Molecular Mechanism of Cannabinoids in Cancer Progression – PMC

47], and displays inverse agonism to human CB2RnHighlight:anti-cancer effects by inducing apoptosis and inhibiting cell migration, and metastasis in different cancer typesnSticky notes:Some of the CBD anti-cancer activitiesnHighlight:THC + CBD (at a 1:1 ratio), exerts a strong anti-tumoral action in glioma xenograftsnHighlight:cannabichromene (CBC) has anti-proliferative action in prostate cell lines, in colorectal cancer Caco-2 cells, and MDA-MB-231 and MCF-7 breast cancer cell lines.nSticky notes:Alternate cannabinoid anticancer effectsnHighlight:Cannabidivarin (CBVD) and cannabinol (CBN) have pro-apoptotic effects on human prostate cell lines.nHighlight:CBVD inhibits the growth of colon cancer cells while CBN does so in breast cancer cellsnHighlight:Cannabidiolic acid (CBDA) inhibited the invasivity of breast cancer cells and downregulated the c-fos and the COX-2nHighlight:Several studies have demonstrated that cannabinoids mediated cell cycle dysregulation and inhibition of proliferation in cancer cells.nHighlight:accumulation of cells in the G1 phase and decrease of cells in the S phase of the cell cycle,nHighlight:increase in the expression of p27 and a decrease of Cdk4nHighlight:downregulation of Cdk4nHighlight:inactivation of pRbnHighlight:stopped cell cycle in phase G0-G1 and significantly increased the expression levels of protein ataxia telangiectasia-mutated gene (ATM) and p53 and reduced p21, CDK2, and Cyclin E protein levelsnHighlight:cell cycle stops at the G2-M phase, by reduction of Cdc2 and induction of ROS synthesis, provoking cell deathnHighlight:Cannabinoids activate apoptosis either through CB1 or CB2 receptors.nHighlight:increased the protein levels of cleaved caspase-3 and caspase-9nHighlight:CBD increased Bax and decreased Bcl-2 expression levels, causing a reduction of the ratio of Bcl-2/BaxnHighlight:increase of mitochondrial membrane permeability and a decrease of mitochondrial transmembrane potentialnHighlight:CBD treatment increased NoxanHighlight:THC, via CB1R activation, inhibited both PI3K/Akt and RAS-MAPK/ERK survival pathwaysnHighlight:CBD inhibited the survival of both estrogen receptor-positive and estrogen receptor-negative breast cancer cell lines and induced apoptosis cell death in a concentration-dependent manner compared with MCF-10A cells, non-tumorigenic mammary cells.nHighlight:activation of caspase-8nHighlight:release of cytochrome c and SMAC into the cytosol, and increased levels of Fas-LnHighlight:, CBD enhanced ROS generationnSticky notes:Depletes GSH, similar to vitamin CnHighlight:CBD with THC, CBG, CBN—this combination is called C6—induced cell cycle block in G2 phasenSticky notes:“C6”nHighlight:increase in the levels of activated caspase-3 and a reduction in the levels of Bcl-2nHighlight:endocannabinoid treatment activated the Erk pathway and at the same time produced a decrease in the activation levels of the Akt pathwaynHighlight:THC via activation of CB1R induced ceramide accumulation and Raf1/ERK activationnHighlight:Autophagy is a mechanism that leads to the degradation of damaged cytoplasmic componentsnHighlight:diminishes intracellular glutathione levelsnHighlight:Cannabinoids can induce autophagy in several cell lines and mouse models of cancer.nHighlight:most important mechanism by which cannabinoids cause autophagy is the accumulation of ceramide in tumor cells.nSticky notes:KEY POINTnHighlight:accumulation of ceramide in the cell stimulates the stress response of the ER and the activation of different proteins CHOP, ATF-4, and p8, which promote the interaction of tribbles pseudokinase 3 (TRIB3) with Akt, causing the inhibition of the PI3K/AKT/mTOR pathwaynHighlight:The signaling pathway p8/ATF4/CHOP/TRIB3, followed by the inhibition of the PI3K/AKT/mTOR cascade, is probably the most important antitumoral mechanism of cannabinoids.nHighlight:direct inhibitor of mTORC1nHighlight:reduced levels of tau and amyloid proteins in the brainnHighlight:THC-CBD combination strongly augmented the levels of the cleaved LC3-II form and the LC3-II/LC3-I rationSticky notes:AutophagynnHighlight:Cannabinoids effects have been shown to have anticarcinogenic properties by inhibiting the migratory and invasive capacity of tumoral cellsnHighlight:reducing the activity and intracellular levels of the metalloproteases MMP2 and MMP9nHighlight:Cannabidiol (CBD) can induce cell death in multiple myeloma (MM)nHighlight:SPARC is a matricellular protein important in tissue remodeling and extracellular matrix deposition. The release of SPARC is prevented by WINnHighlight:increase the release of extracellular vesicles containing miR-29b1nHighlight:CBD-THC combination was able to reduce cell migration of the MMnHighlight:treatment of CBD/THC in combination with other chemotherapeutic drugs acts in a synergic way, suggesting their use in combinatory therapy in several types of human cancersnHighlight: poor prognosis of breast cancer is correlated with high levels of metalloproteasesnHighlight:Cannabinoids modulated MMP activity via inhibition of MMP2 and activation of the MMP9 gene.nHighlight:high levels of metalloprotease, amplification, or overexpression of the ERB2 gene have been found in the biopsies of breast tumorsnHighlight:inhibition of adhesion and migrationnHighlight:THC, via CB receptors, inhibited EGF-induced growth, chemotaxis, and chemoinvasionnHighlight:THC reduced the EGF-induced phosphorylation of ERK1/2, JNK1/2, and AKT, responsible for the reduced migration and invasion observed in lung cancer cellsnHighlight:growth of solid tumors is dependent on the generation of new vascular supplynHighlight:Cannabinoids, in cancer cell, can block the activation of the vascular endothelial growth factor (VEGF) pathway, which is an inducer of angiogenesisnHighlight:main ligand (VEGF) and the active forms of its main receptors (VEGFR1 and VEGFR2), are downregulated in skin carcinomas, gliomas, and thyroid carcinomas after cannabinoids treatmentnHighlight:decrease the formation of distant tumor masses in animal modelsnHighlight:inhibit adhesion, migration, and invasiveness of glioma, breast, lung, and cervical cancer cells in vitro culturenHighlight:modulation of extracellular proteases (MMP2) [107] and their inhibitors such as tissue inhibitors of matrix metalloproteinases 1 (TIMP1)nHighlight:general role of the ceramide and p8 regulated pathway in the antitumor activity of cannabinoids that target CB1 and CB2 receptorsnHighlight:CBD, by acting independently of CB1 and CB2 receptors, produced an antitumor effect including the reduction of invasiveness and metastasis in different cancer animal modelsnHighlight:downregulation of the helix–loop–helix transcription factor inhibitor of DNA binding 1 (ID1)nHighlight:Acquisition of invasive traits by tumor cells involve specific phenotypic changes associated with epithelial to mesenchymal transition (EMT), and regulated transdifferentiation process in which carcinoma cells lose cell-to-cell junctions and cell polarity and acquire migratory and invasive propertiesnHighlight:cannabinoid agonist WINnHighlight:WIN treatment resulted in the downregulation of cyclooxygenase-2 (COX-2) expression and decreased the phosphorylation of AKT, and inhibited EMTnHighlight:JWH-015 treatment of A549 lung cancer cells co-cultured with M2 polarized macrophages reduced the expression of FAK, VCAM1, and MMP2nHighlight:JWH-015 decreased lung tumor lesions, tumor growth, and also inhibited macrophage recruitment and EMT to the tumor site via EGFRnHighlight:inhibiting EMT and downregulating matrix metalloproteinase 9 (MMP 9) gene expression in aggressive human EC cellsnHighlight:THC and CBD inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD enforced the effect of THCnHighlight:THC and CBD (alone and/or in combination) affected proliferation, EMT, and migration in vitronHighlight:anandamide treatment upregulated epithelial markers, like E-cadherin with a concomitant decrease in protein levels of mesenchymal markers, including vimentin and SNAIL1n]]>