CBD also exerted complex antiinflammatory actions that were . We additionally found that CBD also prevented the “pro-acne” LA-T .. is mediated by upregulation of tribbles homolog 3 and inhibition of the NF-κB pathway. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB . acne agents, which target multiple pathogenetic steps of acne Lipostatic activity of CBD is mediated by TRPV4. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol The involvement of CB₂ receptors was not dependent on a CBD-mediated upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. . A model of acute lymphoblastic disease, the Jurkat T cell line, has been used.
CBD and upregulation of tribbles t inhibition of is 3 by Antiinflammatory of action mediated homolog
Conditions were as in Figure 1 , except that no LPS was added. These concentrations were chosen following our previous reports [8, 9]. T-cell proliferation was analyzed using [ 3 H]thymidine incorporation as previously reported . Similar results were observed when T MOG cells were stimulated with 2. MOG 35—55 -treated cells. Previous work from our laboratory showed that these genes were also significantly upregulated by CBD .
These results demonstrate that DMH-CBD is inducing a metabolic adaptation program typical for nutrient limiting conditions, characterized by repression of protein synthesis and upregulation of amino acid biosynthesis and transporter genes [ 32 ]. This suggests that p8 promotes the transcription of stress-regulated genes via a positive feedback on ATF4 pathway [ 33 ]. This result is in agreement with Sato et al.
In this regard, it was shown that Hmox1 induction drives a shift to M2 macrophage phenotype, characterized by its intracellular redox status, consisting of high expression of scavenging molecules and GSH [ 42 , 43 ].
Cannabinoids, including CBD, have been shown to possess anti-proliferative properties in highly proliferative cell lines, including transformed T-cell lines [ 44 — 46 ].
For example, CBD inhibits proliferation by inducing cell death in cancer cell lines via the transient receptor potential vanilloid channel 2 [ 47 , 48 ] and THC reduces proliferation and leads to cell death of C6 glioma cells via CB 1 receptor [ 49 ]. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
This work was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. The funding organization s played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci ;9: Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol ; Early phytocannabinoid chemistry to endocannabinoids and beyond.
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A role for transient receptor potential vanilloid type Int J Cancer ; Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.
Delta9-tetrahydrocannabinol increases C6 glioma cell death produced by oxidative stress. Cannabidiol-induced apoptosis in primary lymphocytes is associated with oxidative stress-dependent activation of caspase Toxicol Appl Pharmacol ; The study showed that, although the apoptotic effect of thc on glioma cells relied on the stimulation of cannabinoid receptors and activation of the p8-mediated autophagy pathway, the differences in the sensitivity to thc -induced cell death correlated with enhanced expression of a particular set of genes in the thc -resistant glioma cells rather than with the presence of different expression levels of cb 1 or cb 2 receptors Interestingly, upregulation of one of those genes, midkine MDK , which encodes a growth factor that was previously associated with increased malignancy and resistance to anticancer therapies in several types of tumours 77 , 78 , correlates with lower overall survival in patients with glioblastoma Moreover, mdk plays a direct role in the resistance to thc action through stimulation of anaplastic lymphoma kinase alk Thus, the stimulation of alk by mdk inhibits the thc -evoked autophagy-mediated cell-death pathway.
Further research should clarify whether that mechanism could also be responsible for the resistance to other therapies of cancer cells expressing high levels of mdk. Interestingly, in vivo silencing of MDK or pharmacologic inhibition of alk in a mouse xenograft model abolishes the resistance to thc treatment of established tumours derived from cannabinoid-resistant glioma cells Taken together, the foregoing findings support the idea that stimulation of the mdk — alk axis promotes resistance to thc antitumour action in gliomas and could help to set a foundation for the potential clinical use of thc in combination with inhibitors of the mdk — alk axis Figure 2.
Glioblastoma is highly resistant to current anticancer therapies 80 — Specifically, resistance of glioma cells to cannabinoid-induced cell death relies, at least in part, on enhanced expression of mdk and the subsequent activation of alk Likewise, enhanced expression of the heparin-bound epidermal growth factor receptor egfr ligand amphiregulin can promote resistance to thc antitumour action by stimulation of extracellular signal-regulated kinase erk The combination of thc with pharmacologic inhibitors of alk or genetic inhibition of MDK enhances cannabinoid action in resistant tumours, which provides a rationale for the design of targeted therapies capable of increasing cannabinoid antineoplastic activity Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide the benchmark agent for the management of glioblastoma 80 , 84 have been shown to produce a strong anticancer action in animal models Combining cannabinoids and temozolomide is thus a very attractive possibility for clinical studies aimed at investigating cannabinoid antitumour effects in glioblastoma.
Other potentially interesting strategies to enhance cannabinoid anticancer action still requiring additional experimental support from data obtained using preclinical models could be to combine cannabinoids with er stress or autophagy inducers or both or with inhibitors of the m torc 1 axis.
In line with that idea, alk inhibitors have started to be used in clinical trials for the management of non-small-cell lung cancer and other types of tumours 86 , Future research should clarify whether this mechanism of resistance to cannabinoid action operates in other types of tumours. In agreement with that possibility, MDK silencing enhanced the sensitivity of cannabinoid-resistant pancreatic cancer cells to thc -induced cell death The release by cancer cells of other growth factors has also been implicated in the mechanism of resistance to cannabinoid antitumour action.
Thus, increased expression of amphiregulin is associated with enhanced resistance to thc antitumour action in glioma xenografts Notably illustrating how the dose of cannabinoids could be crucial for optimal therapeutic effect, low submicromolar concentrations of thc or other synthetic cannabinoid agonists enhance the proliferation of several cancer cell lines in vitro.
That effect relies on activation of the protease adam 17, the shedding of heparin-bound egfr ligands including amphiregulin and the subsequent stimulation of the erk and akt pathways In line with that idea, a recent report showed that treatment with the synthetic cannabinoid CP 55, increases the proliferation of murine glioma cells engineered to express cb 1 or cb 2 receptors only when those receptors are coupled to akt activation Although a pro-tumourigenic effect has not been observed for the growth of tumour xenografts generated with glioma cells and treated with low doses of thc 85 , increased expression of amphiregulin promotes resistance to thc antitumour action through a mechanism that involves the egfr -dependent stimulation of erk and the subsequent inhibition of p8 and trb 3 expression.
Likewise, pharmacologic inhibition of egfr , erk 83 , 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.
The use of combinational anticancer therapies has a number of theoretical advantages over single-agent strategies, because they allow for the simultaneous targeting of tumour growth, progression, and spread at various levels. In line with that idea, recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth.
For example, the administration of thc and temozolomide exerts strong antitumour action in glioma xenografts, an effect that is also evident in temozolomide-resistant tumours A similar effect was observed when thc and cbd were combined with radiotherapy in animal models of glioma.
Interestingly, no toxicity was observed in mice treated with combinations of thc and temozolomide Because most patients with glioblastoma undergo temozolomide treatment, the foregoing findings indicate that the combined administration of temozolomide and cannabinoids could be therapeutically exploited for the management of glioblastoma Figure 2 and perhaps other tumour types such as melanoma Likewise, another study recently showed that the 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 Other reports indicated that anandamide and HU might also enhance the anticancer activity of paclitaxel 89 and 5-fluorouracil 90 respectively.
An additional approach has been to combine thc with cbd , a phytocannabinoid that reduces although to a lower extent than thc the growth of several types of tumour xenografts through a still poorly-defined mechanism 59 , 91 , 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 85 , Moreover, the combination of thc and cbd together with temozolomide produces a striking reduction in the growth of glioma xenografts even when low doses of thc are used Likewise, the combination of thc , cbd , and radiotherapy also produced clear anticancer activity in an orthotopic model of glioma Notably, cbd was also shown to alleviate some of the undesired effects of thc administration such as convulsions, discoordination, and psychotic events, thus improving the tolerability of cannabis-based medicines As mentioned earlier, C.
Thus, we think that clinical studies aimed at analyzing the efficacy of cannabinoids as antitumour agents should be based on the use both of pure substances, such as thc and cbd , and of cannabis extracts containing controlled amounts of thc , cbd , and other cannabinoids. The clinical approval of cannabinoids is largely restricted to palliative uses in various diseases, but since the emergence of promising preclinical data, the antitumour effects of cannabinoids are beginning to be clinically assessed.
In a pilot phase i clinical study, 9 patients with actively- growing recurrent glioblastoma for whom standard therapy had previously failed underwent intracranial thc administration Under those conditions, cannabinoid delivery was safe and could be achieved without significant unwanted effects. In addition, although no statistically significant conclusions can be extracted from a cohort of 9 patients, the results obtained in the study suggest that some patients responded—at least partially—to thc treatment in terms of a decreased tumour growth rate as evaluated by magnetic resonance imaging Importantly, analyses of samples obtained from 2 study patients before and after thc administration indicated that the molecular mechanism of cannabinoid antitumour action—namely, p8 and trib 3 upregulation 35 , 37 , m torc 1 inhibition 37 , stimulation of autophagy and apoptosis 11 , 35 , 37 , inhibition of cell proliferation 11 , decreased vegf signalling 32 , and matrix metalloproteinase 2 downregulation 64 delineated here earlier —also operates in vivo.
Those findings were encouraging and reinforced interest in the potential use of cannabinoids in cancer therapies. However, they also highlighted the need for further research aimed at optimizing the use of cannabinoids in terms of patient selection, combination with other anti-cancer agents, and use of other routes of administration. Administration of endocannabinoids or inhibitors of endocannabinoid-degrading enzymes has been shown to reduce the growth of various tumour xenograft types 95 , 96 and could therefore be a reasonable strategy for targeting cannabinoid receptors for anticancer purposes.
However, as discussed here earlier, the role of the endocannabinoid system, including the endocannabinoid-degrading enzymes, in the control of tumour generation and progression is not well understood.
Because enhancing endocannabinoid tone only has mild antitumour effects in mice and because no inhibitor of endocannabinoid degradation has yet been approved for use in humans, clinical studies aimed at analyzing the efficacy of cannabinoids as antitumour agents should be based on the use of plant-derived or synthetic agonists of cannabinoid receptors rather than on endocannabinoids or inhibitors of endocannabinoid degradation.
The long-known therapeutic properties of C. As already mentioned, C. However, pure drugs are more prone to standardization than complex molecular cocktails. Thus, it would be ideal for studies aiming to investigate the anticancer actions of cannabinoids in patients to be performed comparatively with both pure substances and cannabis extracts containing controlled amounts of thc , cbd , and other cannabinoids.
The most widely used route of administration for recreational and self-medicating marijuana is smoking. Although thc and other phytocannabinoids are rapidly absorbed by inhalation, smoking is an unattractive clinical option. Preclinical work in animal models has typically used peri-tumoural administration of cannabinoids.
Likewise, in the only clinical trial in which a cannabinoid was assayed as an antitumour agent, thc was administered locally intracranial delivery to patients with glioblastoma multiforme Nevertheless, this route of administration has many obvious limitations.
Currently available cannabis-based medicines are administered as capsules or using an oromucosal spray Preclinical animal models have yielded data indicating that systemic oral or intraperitoneal administration of cannabinoids effectively decreases tumour growth GV, CS, and MG. Unpublished observations , and so it seems reasonable that future clinical studies with the goal of determining the efficacy of cannabinoids as antitumour agents use oral or oromucosal routes of administration.
Two currently ongoing clinical trials could shed some light on these issues. The other is a phase ii trial aimed at evaluating the effect of cbd as single treatment in patients with solid tumours https: Hopefully, in the near future, new clinical trials will start, helping to determine whether cannabinoids can be used, for other than their palliative effects, in the treatment of cancer patients. It is widely believed that strategies aimed at reducing mortality from cancer should consist of targeted therapies capable of providing the most efficacious and selective treatment for each individual tumour and patient.
Thus, the major focus of anticancer drug development has progressively moved from nonspecific chemotherapies to molecularly-targeted inhibitors. However, despite the huge amount of preclinical literature on how these rationally designed compounds work, their use in clinical practice is still limited. How do cannabinoid-based medicines fit into this ongoing scenario?
Consider glioma, the type of cancer in which the most detailed cannabinoid research has been conducted to date. As discussed here, engagement of a molecular target the cb receptors by a family of selective drugs thc and other cannabinoid agonists inhibits tumour growth in animal models through a well-established mechanism of action that also seems to operate in human patients.
Moreover, cannabinoids potentiate the antitumour efficacy of temozolomide and alk inhibitors in mice harbouring gliomas. However, further research is required to define the precise molecular cross-talk between cannabinoids and chemotherapeutic drugs and to optimize the pharmacology of preclinical cannabinoid-based combination therapies.
With respect to patient stratification, the particular individuals that are potentially responsive to cannabinoid administration should be unequivocally determined. To that end, high-throughput approaches should be implemented to find cannabinoid therapy—associated biomarkers in tumour biopsies or, ideally, in easily acquired fluids containing circulating cancer cells or enhanced levels of resistance factors that might have been released by cancer cells.
Such biomarkers would conceivably relate to cannabinoid pharmacodynamics—namely, expression and activity of cannabinoid receptors and their downstream cell-death-inducing effectors. The approach would be analogous to the biochemical evaluation of estrogen and ErbB2 receptors, which respectively predict benefit from endocrine therapies and trastuzumab in breast cancer.
Predictive markers to define the sensitivity of a particular tumour to cannabinoid-based therapies could also include the status of growth factors, such as mdk in gliomas, and their receptors and signalling partners. To summarize, cannabinoids induce tumour cell death and inhibit tumour angiogenesis and invasion in animal models of cancer, and there are indications that they act similarly in patients with glioblastoma.
Given that cannabinoids show an acceptable safety profile, clinical trials testing them as single drugs or, ideally, in combination therapies in glioblastoma and other types of cancer are both warranted and urgently needed. GW Pharmaceuticals and Cellmid fund part of the research conducted by our laboratory.
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Journal of Basic and Clinical Physiology and Pharmacology
***P T–treated group. . More- Sebostatic action of CBD is mediated by TRPV4-dependent inter- over, GSK . of CBD is mediated by upregulation of tribbles homolog 3 and inhibition of the. in BV-2 microglia and encephalitogenic T cells In parallel, DMH-CBD upregulated the expression of In addition, DMH-CBD dose-dependently inhibited bles homologue 3 (Trb3) pathway [11, 12]. effects mediated by DMH-CBD within genes involved in . These included tribbles homologue 3. [ Trb3. Action of THC in human organism relies on mimicking noid which gains medical attention is cannabidiol (CBD). It has low affinity for . upregulated in cancer cell lines and in human tumors (CHOP), and Tribbles homolog 3 (TRIB3 ) (Fig. 1) [36 . the regulatory T cells (Tregs) which leads to the inhibition.