Corresponding author: Georgi Momekov ( gmomekov@gmail.com ) Academic editor: Plamen Peikov
© 2020 Margarita Zhelyazkova, Bogdan Kirilov, Georgi Momekov.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Zhelyazkova M, Kirilov B, Momekov G (2020) The pharmacological basis for application of cannabidiol in cancer chemotherapy. Pharmacia 67(4): 239-252. https://doi.org/10.3897/pharmacia.67.e51304
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Chemotherapy is one of the therapeutic approaches for cancer treatment and has demonstrated great success with the introduction of selectively acting molecules against specific biomarkers of some types of tumors. Despite this success there is a large unmet need for novel therapies that provide effective control on the progression of advanced or drug-resistant cancer diseases. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, as possible agents for cancer therapy. We analyzed the anticancer properties and mechanism of action of cannabidiol (CBD), the main non-psychoactive cannabinoid received from hemp of Cannabis plant. Despite of data for pleiotropic effects of CBD, we here present the results for the efficacy of CBD in the modulation of different stages of cancer development. The analysis of the anticancer properties of CBD is made in relation to the proposed or newly discovered molecular targets of action. Thereafter, we consider the specific effects of CBD on primary tumors, their invasiveness and metastases, whether the influence on identified tumor markers in different types of tumors reflect the therapeutic potential of CBD. The studies reviewed herein indicate that CBD elicit activity through the cannabinoid receptor dependent and independent pathways. The processes such as ceramide production, ER-stress, autophagy and apoptosis, angiogenesis and matrix remodeling also appear to regulate the anticancer activity of CBD. So, the pharmacological basis for therapeutic application of CBD is constructed on the scientific data for its antitumor activity, extensively provided studies in vitro and in vivo in animal tumor models, and available data on the safety profile of clinically approved CBD products. We also try to reduce the deficits of our understanding in relation of pharmacological synergistic interactions of CBD with cytostatic drugs, where data remains limited. It is recognized that more studies for defining the specific molecular and signaling mechanisms of anticancer action of cannabinoids, particularly CBD, requires further evaluation. We believe that the therapeutic advantages of CBD are associated not only with its non-psychoactive behavior, but also are related to its influence on the important biochemical pathways and signal molecules, defining the genome instability and specific changes of the malignant tumor cells.
anticancer effect, cannabidiol, mechanism of action, pharmacological interactions, safety profile
In the recent decade many investigators have been trying to establish a scientific base for the therapeutic application of cannabinoids for different diseases including malignant tumors. Interest in the anticancer properties of cannabinoids was renewed after the discovery of the Endocannabinoid system (ECS) which was realized with the cloning of specific cannabinoid receptors (
In 1975
As it is shown in
Cannabidiol (INN) is the non-psychoactive compound derived from Cannabis species that has proposed therapeutic benefits. Cannabidiol is one of some 113 identified cannabinoids in cannabis plants, accounting for up to 40% of the plant‘s extract (
Chemical structures of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), anandamide (AEA) and synthetic cannabinoid agonist WIN55212-2. Chemical name of CBD: 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; IUPAC name: 2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1- yl]-5-pentylbenzene-1,3-diol.
Cannabidiol is evaluated as well tolerated compound with a good safety profile. To date, there is no evidence of recreational use of CBD or any public health related problems to be associated with the use of pure CBD. Reviewed data of the World Health Organization for cannabis-related substances, including cannabidiol, are based on the evaluation of the Expert Committee on Drug Dependence (
Adverse reactions
are documented in clinical trials of Epidiolex (Cannabidiol, INN), and they are included in the characteristic of the product, approved for treatment of Dravet and Lennox-Gastaut syndromes which are both treatment-resistant seizure disorders (
Cannabinoids are metabolized with the cytochrome P450 enzyme system and inhibit predominantly the enzymes CYP3A4 and CYP2D6. THC and CBD have been found to inhibit CYP1A1, 1A2 and 1B1 enzymes during in vitro studies (
Drugs | Effect of the Interaction | Research data |
---|---|---|
Antiplatelets / anticoagulants | Increased risk of bleeding |
In vitro studies found that THC and CBD may inhibit platelet aggregation. In a case study smoking cannabis significantly raised the INR of a patient prescribed warfarin after a mechanical heart valve replacement ( |
Ketoconazole | Increased concentration of CBD and THC | Ketoconazole inhibit CYP3A4, and increased the Cmax of CBD by 89% and THC by 27% Theoretically other inhibitors of CYP3A4 such as clarithromycin or itraconazole might increase the risk of adverse effects of CBD and THC ( |
Rifampicin | Reduction of CBD and THC concentration | Rifampicin induce activity of CYP3A4 and reduce the Cmax of CBD by 52% and THC by 36% ( |
Anti-convulsants | Increased levels of anticonvulsants and hepatotoxicity after valproates | CBD (Epidiolex®) increase bioavailability of topiramate, rufinamide, zonisamide. In addition AST/ALT levels were significantly increased in patients concurrently received valproate and CBD ( |
Clobazam | Increased concentration of clobazam | After four week treatment of children with clobazam and CBD are observed significant increasing of levels of its active metabolite norclobazam and side effects such as drowsiness, ataxia and irritability at 77% of patients. ( |
Phenytoin | Increased concentration of phenytoin |
Theoretically
CBD as an inhibitor of CYP2C19 may increase plasma concentrations of phenytoin ( |
The identified molecular targets of CBD and other cannabinoids include numerous classical ion channels, receptors, transporters, enzymes, and newly identified signal proteins (reviewed data of
The identified target receptors are presented in
A number of mutations that inhibit apoptosis have been found in tumors. In the first phase of tumor progression the cancer cells become locally invasive; in the second phase the most lethal attribute of cancer cells is their ability to disseminate and colonize secondary sites with metastases. Tumor progression is defined by irreversible changes in the tumor characteristics, reflecting genetically altered subpopulation of cells (
As it is summarized in
CBD induces two forms of the programmed cell death: autophagy and intrinsic or mitochondria-mediated apoptosis, as it is shown on breast cancer cells by
Some of the potential biological targets of Cannabidiol (CBD): cannabinoid receptors CB1, and CB2; ion channel receptors, incl. transient receptor potential vanilloid (TRPV) type 1 and 2; EGF-R, epidermal-growth factor receptor; ‘orphan’ G protein-coupled receptors, GPR55 and GPR3, GPR6; peroxisome proliferator-activated receptor, PPAR; vascular endothelial growth factor, VEGF-R; allosteric modulation and enhanced activity at αIγ glycine receptor; enhanced activity at the 5-HT1a, adenosine and N-acetylcholine receptors; inhibiting activity on mu and delta opioid receptors. Note: (+) stimulation; (-) inhibition.
Effects | Target receptors | Autophagy / apoptosis | ROS | Cell signaling pathway and target signal molecules | |
---|---|---|---|---|---|
Breast cancer | ↓ pro-survival pathways | ||||
↓ proliferation | TRPV1; EGF-R | NC | + | ↑ | PI3K/Akt** and |
↓ viability | CB2-R; | + | + | ↑ | Raf1/MEK/ERK |
non-CB1-R. | ↓ EGF; ↓ Id-1; ↑ cytochrome C; | ||||
↓ invasion* | NC | NC | ↑ | Bid translocation. | |
Glioma, Glioblastoma | ↓ Ras/Raf/MEK/ERK | ||||
↓ proliferation | non-CB1; | NC | + | ↑ | (↓ p-ERK; ↓ p-Akt); |
non-TRPV1; | ↑ Caspase activity; ↑ ceramide | ||||
↓ invasiveness* | CB2; TRPV2 | NC | ↓ HIF-1α; ↓ MMP-2,-9 | ||
↓ migration* | ↓ Id-1; ↓Sox-2 (protein) | ||||
↓ angiogenesis | VEGF-R? | NC | ↓ VEGF and other factors | ||
Lung cancer | ↓ PPARγ and COX-2 | ||||
↓ proliferation | CB-R | + | + | ↑ | ↑ p-p38; ↑ p-ERK |
TRPV1 | |||||
↓ invasiveness* | ↑ ICAM-1; ↑ TIMP-1 (protein) | ||||
↓ metastases* | PPARγ | NC | NC | ↓ MMP-9. | |
Colon cancer | ↑ caspase-3 activity; COX-2 | ||||
↓ proliferation | CB1/CB2; | NC | + | NC | ↑ ceramide; ↓ Akt; ↑ 2-AG; |
Chemoprevention | TRPV1; PPARγ | TNFα-mediated apoptosis. | |||
Pancreatic cancer | |||||
↓ proliferation | GPR55 | NC | + | NC | ER-stress-related genes |
CB1, CB2 ? | ECS pathway ? | ||||
Prostate cancer | |||||
↓ or ↑ proliferation | CB1, CB2 or | NC | + | ↑ | ECS pathway ? |
other receptors | (with other cannabinoids) | ↓ enzymes (FAAH, MAGL) | |||
↑ CHOP10 (protein) | |||||
Leukaemia/Lymphoma | caspase-3,-8,-9 activation | ||||
↓ viability; | CB2 | NC | + | ↑ | ↓ p-38 MAPK |
cytoreduction | ↓ Bid translocation | ||||
↑ cytochrome C | |||||
Multiple myeloma | Mitochondrial and ROS-mediated necrosis | ↓ ERK activity | |||
↓ proliferation | TPRV2 | ↑ | ↓ p-Akt | ||
Cell cycle arrest in G1 |
Moreover, CBD induces endothelial cell cytostasis and inhibits angiogenesis in vivo by receptor-mediated manner (
Breast cancer can be divided into three sub-types: hormone sensitive, HER2-positive, and triple negative breast cancer. CB1 receptors were reported to be present in 28% of all breast carcinoma patients, CB2 receptors were found in 72% of breast carcinomas and 91% of these tumors were HER2 positive. A correlation between CB2 receptor expression and breast cancer aggressiveness has been proposed (
In 2006 for the first time
The excellent experiments provided by
Glioma is CNS brain tumor subtype from glial tissue and accounts for approximately 80% of all primary malignant brain tumors (
There are many investigations with THC and synthetic cannabinoids, including a clinical trial. The pre-clinical results demonstrate specific cytotoxicity of cannabinoids, including CBD, in glioma cell line U87-MG and U373 and subcutaneous animal models through the induction of apoptosis (
The expression of the cannabinoid receptors in non-small-cell lung cancer (NSCLC) was defined (24% – for CB1 and 55% – for CB2), which suggests the important role of these receptors in tumor development (
It was established that there is a positive correlation between CB2 receptor expression and human colon cancer growth. So, the expression of CB2 receptor is a poor prognostic marker in advanced stages of colon cancer (
Pancreatic cancer is a type of cancer that has some of the lowest survival rates because there are very few, and mostly only palliative care, treatments available. It was discovered that the ECS plays an active role in pancreatic carcinogenesis. It was obtained that CB1 and CB2 receptor expression was elevated in human pancreatic tumors when compared to normal pancreas. Although the levels of endocannabinoids (AEA, 1-AG, 2-AG) were unchanged in pancreatic cancer compared to normal human pancreas, high levels of CB1 receptor expression and low levels of endocannabinoid degrading enzymes (FAAH and MAGL), are associated with shorter survival (
The available three common primary therapies for prostate cancer (chirurgical, radiotherapy and brachytherapy) showed a unique pattern of changes in quality of life related to urinary symptoms, sexual and bowel function, and vitality or hormonal function of patients. It was obtained for the first time that the levels of CB1 and CB2 receptor was elevated in prostate cancer compared to normal prostate tissue (
The study of McKallip scientific group (2002) demonstrate that ligation of CB2 receptors can induce apoptosis in a wide range of cancers of immune-cell origin. After that
Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow (
The excellent investigations of Morelli et al. (
Many in vitro and in vivo studies have shown the anticancer activity of CBD, with reports advocating for investigations of combination therapy approaches that could better leverage these effects in clinical translation. In fact, the administration of CBD together with some anticancer drugs has been shown to increase the susceptibility of glioblastoma cells to the cytotoxic effects of drugs (
The scientific group of prof. M. Falaska demonstrated some striking experimental evidence regarding CBD and combination chemotherapy. Mice with pancreatic cancer survived nearly three times longer when their cytostatic treatment was combined with the cannabis-derived compound. Gemcitabine and synthetic cannabinoids combinations trigger autophagy in pancreatic cancer cells through a ROS-mediated mechanism (
Synergistic pharmacological effects are observed also for cannabinoids and paclitaxel in gastric cancer cell lines (
Available pre-clinical data for combination treatment with CBD and cytostatic agents are very limited. Additionally, the experiments are provided with different methodical approaches and there is a difficulty to make a comparative analysis. There is an urgent need to apply standard procedure for quantitative assay of the combination treatment as recommended by Chou TC (
Another direction for using cannabinoids is as adjunctive drugs. The aim of this treatment is to prevent or reduce cytostatic-induced side-effects. In particular, THC (Marinol), its analog nabilone (Cesamet), and buccal spray Sativex (Nabiximol, containing THC and CBD 1:1) were brought onto the market in several countries owing to their ability to inhibit chemo- and radiotherapy-induced side effects (
The most terrible unwanted effect of some cytostatic drugs, including taxanes, platinum agents and Vinca alkaloids is drug-induced peripheral neuropathy. This side effect occurs in 30–40% of patients but incidences can reach 75% with certain regimens of chemotherapy. The pre-clinical investigations of
The available scientific pre-clinical data show that CBD may be applied in cancer therapy. Its low toxicity and non-psychoactive profile of action are a good starting point for clinical trial and suggest possible exploitation for prolonged treatment. CBD has anticancer activity in different type malignant tumors and more interesting this cannabinoid has influence on tumor progression. Significantly important are data for its synergistic anticancer activity with other cytostatic drugs, its tumor-sensitizing or protective effects which create a possibility for application of CBD as a component of combination schedule of chemotherapy or as adjunctive drug. In the light of its safety record and considering that CBD is currently used in clinical practice, the findings here summarized suggest that CBD might be worthy of clinical consideration for cancer therapy. It may be proposed that cannabinoid effectiveness of CBD is directed against the changes in the tumor cells received in the different stages of cancerogenesis, reducing the expression of the Id-1 gene, and some other signal molecules that are over-expressed in aggressive forms of cancer (