TABLE 3.
Pharmacological activities, mechanism and therapeutic potential of JWH133 in the in vitro studies.
| Experimental model | JWH133 concentration | Indication/Disease | Demonstrated actions and mechanisms | References |
|---|---|---|---|---|
| Plasmacytoid dendritic cells stimulated with CpGODN Type A 2216 | 0.001, 0.01, and 0.1 μM | Inflammation | Suppresses CpG-stimulated IFNα and TNFα dependent on modifying the phosphorylation of AKT | Henriquez et al. (2019) |
| LPS/IFN-γ or Theiler’s virus (TMEV)-activated macrophages | 10 nM | Inflammation | Inhibits IL-12p40 production and enhances IL-10 biosynthesis via activation of ERK1/2 MAP kinase | Correa et al. (2005) |
| 100 nM, 1 μM, and 5 μM | ||||
| Human coronary artery endothelial cells (HCAECs) activated with TNF-α | 0.5, 2.5, and 4 μM | Atherosclerosis | Attenuates TNF-α-triggered NF-κB and RhoA activation, upregulates of adhesion molecules ICAM-1 and VCAM-1, decreases expression of monocyte chemoattractant protein, TEM of monocytic THP-1 cells, and monocyte-endothelial adhesion | Rajesh et al. (2007) |
| Human coronary artery smooth muscle cells (HCASMCs) activated with TNF-α | 0.5–4 μM | Atherosclerosis | Mitigates the activation of induced Ras, mitogen-activated protein kinases (p38 MAPK, ERK ½), stress-activated protein kinases (SAPK)/Jun amino-terminal kinases (JNK) and Akt | Rajesh et al. (2008) |
| Human neutrophils | 0.3 and 1 μM | Atherosclerosis | Suppresses neutrophil production of MMP-9 via attenuation of ERK1/2 phosphorylation | Montecucco et al. (2012) |
| Normal-cultured and oxidative low-density lipoprotein (OxLDL)-loaded RAW264.7 and primary macrophages | 0.1, 1, and 10 μM | Atherosclerosis | Improves efferocytosis via increasing expression of tyrosine kinase family phagocytic receptors, inhibition of RhoA GTPase stimulation, and alleviation of oxidative/inflammation responses | Jiang et al. (2016) |
| Human osteoblastic hFOB 1.19 cells | 1, 2, 5 | Osteoporosis | Osteogenic differentiation mediated by CB2R dependent mechanism involved autophagy activation and p62- mediated Nrf2 degradation | Xu et al. (2020) |
| 10, and 20 μM | ||||
| Methylprednisolone-induced osteoclast overactivity from healthy donors | 100 nM from day 14 to day 21 | Osteoporosis | Reduces bone resorption dependent on PKC βII signaling | Bellini et al. (2017) |
| MDA-MB231 and MDA-MB468 cells | 0.1–10 μmol/L | Breast cancer | Inhibits cell proliferation and migration | Qamri et al. (2009) |
| Rat glioma C6 cell | 100 nM | Brain cancer | Induces apoptosis via ceramide synthesis and ERK1/2 activation | Sánchez et al. (2001) |
| Human umbilical vein endothelial cells (HUVECs) | 25 nM | Brain cancer | Direct inhibition of vascular endothelial cell migration and survival as well as the decrease of the expression of proangiogenic factors (VEGF and angiopoietin-2) and MMP-2 in the tumors | Blázquez et al. (2003) |
| Glioma stem-like cells and glioma cell lines U87MG and U373MG | 30 nM | Brain cancer | Stimulates glia cell differentiation in a CB2R-related mechanism | Aguado et al. (2007) |
| A2058 melanoma cells | 10 μM for 4 h | Brain cancer | Reduces adhesion and transmigration of melanoma cells through the cerebral endothelium | Haskó et al. (2014) |
| A549 cells and HUVECs | 10−4–10–8 mol/l | Lung cancer | Anti-proliferative and anti-angiogenic potential | Vidinský et al. (2012) |
| Downregulates MMP-2 activity | ||||
| A549 cells co-cultured with huvec | 3 μM | Lung cancer | Increases tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) production from lung cancer cells and a consequent stimulation of ICAM-1 expression, thereby modifying the tumor cells microenvironment and inhibiting the angiogenesis | Ramer et al. (2014) |
| Human lung macrophage stimulated with LPS | 1 μM | Lung cancer | Modulates tumor vascularization via reduction of macrophage-derived angiogenic and lymphangiogenic factors | Staiano et al. (2016) |
| T-ALL patients and Jurkat cell line | 100 nM | Leukemia | Anti-proliferative, pro-apoptotic and cell cycle arrest | Punzo et al. (2018a) |
| ARO/IL-12, ARO and ARO/CB2 thyroid carcinoma cells | 2 μM for 24 h | Thyroid carcinoma | IL-12-mediated CB2 upregulation rendered the thyroid cancer cells more responsive to CB2 agonist-induced apoptosis and remission of the tumors | Shi et al. (2008) |
| Saos-2, MG-63, MNNG/HOS, KHOS/NP, Hs888Lu and U-2 OS Osteosarcoma cells | 100 nM for 24 h | Osteosarcoma | Anti-proliferative, pro-apoptotic, anti-invasive effect with downregulation of Notch-1 and MMP-2 | Punzo et al. (2017) |
| Isolated perfused rat hearts subjected to 30 min global ischemia followed by 120 min reperfusion | 1,10, and 100 nmol/L for 15 min before I-R treatment | Myocardial infarction | Increases phosphorylated ERK1/2 and preventing MPTP opening | Li et al. (2014) |
| Adult cardiac myocytes from WT or CB2/mice | 1 µM | Myocardial infarction | Prevention of oxidative stress-induced cardiac myocyte and fibroblast apoptosis and the suppression of myofibroblast activation | Defer et al. (2009) |
| Mice cardiomyocytes under oxygen-glucose deprivation (ODG) | 1, 10, and 100 nM 10 min before OGD challenge | Myocardial infarction | Modulation of NLRP3 inflammasome pathway | Yu et al. (2019) |
| Mouse RAW264.7 macrophages and 3T3-L1 fibroblasts | 1 or 3 μM for 24 h | Obesity | Attenuates pro-inflammatory M1 macrophage cytokines through the Nrf2/HO-1 mechanism | Wu et al. (2020) |
| Obese-derived white adipocyte (ADP) | 100 nM | Obesity | Mitigates the obesity-associated inflammation, and the excess lipid storage in white adipose tissue WAT through modulating perilipin expression, up-regulating IL-4, and stimulating UCP-1 signaling | Rossi et al. (2016) |
| Rat m5F insulinoma β-cells | 10–6 M | Diabetes mellitus | CB2R stimulation is linked to Ca2+ mobilization from the endoplasmic reticulum stores leading to insulin release in pancreatic β-cells | De Petrocellis et al. (2007) |
| Isolated uterus from female ICR mice stimulated with exogenous PGE2 | 10−8–10–5 M, for 20 min | Female reproduction | Mitigation of myometrial contractility dependent on the suppression of prostaglandin release/synthesis | Pagano et al. (2017) |
| SPG germ cells obtained from testes of immature 7-day-old swiss CD-1 mice | 10−6 M for 0–60 min | Spermatogenesis | Pro-differentiated effect via induction of the phosphorylated ERK 1/2 MAPK in spermatogonia and their progression toward meiosis | Grimaldi et al. (2009) |
| SPG germ cells obtained from testes of immature 7-day-old swiss CD-1 mice | 1 µM for 24 h | Spermatogenesis | Accelerates the spermatogenesis process and regulates transcription of the c-Kit and Stra8 genes at meiotic entry through specific alterations of histone modifications | Di Giacomo et al. (2016) |
| Mucosal samples from areas of inflamed/uninflamed colon from IBD patients and Caco-2 cell line | 10 µM for 6 h | Colitis | Enhances colon cells proliferation and migration and affects secretome characteristics that facilitate mucosal healing | Tartakover Matalon et al. (2020) |
| Isolated ileum from Sprague-Dawley rats injected with LPS | 10–2 M | Colitis | Reduces the accelerated contraction induced by LPS via downregulation of the FOS expression in enteric glial and neurons | Duncan et al. (2008) |
| RAW264.7 macrophages activated with LPS | 5 μM for 24 h | Alcoholic liver disease | Anti-inflammatory effects via upregulating of HO-1 in macrophages | Louvet et al. (2011) |
| RAW264.7 macrophages from CB2Mye−/− mice activated with LPS | 5 μM for 6 h | Alcoholic liver disease | Stimulates autophagic process in macrophage mediated the anti-inflammatory and anti-steatogenic activities of CB2R | Denaës et al. (2016) |
| Isolated kupffer cells activated with zymosan A and LPS | 5 μM for 3 h | Liver cirrhosis | Mediates HO-1 pathway which decreases vasoconstrictor production and portal hypertension related to PPARγ and CB2R | Steib et al. (2013) |
| Cultured Th17 lymphocytes | 5 μM | Liver fibrosis | Decreases IL-17 production by Th17 lymphocytes relies on STAT5 pathway, and by dampening the proinflammatory activity of IL-17, while conserving IL-22 production | Guillot et al. (2014) |
| IL-17-induced inflammatory | ||||
| Response on macrophages and hepatic myofibroblasts | ||||
| AML12 cells exposed to TGF-β1 | 1, 3, and 10 μM for 1 h | Liver fibrosis | Transcriptional regulation of the CB2 receptor gene in hepatocytes by LXRα that in turn inhibits USP4-stabilizing TβRI through miR-27b | Wu et al. (2019) |
| Human liver sinusoidal endothelial cells (HLSECs) treated with TNF-α | 0–4 μM for 4 h | Hepatic ischemia/reperfusion | Mitigates the TNF-α-stimulated ICAM-1 and VCAM-1 expression and decreases the adhesion of human neutrophils | Bátkai et al. (2007) |
| Fibroblast-like synoviocytes activated with TNF-α | 1, 10, and 50 μM for 24 h | Rheumatoid arthritis | Inhibits production of pro-inflammatory cytokines, and prevents formation of bone-resorbing cells | Fukuda et al. (2014) |
| Bone marrow-derived macrophages cultured with TNF-α | 1 μM for 24 h | Rheumatoid arthritis | Inhibits osteoclastogenesis and inflammation-mediated bone destruction via inhibiting NF-kB signaling pathway | Zhu et al. (2019) |
| Mesenchymal stromal cells from ITP patients | 2.5 μM for 24 h | Immune thrombocytopenia | CB2 stimulation attenuates apoptosis via Bcl-2 signaling, and restores the immune-modulatory properties of MSCs | Rossi et al. (2019a) |
| Mice lung fibroblasts exposed to TGF-β1 | 10 μM for 48 h | Pulmonary fibrosis | Inhibited firbosis via repressing TGF-β1/Smad2 signaling pathway | Fu et al. (2017) |
| Human Adipose tissue mesenchymal stromal cells (atMSCs) | 1, 3, 10, and 30 μM | Wound healing | Enhances secretion of VEGF, TGF-β1 and HGF, which in turn enhances the regenerative activity of at MSCs | Ruhl et al. (2020) |
| Mesenchymal stem cells | 3 μM for 1 h or 6 h | Bone healing | Induction of p42/44 MAPK that mediates migration of mesenchymal stem cells | Schmuhl et al. (2014) |
| Human Tenon’s fibroblasts exposed to TGF-β1 | 0.5 μM for 24 h before TGF-β1 | Wound healing | Suppresses ECM synthesis and MAPKs (ERK1/2, p38, and JNK) induced by TGF-β1 and reduces the contractility of HTFs | Guan et al. (2017) |
| Corneal epithelial cells | 300 nM | Wound healing | Exerts chemorepulsive activity | Murataeva et al. (2019) |
| Stimulates p-ERK and cAMP production | ||||
| Differentiating oligodendrocyte progenitor cells | 0.1, 0.5, and 1 µM for 48 h | Brain repair | Enhances oligodendrocyte differentiation dependent on stimulation of p-Akt and mTOR signaling | Gomez et al. (2011) |