The heterogeneity and complexity of Cannabis extracts as antitumor agents

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“The Cannabis plant contains over 100 phytocannabinoids and hundreds of other components. The biological effects and interplay of these Cannabis compounds are not fully understood and yet influence the plant’s therapeutic effects.

Here we assessed the antitumor effects of whole Cannabis extracts, which contained significant amounts of differing phytocannabinoids, on different cancer lines from various tumor origins.

Our results show that specific Cannabis extracts impaired the survival and proliferation of cancer cell lines as well as induced apoptosis.

Our findings showed that pure (-)-Δ9trans-tetrahydrocannabinol (Δ9-THC) did not produce the same effects on these cell lines as the whole Cannabis extracts. Furthermore, Cannabis extracts with similar amounts of Δ9-THC produced significantly different effects on the survival of specific cancer cells.

In addition, we demonstrated that specific Cannabis extracts may selectively and differentially affect cancer cells and differing cancer cell lines from the same organ origin. We also found that cannabimimetic receptors were differentially expressed among various cancer cell lines and suggest that this receptor diversity may contribute to the heterogeneous effects produced by the differing Cannabis extracts on each cell line.

Our overall findings indicate that the effect of a Cannabis extract on a specific cancer cell line relies on the extract’s composition as well as on certain characteristics of the targeted cells.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26983

“Many previous reports highlight and demonstrate the anti-tumor effects of cannabinoids. In the last decade, accumulating evidence has indicated that phytocannabinoids might have antitumor properties. A number of in vitro and in vivo studies have demonstrated the effects of phytocannabinoids on tumor progression by interrupting several characteristic features of cancer. These studies suggest that specific cannabinoids such as Δ9-THC and CBD induce apoptosis and inhibit proliferation in various cancer cell lines.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26983&path%5B%5D=85698

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Antitumor Cannabinoid Chemotypes: Structural Insights.

Image result for frontiers in pharmacology“Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy.

Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors.

Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein-coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH).

In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic.

This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/31214034

“The first report on the antitumor activity of phytocannabinoids was published over four decades ago. During these last years, significant research has been focused on the therapeutic potential of cannabinoids to manage palliative effects in cancer patients. Besides such palliative applications, some cannabinoids have shown anticancer properties. Since inflammation is a common risk factor for cancer, and some cannabinoids have shown anti-inflammatory properties, they could play a role in chemoprevention.” https://www.frontiersin.org/articles/10.3389/fphar.2019.00621/full
“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557
“Antitumor effects of cannabidiol” http://www.ncbi.nlm.nih.gov/pubmed/14617682
“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/29940172
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Should Oncologists Recommend Cannabis?

“Cannabis is a useful botanical with a wide range of therapeutic potential. Global prohibition over the past century has impeded the ability to study the plant as medicine. However, delta-9-tetrahydrocannabinol (THC) has been developed as a stand-alone pharmaceutical initially approved for the treatment of chemotherapy-related nausea and vomiting in 1986. The indication was expanded in 1992 to include treatment of anorexia in patients with the AIDS wasting syndrome. Hence, if the dominant cannabinoid is available as a schedule III prescription medication, it would seem logical that the parent botanical would likely have similar therapeutic benefits. The system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) has likely developed to help us modulate our response to noxious stimuli. Phytocannabinoids also complex with these receptors, and the analgesic effects of cannabis are perhaps the best supported by clinical evidence. Cannabis and its constituents have also been reported to be useful in assisting with sleep, mood, and anxiety. Despite significant in vitro and animal model evidence supporting the anti-cancer activity of individual cannabinoids-particularly THC and cannabidiol (CBD)-clinical evidence is absent. A single intervention that can assist with nausea, appetite, pain, mood, and sleep is certainly a valuable addition to the palliative care armamentarium. Although many healthcare providers advise against the inhalation of a botanical as a twenty-first century drug-delivery system, evidence for serious harmful effects of cannabis inhalation is scant and a variety of other methods of ingestion are currently available from dispensaries in locales where patients have access to medicinal cannabis. Oncologists and palliative care providers should recommend this botanical remedy to their patients to gain first-hand evidence of its therapeutic potential despite the paucity of results from randomized placebo-controlled clinical trials to appreciate that it is both safe and effective and really does not require a package insert.”

https://www.ncbi.nlm.nih.gov/pubmed/31161270

https://link.springer.com/article/10.1007%2Fs11864-019-0659-9

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Modulation of the Endocannabinoid System as a Potential Anticancer Strategy.

 Image result for frontiers in pharmacology“Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the Gi/o protein-coupled transmembrane cannabinoidreceptors CB1 and CB2. As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O-arachidonoylethanolamine, N-arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31143113

“In addition to the palliative effects of cannabinoid compounds in cancer treatment, the endocannabinoid system provides several targets for systemic anticancer treatment. Accordingly, preclinical studies suggest cannabinoids inhibit cancer progression via inhibition of cancer cell proliferation, neovascularization, invasion and chemoresistance, as well as induction of apoptosis, autophagy and increase of tumor immune surveillance.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.00430/full

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Medical Cannabis Use in Glioma Patients Treated at a Comprehensive Cancer Center in Florida.

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“Glioma is a devastating primary tumor of the central nervous system with difficult-to-manage symptoms.

Cannabis products have been postulated to potentially benefit glioma patients. Recent state legalization allowed investigators an opportunity to study glioma patients’ adoption of medical marijuana (MM).

Objective: Our goals were to: (1) determine the prevalence of marijuana use, both through physician recommendation and self-medication, and (2) evaluate its perceived risks and benefits in glioma patients.

Results: A total of 73 patients were surveyed. The majority of participants were aware that MM was legal in the state, and most reported learning of this through the media. Over 70% of participants reported having considered using MM, and a third reported using marijuana products after their diagnosis. Most received recommendations from friends/family rather than a medical provider, and only half of the users had obtained a physician’s recommendation. Users generally reported benefits.

Conclusions: With the increasing national conversation that accompanies legalization, glioma patients are pursuing marijuana for the treatment for their symptoms. More research and education is needed to bring health care providers into the conversation.”

“A glioma is a primary brain tumor that originates from the supportive cells of the brain, called glial cells.” http://neurosurgery.ucla.edu/body.cfm?id=159
“Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death.” https://www.ncbi.nlm.nih.gov/pubmed/15275820
“A meta-analysis of 34 in vitro and in vivo studies of cannabinoids in glioma reported that all but one study confirmed that cannabinoids selectively kill tumor cells.”  https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/_7
“Since cannabinoids kill tumor cells without toxicity on their non transformed counterparts, they can represent a class of new potential anticancer drugs.”                                        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835116/ 
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Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells.

Related image“Despite advances in glioblastoma (GBM) therapy, prognosis of the disease remains poor with a low survival rate.

Cannabidiol (CBD) can induce cell death and enhance radiosensitivity of GBM but not normal astrocytes.

Inhibition of ATM kinase is an alternative mechanism for radiosensitization of cancer cells.

In this study, we increased the cytotoxic effects of the combination of CBD and γ-irradiation in GBM cells through additional inhibition of ATM kinase with KU60019, a small molecule inhibitor of ATM kinase.

We observed in GBM cells treated by CBD, γ-irradiation and KU60019 high levels of apoptosis together with strong upregulation of the percentage of G2/M-arrested cells, blockade of cell proliferation and a massive production of pro-inflammatory cytokines.

Overall, these changes caused both apoptotic and non-apoptotic inflammation-linked cell death. Furthermore, via JNK-AP1 activation in concert with active NF-κB, CBD upregulated gene and protein expression of DR5/TRAIL-R2 and sensitize GBM cells to TRAIL-induced apoptosis. In contrast, CBD notably decreased in GBM surface levels of PD-L1, a critical immune checkpoint agent for T-lymphocytes. We also used in the present study TS543 human proneural glioma cells that were grown as spheroid culture. TS543 neurospheres exhibited dramatic sensitivity to CBD-mediated killing that was additionally increased in combination with γ-irradiation and KU60019.

In conclusion, treatment of human GBM by the triple combination (CBD, γ-irradiation and KU60019) could significantly increase cell death levels in vitro and potentially improve the therapeutic ratio of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/30783513

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26582&path[]=82682

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WIN55,212-2 induces caspase-independent apoptosis on human glioblastoma cells by regulating HSP70, p53 and Cathepsin D.

Toxicology in Vitro

“Despite the standard approaches to treat the highly aggressive and invasive glioblastoma (GBM), it remains incurable.

In this sense, cannabinoids highlight as a promising tool, because this tumor overexpresses CB1 and/or CB2 receptors and being, therefore, can be susceptible to cannabinoids treatment.

Thus, this work investigated the action of the cannabinoid agonist WIN55-212-2 on GBM cell lines and non-malignant cell lines, in vitro and in vivo. WIN was selectively cytotoxic to GBM cells. These presented blebbing and nuclear alterations in addition to cell shrinkage and chromatin condensation. WIN also significantly inhibited the migration of GAMG and U251 cells.

Finally, the data also showed that the antitumor effects of WIN are exerted, at least to some extent, by the expression of p53 and increased cathepsin D in addition to the decreased expression of HSP70.This data can indicate caspase-independent cell death mechanism. In addition, WIN decreased tumoral perimeter as well as caused a reduction the blood vessels in this area, without causing lysis, hemorrhage or blood clotting.

So, the findings herein presented reinforce the usefulness of cannabinoids as a candidate for further evaluation in treatment in glioblastoma treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30776504

https://www.sciencedirect.com/science/article/pii/S0887233318307537?via%3Dihub

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On the influence of cannabinoids on cell morphology and motility of glioblastoma cells.

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“The mechanisms behind the anti-tumoral effects of cannabinoids by impacting the migratory activity of tumor cells are only partially understood. Previous studies demonstrated that cannabinoids altered the organization of the actin cytoskeleton in various cell types.

As actin is one of the main contributors to cell motility and is postulated to be linked to tumor invasion, we tested the following hypothesizes: 1) Can cannabinoids alter cell motility in a cannabinoid receptor dependent manner? 2) Are these alterations associated with reorganizations in the actin cytoskeleton? 3) If so, what are the underlying molecular mechanisms?

Three different glioblastoma cell lines were treated with specific cannabinoid receptor 1 and 2 agonists and antagonists. Afterwards, we measured changes in cell motility using live cell imaging and alterations of the actin structure in fixed cells. Additionally, the protein amount of phosphorylated p44/42 mitogen-activated protein kinase (MAPK), focal adhesion kinases (FAK) and phosphorylated FAK (pFAK) over time were measured.

Cannabinoids induced changes in cell motility, morphology and actin organization in a receptor and cell line dependent manner. No significant changes were observed in the analyzed signaling molecules. Cannabinoids can principally induce changes in the actin cytoskeleton and motility of glioblastoma cell lines. Additionally, single cell motility of glioblastoma is independent of their morphology. Furthermore, the observed effects seem to be independent of p44/42 MAPK and pFAK pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/30753211

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212037

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Case Report: Clinical Outcome and Image Response of Two Patients With Secondary High-Grade Glioma Treated With Chemoradiation, PCV, and Cannabidiol.

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“We describe two patients with a confirmed diagnosis of high-grade gliomas (grades III/IV), both presenting with O6-methylguanine-DNA methyltransferase (MGMT) methylated and isocitrate dehydrogenase (IDH-1) mutated who, after subtotal resection, were submitted to chemoradiation and followed by PCV, a multiple drug regimen (procarbazine, lomustine, and vincristine) associated with cannabidiol (CBD).

Both patients presented with satisfactory clinical and imaging responses at periodic evaluations. Immediately after chemoradiation therapy, one of the patients presented with an exacerbated and precocious pseudoprogression (PSD) assessed by magnetic resonance imaging (MRI), which was resolved in a short period. The other patient presented with a marked remission of altered areas compared with the post-operative scans as assessed by MRI.

Such aspects are not commonly observed in patients only treated with conventional modalities. This observation might highlight the potential effect of CBD to increase PSD or improve chemoradiation responses that impact survival. Further investigation with more patients and critical molecular analyses should be performed.”

https://www.ncbi.nlm.nih.gov/pubmed/30713832

“These observations are of particular interest because the pharmacology of cannabinoids appears to be distinct from existing oncology medications and may offer a unique and possibly synergistic option for future glioma treatment.”

https://www.frontiersin.org/articles/10.3389/fonc.2018.00643/full

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Synthetic Cannabinoids Influence the Invasion of Glioblastoma Cell Lines in a Cell- and Receptor-Dependent Manner.

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“The current treatment of glioblastoma is not sufficient, since they are heterogeneous and often resistant to chemotherapy.

Earlier studies demonstrated effects of specific cannabinoid receptor (CB) agonists on the invasiveness of glioblastoma cell lines, but the exact mechanism remained unclear.

Three human glioblastoma cell lines were treated with synthetic CB ligands. The effect of cannabinoids on microRNAs (miRs), Akt, and on the expression of proliferation and apoptosis markers were analyzed.

Furthermore, in a model of organotypic hippocampal slice cultures cannabinoid mediated changes in the invasiveness were assessed. MicroRNAs and the activation of Akt which are related to cell migration, apoptosis, and proliferation were evaluated and found not to be associated with changes in the invasiveness after treatment with CB ligands.

Also proliferation and/or apoptosis were not altered after treatment. The effects of cannabinoids on invasiveness could be blocked by the application of receptor antagonists and are likely mediated via CB₁/CB₂.

In conclusion, our results suggest that cannabinoids can influence glioblastoma cell invasion in a receptor and cell type specific manner that is independent of proliferation and apoptosis. Thus, cannabinoids can potentially be used in the future as an addition to current therapy.”

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