Rimonabant Kills Colon Cancer Stem Cells without Inducing Toxicity in Normal Colon Organoids

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“Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel.

Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC.

Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.

 Anti-tumor action of cannabinoids in CRC was strongly supported by several authors.
The Endocannabinoid (EC) system role in the progression of CRC has been analyzed in vivo in the mouse model of azoxymethane-induced colon carcinogenesis, where cannabinoids-mediated reduction of precancerous lesions in the mouse colon was found.
In CRC cells, agonists and antagonists of both cannabinoid receptors, CB1 and CB2, showed anti-tumor action through induction of cell death with different mechanisms ranging from apoptosis to mitotic catastrophe”
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The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy.

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“Epilepsy, commonly encountered by patients with brain tumors, is often refractory to standard therapies. Our aim was to examine the safety and efficacy of pharmaceutical grade cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) in those patients with epilepsy with concomitant tumors enrolled in The University of Alabama at Birmingham CBD Program (NCT02700412 and NCT02695537). Of the three patients with refractory seizures and a history of a primary brain tumor, two had improvement in seizure frequency and all three had improvement in seizure severity. These pilot results suggest that CBD should be further studied for the treatment of brain tumor-related epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/29063814

http://www.tandfonline.com/doi/abs/10.1080/13554794.2017.1391294?journalCode=nncs20

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Cannabis sativa Extract Reduces Cytoskeletal Associated Proteins in Breast Cancer Cell Line

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Synergistic interaction of the cannabinoid and death receptor systems: A potential target for future cancer therapies?

FEBS Letters

“Cannabinoid receptors have been shown to interact with other receptors, including Tumor Necrosis Factor Receptor Superfamily (TNFRS) members, to induce cancer cell death. When cannabinoids and death-inducing ligands (including TRAIL) are administered together, they have been shown to synergize and demonstrate enhanced antitumor activity in vitro. Certain cannabinoid ligands have been shown to sensitize cancer cells and synergistically interact with members of the TNFRS, thus suggesting that the combination of cannabinoids with death receptor (DR) ligands induces additive or synergistic tumor cell death. This review summarizes recent findings on the interaction of the cannabinoid and DR systems and suggests possible clinical co-application of cannabinoids and DR ligands in the treatment of various malignancies.”

https://www.ncbi.nlm.nih.gov/pubmed/28948607

http://onlinelibrary.wiley.com/doi/10.1002/1873-3468.12863/abstract?systemMessage=Wiley+Online+Library+will+be+unavailable+on+Saturday+7th+Oct+from+03.00+EDT+%2F+08%3A00+BST+%2F+12%3A30+IST+%2F+15.00+SGT+to+08.00+EDT+%2F+13.00+BST+%2F+17%3A30+IST+%2F+20.00+SGT+and+Sunday+8th+Oct+from+03.00+EDT+%2F+08%3A00+BST+%2F+12%3A30+IST+%2F+15.00+SGT+to+06.00+EDT+%2F+11.00+BST+%2F+15%3A30+IST+%2F+18.00+SGT+for+essential+maintenance.+Apologies+for+the+inconvenience+caused+.

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Cannabinoids as Anticancer Drugs.

Advances in Pharmacology

“The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.sciencedirect.com/science/article/pii/S105435891730039X?via%3Dihub

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A Review of the Therapeutic Antitumor Potential of Cannabinoids.

:Image result for J Altern Complement Med.

“The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment.

RESULTS:

Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of “cannabinoid sensitizers.” Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness.

CONCLUSIONS:

A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with standard anticancer strategies. With such knowledge, cannabinoids could become a therapy of choice in contemporary oncology.”

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The Role of Cannabinoids in the Treatment of Cancer in Pediatric Patients.

“Cannabis has been used in folk medicine to alleviate pain, depression, amenorrhea, inflammation and numerous other medical conditions. In cancer patients specifically, cannabinoids are well known to exert palliative effects; their best-established use is the inhibition of chemotherapy-induced nausea and vomiting, but they are applied also to alleviate pain, stimulate appetite, and attenuate wasting. More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death.

Anti-cancer efficacy of cannabinoids:

The ability of cannabinoids to reduce tumor growth was reported for the first time by Munson et al. in 1975. They showed by in vitro and in vivo experiments that several phytocannabinoids, including THC, decreased Lewis lung adenocarcinoma proliferation in a dose-dependent manner. Nevertheless, it was not until the 2000s that the interest in these compounds as anti-cancer agents was renewed, predominantly due to the work of Guzman in gliomas, and the demonstration of cannabinoids’ anti-cancer effects on various types of tumors. The anti-tumorigenic effect of the endo- and phytocannabinoids was demonstrated in several in vitro and in vivo models of a wide variety of adult tumors including glioma, prostate, breast, leukemia, lymphoma, pancreas, melanoma, thyroid, colorectal and hepatocellular carcinoma tumors.

Given our positive results, we suggest that non-THC cannabinoids such as CBD might provide a basis for the development of novel therapeutic strategies without the typical psychotropic effects of THC that limit its use in pediatric patients.

Overall, the cannabinoids, and specifically the non-psychoactive CBD, may show future promise in the treatment of cancer”

https://www.ima.org.il/FilesUpload/IMAJ/0/228/114216.pdf

https://www.ima.org.il/imaj/ViewArticle.aspx?aId=4044

https://www.ncbi.nlm.nih.gov/pubmed/28457057

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Anti-inflammatory effects of the cannabidiol derivative dimethylheptyl-cannabidiol – studies in BV-2 microglia and encephalitogenic T cells

“Preparations derived from Cannabis sativa (marijuana and hashish) have become widespread since ancient times, both as therapeutic agents and in recreational smoking.

Among the more than 60 phytocannabinoids identified in Cannabis extracts, the two most abundant are Δ9-tetrahydrocannabinol (THC), the major psychotropic constituent, and cannabidiol (CBD), the major non-psychoactive component.

Cannabinoids were shown to exert a wide range of therapeutic effects, and many of the cannabinoids, especially CBD, were shown to possess potent anti-inflammatory and immunomodulatory activities. In addition, it was shown that several cannabinoids have pro-apoptotic, neuroprotective, and antitumor properties

Dimethylheptyl-cannabidiol (DMH-CBD), a non-psychoactive, synthetic derivative of the phytocannabinoid cannabidiol (CBD), has been reported to be anti-inflammatory in RAW macrophages. Here, we evaluated the effects of DMH-CBD at the transcriptional level in BV-2 microglial cells as well as on the proliferation of encephalitogenic T cells.

The results show that DMH-CBD has similar anti-inflammatory properties to those of CBD. DMH-CBD downregulates the expression of inflammatory cytokines and protects the microglial cells by inducing an adaptive cellular response against inflammatory stimuli and oxidative injury. In addition, DMH-CBD decreases the proliferation of pathogenic activated TMOG cells.

Several CBD derivatives were also shown to have anti-inflammatory and anti-proliferative properties.

The results show that DMH-CBD induces similar anti-inflammatory, anti-proliferative, and stress response effects to those previously observed for CBD.”

https://www.degruyter.com/view/j/jbcpp.2016.27.issue-3/jbcpp-2015-0071/jbcpp-2015-0071.xml

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Dietary ω-3 Polyunsaturated Fatty Acids Inhibit Tumor Growth in Transgenic ApcMin/+ Mice, Correlating with CB1 Receptor Up-Regulation.

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“Mediterranean diet components, such as olive oil and ω-3 polyunsaturated fatty acids (ω-3 PUFAs), can arrest cell growth and promote cell apoptosis.

Recently, olive oil has been demonstrated to modulate type-1 cannabinoid (CB1) receptor gene expression in both human colon cancer cells and rat colon. The aim of this study was to investigate a possible link between olive oil and ω-3 PUFAs effects and CB1 receptor expression in both intestinal and adipose tissue of ApcMin/+ mice.

To confirm the role for the CB1 receptor as a negative modulator of cell proliferation in human colon cancer, CB1 receptor gene expression was also detected in tumor tissue and in surrounding normal mucosa of patients with colorectal cancer (CRC).

Dietary ω-3 PUFAs significantly inhibited intestinal polyp growth in mice, correlating with CB1 receptor gene and protein expression induction. CB1 receptor gene up-regulation was also detected in adipose tissue, suggesting a close communication between cancer cells and the surrounding environment. Tissue CB1 receptor induction was associated with a concurrent inactivation of the Wnt/β-catenin pathway.

Moreover, there was a significant reduction in CB1 receptor gene expression levels in cancer tissue compared to normal surrounding mucosa of patients with CRC, confirming that in cancer the “protective” action of the CB1 receptor is lost.”

https://www.ncbi.nlm.nih.gov/pubmed/28245562

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Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.

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“Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined.

Here we have investigated their anti-tumor effect in multiple myeloma (MM).

We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells.

Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis.

Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo.

Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM.”

https://www.ncbi.nlm.nih.gov/pubmed/27778331

http://www.thctotalhealthcare.com/category/multiple-myeloma/

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