Anticancer mechanisms of cannabinoids - 0 views
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modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival
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cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals
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Cannabis sativa L. (marijuana)
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of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
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Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
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two major cannabinoid-specific receptors—cb1 and cb2
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transient receptor potential cation channel subfamily V, member 1
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orphan G protein–coupled receptor 55
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Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
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the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
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cardiovascular tone, energy metabolism, immunity, and reproduction
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cannabinoids are well known to exert palliative effects in cancer patients
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best-established use is the inhibition of chemotherapy-induced nausea and vomiting
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thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
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cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
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cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
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pharmacologic activation of cannabinoid receptors decreases tumour growth
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endocannabinoid signalling can also have a tumour-suppressive role
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pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
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most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
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impair tumour angiogenesis and block invasion and metastasis
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thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
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Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
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autophagy is important for cannabinoid antineoplastic activity
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autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
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the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
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glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
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other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
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thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
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cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
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In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
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In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
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cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
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the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
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cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
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cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
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ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
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recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
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combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
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Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
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Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
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Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
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Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
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pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids