Cannabinoids in the landscape of cancer – PMC

Cannabis sativa L. plantnHighlight:growing body of evidence from cell culture and animal studies in support of cannabinoids possessing anticancer properties.nHighlight:Phyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivonHighlight:these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets.nHighlight:cannabinoid receptors; CB1 and CB2, but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2.nHighlight:Cannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs.nHighlight:Since time immemorial, the Cannabis plant has been used as a source of fibre, herbal remedy, medicinal and religious purposesnHighlight:during the twentieth century, its utilisation in Western medicine started to decline as a result of political prejudices and economic interests rather than scientific or medical reasonsnHighlight:Increasing data from and in vivo studies have started to show evidence of cannabis in modulating signalling pathways involved in cancer cell proliferation, autophagy, apoptosis and inhibition of angiogenesis and metastasisnHighlight:Emerging reports have also indicated synergistic effects of cannabinoids in combination with antineoplastic drugsnHighlight:cannabinoids as shown in Fig. 1, terpenoids and flavonoidsnHighlight:Cannabinoids interact directly with cannabinoid receptors, which include G-protein coupled receptors (cannabinoid receptor 1, CB1 and cannabinoid receptor 2, CB2), ligand-gated ion channels (i.e. vanilloid cell surface channels) and nuclear receptors (i.e. peroxisome proliferator-activated receptor gamma, PPARγ) (Moreno et al. ; Śledziński et al. ) comprising the endogenous endocannabinoid system (ECS)nHighlight:Three major classifications of cannabinoids include phytocannabinoids (plant-based), such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), endocannabinoids (or endogenous cannabinoids) which include anandamide (AEA) and 2-arachidonolyglycerol (2-AG) and synthetic cannabinoidsnHighlight:endogenous endocannabinoidsnHighlight:varying affinities of phytocannabinoids for the classical CB1 and CB2 receptors with agonistic and antagonistic behaviours nHighlight:cannabinoids can interact with multiple orphan G-protein coupled receptors (GPCRs) including GPR12, GPR18, GPR35, GPR55, GPR119, opioid and serotonin receptorsnHighlight:interaction of GPCRs is crucial for maintaining the ECS as it allows the production of endocannabinoids from cells through activation of Gq/11 or Gs proteins causing the activation of the cannabinoid receptornHighlight:cannabinoids action synergistically with chemotherapy drugs as ceramide may have the ability to sensitize the cancer cells to chemotherapy agents.nHighlight:cannabinoids action has been through modulating the cell cyclenHighlight:CBD-induced cell cycle arrest at the G0G1 phase and retardation in this phase corresponded to a reduction in CDK2/cyclin E protein levels nHighlight:Apoptotic changes are prevalent in cannabinoids mechanism of actionnHighlight:increase in cleaved caspase-3 and -9 levels and activation of the mitochondrial apoptotic pathwaynHighlight:increases in proapoptotic proteins, such as BAD and BaxnHighlight:cannabinoids downstream effects.nHighlight:Overall cannabinoids induce apoptosis to inhibit proliferation, downregulate the vascular endothelial growth factor (VEGF) pathway affecting angiogenesis and dampen metastasis by inhibiting cell adhesion and migration through modifying matrix metalloproteinase 2, 9 (MMP2, 9), tissue inhibitor of matrix metalloproteinases 1 (TIMP1), inhibitor of DNA binding 1 (ID1) and inducing ER stressnSticky notes:Need to read this review article from Velasco et alnHighlight:Cancer stem cells (CSCs), a subpopulation of stem cells expressing CD44, CD24 and CD133, are tumorigenic with demonstrated resistance to certain chemotherapeutics and also play a role in metastasisnHighlight:involvement of cannabinoids in inhibiting CAFs and CSCs in prostate and breast cancer modelsnHighlight:remains ambiguity in its precise role within cancer pathophysiologynHighlight:upregulation in the CB1 and CB2 receptors, endogenous ligands and over-activation of the ECS correlates with more aggressive tumours (Dariš et al. ) although other reports have concluded the contrarynHighlight:different tumour types have been shown to exhibit various levels of CB receptors as well as ECS componentsnHighlight:The role of the endogenous endocannabinoids and CB receptors within each cancer system is specific to the underlying cancer, therefore conflicting data can be presented across different cancersnSticky notes:Important point!!nHighlight:some cannabinoids have shown oncological effects independent of known CB receptorsnHighlight:downstream activation and crosstalk of signalling pathways of cannabinoid and non-cannabinoid receptors.nHighlight:Activation of the cannabinoid receptors CB1 and CB2 (red arrows) via cannabinoids stimulate ERK1/2 signalling which activates p27 and p21 causing a decrease in cyclins D and E, cdc2 and cdk2 through an increase in pRb, leading to cell cycle arrest.nHighlight:Inhibition of the P13K pathway leads to a decrease in Akt which inhibits cell proliferation.nHighlight:An increase in ceramide level in turn increases the stress protein p8/Nupr1 and TRIB3 which activates upregulation of ATF4 and CHOP proteins.nHighlight:A decrease in Akt leads to a downregulation in mTORC1 signalling causing autophagy.nHighlight:cannabinoids mechanism of action has been discerned from in vitro and in vivo studies.nHighlight:∆9-THC trends in inducing apoptosis and cytotoxicity through CB receptor-dependent pathways; CBD exhibits its activity via orphan GPCRs and non-GPRCs-mediated signallingnHighlight:Studies have reported positive upregulation of ceramide sphingolipid metabolism, leading to the subsequent arrest of the cell cycle and apoptosis via downstream activation of signals through extracellular regulated kinase (ERK) upon cannabinoid actionnHighlight:An increase in ceramide level has also been associated with ER stress in cannabinoid-induced apoptosis in tumour cells nHighlight:inhibits FAAH and FABP (Fatty Acid-Binding Protein)nHighlight:Both effects result in indirect activation of CB1 and CB2 receptors through increased extracellular concentration of anandamidenHighlight:CBD activates the 5-HT1A serotonin receptor, PPARγ and the transient receptor potential cation subfamily channels; TRPV1, TRPV2 and TRPA1nHighlight:CBD is also an antagonist of GPR55, transient receptor potential cation channel subfamily M member 8 (TRPM8) and T-type Ca2+ channelsnHighlight:Brief activation of the ERK cascade leads to cell survival and proliferation, whilst chronic activation is pro-apoptoticnHighlight:Cannabinoids in combination with chemotherapy agents have shown promising results in pancreatic cancer cell line studiesnHighlight:synergistic effects of CBD on gemcitabine’s mode of action in vivonHighlight:intratumour (IT) administration of low doses of cannabinoids has improved efficacy of the drug as well as survivalnHighlight:cannabinoids were combined with radiotherapy in treating pancreatic cancernHighlight:PDL-1 (a key target for immune checkpoint blockade) expression was reduced in mice tumours via the PAK-1-dependent pathway (p-21 activated kinase 1) activated by Kirsten rat sarcoma (KRAS)nHighlight:KRASnHighlight:inhibition of cell proliferation and invasiveness, a downregulation of ERK and Akt signalling and a decrease in the hypoxia-inducible factor HIF-1α expressionnHighlight:CBD was more potent in these effects when compared to ∆9-THCnHighlight:∆9-THC reduced the number of Ki67 immuno-reactive nucleinHighlight:anticancer effects of cannabinoid treatment in glioma as a single therapy and also as an addition in combination treatment.nHighlight:∆9-THC induced the effects of stimulation of ceramide synthesis de novonHighlight:reported an effective tumour reduction when CBD and ∆9-THC with TMZ were co-administered and that treatment with a high ratio of CBD was most efficaciousnHighlight:suggest exposure to ∆9-THC may increase susceptibility to breast cancer which does not express cannabinoid receptors and is resistant to ∆9-THC-induced aponHighlight: CB2 expression was also found to be correlated with tumours that had a low response to conventional therapies and that were also positive for certain prognostic markers including oestrogen, progesterone receptors and the presence of ERBB2/HER-2 oncogenenHighlight:psychotropic effects of cannabinoids are mediated via the CB1 rather than CB2nSticky notes:Important point—CB1 mediates cannabinoid psychotropic effectsnHighlight:∆9-THC was able to disrupt the HER2–CB2R complex by selective binding to CB2R.nSticky notes:HeterodimernHighlight:antitumour efficacy of a botanical drug preparation to be more potent than pure ∆9-THC nHighlight:CBD was the most potent in its antiproliferative activitynHighlight:direct or indirect activation of the receptors CB2 and TRPV1, receptor-independent elevation of intracellular Ca2+ and ROS generationnHighlight:CBD induced ER stress which led to the inhibition of AKT and mTOR signallingnHighlight:tumour-associated macrophages (TAMs) which are a class of immune cells contributing to the immunosuppressive TMEnHighlight:M1 (anti-tumorigenic) and M2 (pro-tumorigenic)nHighlight:CBD inhibited EGF-induced proliferation and chemotaxis in the cell linesnHighlight:inhibition of matrix metallopeptidase 2 and 9 (MMP2 and MMP9) secretionnHighlight:reduction in tumour growth and metastasis and inhibition of the recruitment of total and M2 macrophages to the stroma of the primary tumour and secondary lung metastasisn]]>

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.


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