CBN: The cancer fighting Cannabinoid

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“CBN, cannabinol, is a mildly psychoactive cannabinoid found within the cannabis plant. We examine the very complex mechanisms that give allowance for this cannabinoids entrance into the cell membrane and its effect on cannabinoid receptors and the inhibition of the enzyme adenylate cyclase that is responsible for phosphate production. Prior study bears weight accordingly; we examine this phosphate as a potent energy source, the enzymes responsible for cell replication cycle and inhibition thereof. Moreover, how IL-2, (Interleukin-2), a type of cytokine signaling molecule in the immune system stops being produced when immune T cells are exposed to cannabinoids. How IL-2 stimulates the cell cycle via promotion of the c-Fos protein and is responsible for modulation of the immune response. This is shown by Faubert and Kaminski, that administration of CBN can slow cell replication and endure cell death (apoptosis).”

http://www.imedpub.com/proceedings/cbn-the-cancer-fighting-cannabinoid-5528.html

“Programmed Cell Death (Apoptosis)” http://www.ncbi.nlm.nih.gov/books/NBK26873/

The Endocannabinoid System, Our Universal Regulator

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“The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body, which encompasses the brain, endocrine, and immune system, to name a few. ECS is a unique system in multiple dimensions.

To begin with, it is a retrograde system functioning post- to pre-synapse, allowing it to be a “master regulator” in the body. Secondly, it has a very wide scope of influence due to an abundance of cannabinoid receptors located anywhere from immune cells to neurons. Finally, cannabinoids are rapidly synthesized and degraded, so they do not stay in the body for very long in high amounts, possibly enabling cannabinoid therapy to be a safer alternative to opioids or benzodiazepines. This paper will discuss how ECS functions through the regulation of neurotransmitter function, apoptosis, mitochondrial function, and ion-gated channels. The practical applications of the ECS, as well as the avenues for diseases such as epilepsy, cancer, amyotrophic lateral sclerosis (ALS), and autism, which have no known cure as of now, will be explored.

The ECS is one of the, if not the most, important systems in our body. Its role in the homeostatic function of our body is undeniable, and its sphere of influence is incredible. Additionally, it also plays a major role in apoptotic diseases, mitochondrial function, and brain function.

Its contribution is more than maintaining homeostasis; it also has a profound ability in regulation. Working in a retrograde fashion and with a generally inhibitory nature, ECS can act as a “kill switch.” However, it has been shown to play an inhibitory or stimulatory role based on the size of the influx of cannabinoids, resulting in a bimodal regulation. Furthermore, due to the nature of the rate of degradation of cannabinoids, it does not have as many long-term side effects as most of the current drugs on the market.

The ECS may not only provide answers for diseases with no known cures, but it could change the way we approach medicine. This system would allow us to change our focus from invasive pharmacological interventions (i.e. SSRIs for depression, benzodiazepines for anxiety, chemotherapies for cancer) to uncovering the mystery of why the body is failing to maintain homeostasis. Understanding the roles of ECS in these diseases confers a new direction for medicine which may eradicate the use of some of the less tolerable therapeutics.”

https://www.jyi.org/2018-june/2018/6/1/the-endocannabinoid-system-our-universal-regulator

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

Cannabinoids: a new approach for pain control?

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“To analyze available data related to the use of cannabinoids in medicine, with a special focus on pain management in cancer. The use of cannabis for medical purposes is growing but there are still numerous questions to be solved: effectiveness, safety, and specific indications.

RECENT FINDINGS:

There is considerable variation between countries in the approaches taken, reflecting a variety of historical and cultural factors and despite few randomized controlled studies using natural cannabinoids, there is a trend to state that the use of cannabis should be taken seriously as a potential treatment of cancer-related pain. Cannabidiol, a nontoxic phytocannabinoid with few side-effects is promising in various indications in medicine.

SUMMARY:

The endocannabinoid system is a potential therapeutic target. Cannabinoids may be considered as potential adjuvant in cancer-related pain management. Cannabidiol appears to be the drug of choice. Analgesic trial designs should evolve to get closer to real-life practice and to avoid biases.”

https://www.ncbi.nlm.nih.gov/pubmed/30789867

https://insights.ovid.com/crossref?an=00001622-900000000-00002

Dronabinol for the Treatment of Paraneoplastic Night Sweats in Cancer Patients: A Report of Five Cases.

 View details for Journal of Palliative Medicine cover image“Night sweats significantly impact the quality of life for cancer patients and are often resistant to treatment.

Cannabinoids have been shown to modulate cytokine activity and produce hypothermia in animal models, suggesting that they may be a promising candidate for palliation of night sweats in patients with oncologic disease.

A retrospective record search identified five cancer patients who had tried oral dronabinol for palliation of their night sweats between 2013 and 2016 and subjectively reported on its efficacy.

 

RESULTS:

Treatment of five patients with advanced cancer with synthetic orally administered dronabinol resulted in the successful management of persistent symptomatic paraneoplastic night sweats.

CONCLUSION:

Dronabinol and/or medicinal cannabis are promising therapies for palliation of night sweats in cancer patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30759037

https://www.liebertpub.com/doi/10.1089/jpm.2018.0551

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

Synthetic Cannabinoid Activity Against Colorectal Cancer Cells

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“Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and new therapeutic strategies are still required. Here we screened a synthetic cannabinoid library to identify compounds that uniformly reduce the viability of seven CRC cell lines.

We identified 10 compounds from the library that were able to reduce cell viability of CRC cell lines.

Conclusion: We identified three families of cannabinoid compounds that reduce CRC cell viability through a noncanonical receptor mechanism. Future modification of these compounds may lead to the development of novel therapies to treat this disease.”

https://www.liebertpub.com/doi/10.1089/can.2018.0065

“Cannabinoid compounds may inhibit growth of colon cancer cells”  https://news.psu.edu/story/557660/2019/02/06/research/cannabinoid-compounds-may-inhibit-growth-colon-cancer-cells

“CANNABIS COMPOUNDS SLOW COLON CANCER IN THE LAB”  https://www.futurity.org/cannabinoids-colon-cancer-1975272/

“Synthetic cannabis may stop colorectal cancer from growing, study suggests”  https://www.dailymail.co.uk/health/article-6674275/Synthetic-cannabis-stop-colorectal-cancer-growing-study-suggests.html

Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting.

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“Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.”

https://www.ncbi.nlm.nih.gov/pubmed/30720344

https://www.futuremedicine.com/doi/10.2217/fon-2018-0530

New Prospect for Cancer Cachexia: Medical Cannabinoid.

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“Cachexia is a common term for the wasting symptoms which may appear in almost every chronic illness, such as AIDS, tuberculosis, and cancer. Cancer cachexia (CCA) is a result of the interaction between the host and the tumor, mainly manifested in short-term wasting, malnutrition, and so on. Due to the chronic food shortages, absorption dysfunction and metabolic disorders, all of these eventually lead to hypoimmunity, organ failure, and higher susceptibility to pathogenic microorganisms. And then increased morbidity and mortality rates as well as reduced tolerance to anti-cancer treatments will be resulted in patients with CCA. Up to now, no standard guidelines have been established for cachexia treatment. Moreover, progestagens, the only drugs approved by FDA for cancer-related cachexia, can only increase adipose tissue and have not been confirmed to augment lean body mass. Cannabinoid, such as Δ-9-tetrahydrocannabinol (THC) and cannabidiol, is one of a class of diverse chemical compounds. Previous studies have showed that cannabinoid had considerable potential to improve the appetite, body weight, body fat level, caloric intake, mood, quality of life in kinds of diseases. This review will elaborate the anti-CCA role of cannabinoid and explore that whether cannabinoid is effective for CCA and provide a basis for guiding clinical drug use.”

https://www.ncbi.nlm.nih.gov/pubmed/30719170

http://www.jcancer.org/v10p0716.htm

Role of miRNA in the regulation of cannabidiol-mediated apoptosis in neuroblastoma cells.

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“Neuroblastoma (NBL) is one of the most common childhood cancers that originate from the immature nerve cells of the sympathetic system. Studies with NBL cancers have also shown that miRNAs are dysregulated and may play a critical role in pathogenesis.

Cannabidiol (CBD) is a non-psychoactive compound found in marijuana which has been previously shown by our laboratory and others to induce apoptosis in cancer cells. However, there are no studies reported to test if CBD mediates these effects through regulation of miRNA.

In the current study, therefore, we investigated if CBD induces apoptosis in human NBL cell lines, SH SY5Y and IMR-32, and if it is regulated by miRNA.

Our data demonstrated that CBD induces apoptosis in NBL cells through activation of serotonin and vanilloid receptors. We also found that caspase-2 and -3 played an important role in the induction of apoptosis. CBD also significantly reduced NBL cell migration and invasion in vitro.

Furthermore, CBD blocked mitochondrial respiration and caused a shift in metabolism towards glycolysis. CBD altered the expression of miRNA specifically, down-regulating hsa-let-7a and upregulating hsa-mir-1972. Downregulation of let-7a increased expression of target caspase-3, and growth arrest specific-7 (GAS-7) genes. Upregulation of hsa-mir-1972 caused decreased expression of BCL2L1 and SIRT2 genes.

Together, our studies suggest that CBD-mediated apoptosis in NBL cells is regulated by miRNA.”