cannabinoids in B cell lymphoma using canine as a model due to striking similarities b/w canine and human B cell lymphoma in histology, biology and gene expression. For this study, Canine B cell lymphoma cell lines 1771 and CLBL1 were cultured in RPMI. Expression of cannabinoid receptors studied using qPCR. Based on receptor expression cells were treated with receptor agonists (AEA, 2AG, CBD, THC, WIN and HU-210,) and antagonists (S16 and S28). Cell viability assessed using MTT assay. Biochemical analysis performed using spectrofluorometry to evaluate apoptotic makers involved in inducing cell death. Data was analyzed using ordinary one way ANOVA on Prism software. All B cell lymphoma cell lines showed positive expression of CB1 and CB2 receptors. Cell viability assay demonstrated a dose-dependent decrease in cell proliferation with all cannabinoid receptor agonists used except for 2AG. Biochemical analysis showed a decrease in nitrite and caspase activity in treated cells as compared to control untreated cells. Our results suggest that cannabinoids have an anti-proliferative and apoptotic effect on canine lymphoma cells and it can be developed as a potential anti-cancer agent for the treatment of canine and human B cell lymphoma.

Citation Format: Saba Omer, Dawn Boothe, Mohammed Mansour, Muralikrishnan Dhanasekaran, Satyanarayana Pondugula. Anti-proliferative effect of cannabidiol (CBD) against B and T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-047.

Cbd and non hodgkin's lymphoma

There have been intriguing results from lab experiments looking at a number of different cancers, including glioblastoma brain tumours, prostate, breast, lung, and pancreatic cancers. But the take-home message is that different cannabinoids seem to have different effects on various cancer types, so they are far from being a ‘universal’ treatment.

Cannabis in clinical trials

We’ve also supported a trial that’s testing the benefits of a man-made cannabinoid called dexanabinol in patients with different types of advanced cancer. The trial finished recruiting in 2015 and researchers established a safe dose of the drug, but further development of the drug was stopped due to a lack of evidence around the drug’s effectiveness. Full trials results are yet to be published.

Can cannabis prevent cancer?

Many researchers worldwide are actively investigating cannabinoids, and Cancer Research UK is supporting some of this work. These studies use highly purified chemicals found in the cannabis plant, or lab-made versions of them, and there is genuine interest in these as potential cancer treatments. But this is very different to street-bought cannabis and hemp oil available online or on the high street, for which there is no evidence of any impact on cancer.