1. Introduction
2. Pharmacology, Toxicology, and Route of Administration
2.1. Pharmacokinetics
2.2. Pharmacodynamics
2.3. Pharmacological Actions and Indications
2.4. Toxicology
2.5. Route of Administration and Dosage
2.6. Cannabidiol and Hepatotoxicity: A Debate
3. Anticancer Effects of CBD in In Vitro and In Vivo Studies
4. Immunomodulatory Effects of CBD
5. CBD in Inflammation-associated Carcinogenesis
6. Anti-angiogenic Effects of CBD
7. Clinical Evidence of the Anticancer Effects of CBD
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
5-HT1A | Serotonin receptor type 1A |
ACF | Aberrant crypt foci |
AD | Alzheimer’s disease |
Aᵦ42 | Amiloid beta 42 |
BCE | Before Common Era |
BRCA-1 | Breast cancer gene 1 |
BRCA-2 | Breast cancer gene 2 |
cAMP | Cyclic adenosine monophosphate |
CB1, CB2 | Cannabinoid receptor 1,2 |
CBD | Cannabidiol |
CBR | Cannabinoid receptor |
CD-1; 4 | Cluster of differentiation 1; 4 |
CGS | Glioma stem cells |
CID 16020046 | Inverse agonist at the former orphan receptor GPR55 |
COX | Cyclooxygenase |
CT | Computed tomography scan |
CXCL16 | Chemokine (C-X-C motif) ligand 16 |
DNA | Deoxyribonucleic acid |
EAE | Experimental autoimmune encephalomyelitis |
EC50 | Half maximal effective concentration |
EGF/EGFR | Epidermal growth factor/epidermal growth factor receptor |
ELISA | Enzyme-linked immunosorbent assay |
EMA | European Medicine Agency |
EMV | Exosome and microvesicle |
ENT-1 | Equilibrative nucleoside transporter-1 |
ET-1 | Endothelin-1 |
FDA | Food and Drug administration |
GABA | Gamma-aminobutyric acid |
GI | Gastro-intestinal |
GPR55 | G-coupled protein receptor-55 |
GSC | Glioma stem cell |
GW9662 | Potent antagonist of Peroxisome proliferator-activated receptor gamma |
GPX | Glutathione peroxidase |
HUVEC | Human umbilical vein endothelial cells |
HIF-1a | Regulatory subunit of the hypoxia- inducible transcription factor |
i.p. | Intraperitoneal |
IC50 | Half maximal inhibitory concentration |
ICAM | Inter-intracellular adhesion molecule |
ICR | Institute of Cancer Research |
IFN-γ | Interferon Gamma |
IGHM | Immunoglobulin heavy constant Mu |
IL-2,6,8,9,12,IL-1A; 17A/F2 | Interleukin 2, 6,8,9,12, 1A, 17A/F2, |
iNOS | Inducible nitric oxide synthase |
Ki | Inhibitory constant binding affinity |
KPC | KRAS, p53, Cre mice |
MDA | Malonaldehyde |
MIP-1α,1ᵦ,2 | Macrophage inflammatory protein 1α,1ᵦ, 2 |
MMP2,9 | Matrix metalloproteinase-2, 9 |
mRNA | Messenger RNA |
Mtor | Mammalian target of rapamycin |
NFκB | Nuclear factor κB |
n.d. | Not determined |
PAI-1 | Plasminogen activator inhibitor-1 |
PDGF-AA | Platelet-derived growth factor subunit A |
PERK | Extracellular signal-regulated kinase phosphorylation |
Phospho-Akt | Phosphorylated AKT |
PPARγ | Nuclear peroxisome proliferation activated receptor |
PSA | Prostate-specific antigen |
PTEN | Phosphatase and tensin homolog |
ROS | Reactive oxygen species |
RT-PRC | Real-time polymerase chain reaction |
s.c. | Sub cutaneous |
S100A10B | S100 calcium-binding protein A10 |
S1P | Sphingosine-1-phosphate |
S1PR1 | Sphingosine-1-phosphate receptor 1 |
Serpin E1 | Serpin Family E Member 1 |
SGPL1 | Sphingosine-1 phosphate lyase |
SiRNA | Small interfering RNA |
SOD | Superoxide dismutase |
STAT-3,5 | Signal transducers and activators of transcription 3,5 |
TGFBA | Transforming growth factor beta, alpha |
THC | Tetrahydrocannabinol |
THCA | Tetrahydrocannabinolic acid |
TIMP1 | Tissue inhibitor of matrix metalloproteinases1 |
TNF-α | Tumor necrosis factor α |
Tp53 | Tumor protein p53 |
TRP | Transient receptor potential |
TRPA | Transient receptor potentialankyrin |
TRPV1 | Transient receptor potential vanilloid type1 |
TRPV2 | Transient receptor potential vanilloid type 2 |
TRPM8 | Transient receptor potentialmelastatin 8 |
uPA | Urokinase-type plasminogen activator |
VEGF | Vascular endothelial growth factor |
VR1, VR2 | Vanilloid receptor 1, 2 |
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Receptor | Effect | Ki; EC50; IC50 | References |
---|---|---|---|
CB1 | Antagonist | Ki = 4350–4900 nM | [43,44] |
CB2 | Inverse agonist | Ki = 2860–4200 nM | [43,45] |
GPR55 | Antagonist | IC50 = 445 nM | [45] |
TRPM8 | Antagonist | IC50 = 80–140 nM | [46,47] |
TRPV1 | Agonist | EC50 = 1000 nM | [46,48] |
TRPV2 | Agonist | EC50 = 1250 nM | [46,48] |
TRPV3 | Agonist | EC50 = 3700 nM | [46,49] |
TRPA1 | Agonist | EC50 = 110 nM | [46,48] |
PPARϒ | Agonist | EC50 = 20,100 nM | [50] |
CYP 450 – Isoenzymes | Substrates | Inducers | Inhibitors |
---|---|---|---|
CYP3A4 | CBD Alprazolam Diazepam Amlodipine Simvastatine Atorvastatine Apixaban Rivaroxaban | Carbamazepine Fenitoine Phenobarbital | Eritromicine Claritromicine Verapamil Diltiazem Fluconazol Itraconazol |
CYP2C19 | CBD Clopidogrel Fenitoine Diazepam | Carbamazepine Rifampicine | Fluoxetine Fluvoxamine Ketoconazole Omeprazole |
CYP1A2 | Theophylline Clozapine Naproxen | CBD Tobacco smoke | Ciprofloxacine Ofloxacine Levofloxacine Amiodarone |
P-Glycoproteine (intestinal absorption) | Loperamide Morphine Dabigatran Atorvastatine Simvastatine Paclitaxel Antraciclines | Carbamazepine Rifampicine Phenobarbital | CBD Ketoconazol Itraconazol Eritromicine Clarytromicine Propafenone Amiodarone |
Type/Cancer Cell Line | Cell Line | In vitro | In vivo | Conc. | Conclusion | Ref. |
---|---|---|---|---|---|---|
Colorectal cancer | HCT116 | √ | 0–8 µM 100 mg·kg−1 | CBD induces apoptosis by regulating many pro- and anti-apoptotic proteins, and decreases tumor volume | [105] | |
Colorectal cancer | DLD-1 | √ | 0–8 µM 100 mg·kg−1 | |||
Colon cancer | CaCo-2 HCT116 | √ IC50 = 0.67 µM | √ | 5 mg/kg | Reduced aberrant crypt foci (ACF) number of polyps and tumors | [103] |
Colon cancer | CT26 | √ | 5 mg/kg | CBD induces apoptosis, showed anti-angiogenesis and anti-metastatic effect | [106] | |
Colon cancer | HCT116 | √ | 5 mg·kg−1 | CBD reduces colon cancer cells | [104] | |
Prostate cancer | PC3 | √ | 1–5 µM | CBD reduces exosome release. | [108] | |
Prostate cancer | LNCaP | √ | 1; 10; 100 mg/kg | CBD decreased cell viability and tumor growth | [109] | |
Prostate cancer | DU-145 | √ | 20–80 µg/mL | CBD is a potent inhibitor of cancer cell growth and has lowest potency in non-cancer cells | [110] | |
Prostate cancer | LNCaP | √ | 20–80 µg/mL | |||
Prostate cancer | PC3 LNCaP | √ | 5–15 µM | CBD induces apoptosis | [111] | |
Lung cancer | A549 | √ | 5 mg/kg | CBD decreased tumor growth | [87] | |
Lung cancer | H460 | √ | 3µM | CBD decreased tumor metastasis | [88] | |
Lung cancer | A549 | √ | 3 µM | ICAM-1 present an essential objective for CBD in executing its antitumorigenic function. | [64] | |
Lung cancer | A549 H460 | √ | √ | 3 µmol/L 5–10 mg/kg | CBD induces cancer cell apoptosis | [90] |
Brain tumor | U87 U373 | √ | 5–10 µM | CBD induces apoptosis through activation of serotonin and vanilloid receptors | [113] | |
Brain tumor | GSC | √ IC50 = 3.5 µM | √ | 15 mg/kg | CBD induces apoptosis through the production of ROS | [114] |
Brain tumor | U251 SF126 | √ IC50 = 1.1–1.3 µM | 0.4 µM | CBD induces apoptosis and reduces cell viability and invasion | [115] | |
Brain tumor | U87MG | √ | 10 µM | CBD activates TRPV2 receptors to promote cancer cell death. | [116] | |
Brain tumor | U87MG | √ | 6.7 mg | CBD enhances apoptosis and decreases cell proliferation. | [118] | |
Brain tumor | SH SY5Y IMR-32 | √ | 10 µM | CBD induces apoptosis and reduces cancer cell migration and invasion | [119] | |
Skin cancer | Murine B16F10 melanoma tumors | √ | 5 mg/kg | CBD reduces tumor size | [92] | |
Breast cancer | MDA-MB-231 | √ IC50 = 6–10.6 µM | √ | 10 mg/kg | Decreased tumor growth | [51] |
Breast cancer | T47D MDA-MB-231 | √ | 10 mg/kg | Decreased tumor metastasis | [98] | |
Breast cancer | MDA-MB-231 | √ | 5 mg/kg | CBD induces cancer cells apoptosis | [97] | |
Breast cancer | SUM-159 | √ | √ | 3–18 µM | CBD induces both apoptosis and autophagy-induced death in cancer cells | [99] |
Endothelial cells | HUVEC | √ | √ | 1–19 µM | CBD inhibited cell proliferations and exhibited potent antiangiogenic properties inhibiting cell invasion and migration | [117] |
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