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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Regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways.

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“Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The challenging problem in cancer treatment is to find a way to upregulate radiosensitivity of GBM while protecting neurons and neural stem/progenitor cells in the brain. The goal of the present study was upregulation of the cytotoxic effect of γ-irradiation in GBM by non-psychotropic and non-toxic cannabinoid, cannabidiol (CBD).

We emphasized three main aspects of signaling mechanisms induced by CBD treatment (alone or in combination with γ-irradiation) in human GBM that govern cell death: 1) CBD significantly upregulated the active (phosphorylated) JNK1/2 and MAPK p38 levels with the subsequent downregulation of the active phospho-ERK1/2 and phospho-AKT1 levels. MAPK p38 was one of the main drivers of CBD-induced cell death, while death levels after combined treatment of CBD and radiation were dependent on both MAPK p38 and JNK. Both MAPK p38 and JNK regulate the endogenous TRAIL expression. 2) NF-κB p65-P(Ser536) was not the main target of CBD treatment and this transcription factor was found at high levels in CBD-treated GBM cells. Additional suppression of p65-P(Ser536) levels using specific small molecule inhibitors significantly increased CBD-induced apoptosis. 3) CBD treatment substantially upregulated TNF/TNFR1 and TRAIL/TRAIL-R2 signaling by modulation of both ligand and receptor levels followed by apoptosis.

Our results demonstrate that radiation-induced death in GBM could be enhanced by CBD-mediated signaling in concert with its marginal effects for neural stem/progenitor cells and astrocytes. It will allow selecting efficient targets for sensitization of GBM and overcoming cancer therapy-induced severe adverse sequelae.”

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Compound found in cannabis helps ‘shrink’ four-year-old’s brain tumour

Four-year-old William Frost from Newark

“The family of a four-year-old boy from Nottinghamshire are backing new research into whether a non-psychoactive compound found in cannabis can reduce paediatric brain cancer cells.

Experts from Nottingham’s Children’s Brain Tumour Research Centre, at The University of Nottingham, will test Cannabidiol (CBD) for its effects on paediatric brain tumours in youngsters. This research will form part of the pre-clinical phase of the evaluation of the potential use of cannabidiol in paediatric brain tumours” http://www.nottinghampost.com/compound-found-in-cannabis-helps-shrink-four-year-old-s-brain-tumour/story-30307458-detail/story.html

“Scientists plan study after Nottinghamshire boy’s tumour shrinks during cannabis compound treatment” https://nottstv.com/notts-scientists-treating-brain-tumours-with-cannabis-backed-by-four-year-old-boy-with-the-condition/
 
“Study looks at cannabis ingredient’s ability to help children’s tumours. UK research into cannabidiol (CBD) comes after surge in parents administering it to children without medical advice” https://www.theguardian.com/society/2017/may/02/study-cannabis-cannabidiol-cbd-ability-to-help-children-brain-tumours

 “Little boy’s aggressive brain tumour shrinks thanks to CANNABIS compound, his parents claim” https://www.thesun.co.uk/living/3472080/little-boys-aggressive-brain-tumour-shrinks-thanks-to-cannabis-his-parents-claimed/

“Little boy battling golf ball-sized brain tumour given new lease of life after being given a special OIL” http://www.mirror.co.uk/news/uk-news/little-boy-battling-golf-ball-10347423

 “Four-year-old brain cancer patient sees tumour shrink – thanks to cannabis oil”  http://metro.co.uk/2017/05/03/four-year-old-brain-cancer-patient-sees-tumour-shrink-thanks-to-cannabis-oil-6613034/
Four-year-old William was diagnosed with a brain tumour in 2014
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Cannabinoids as Modulators of Cell Death: Clinical Applications and Future Directions.

 Image result for Rev Physiol Biochem Pharmacol.

“Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic cannabinoids mimic the effects of endocannabinoids.

In recent years, a growing interest has been dedicated to the study of cannabinoids properties for their analgesic, antioxidant, anti-inflammatory and neuroprotective effects. In addition to these well-recognized effects, various studies suggest that cannabinoids may affect cell survival, cell proliferation or cell death. These observations indicate that cannabinoids may play an important role in the regulation of cellular homeostasis and, thus, may contribute to tissue remodelling and cancer treatment.

For a long time, the study of cannabinoid receptor signalling has been focused on the classical adenylyl cyclase/cyclic AMP/protein kinase A (PKA) pathway. However, this pathway does not totally explain the wide array of biological responses to cannabinoids. In addition, the diversity of receptors and signalling pathways that endocannabinoids modulate offers an interesting opportunity for the development of specific molecules to disturb selectively the endogenous system.

Moreover, emerging evidences suggest that cannabinoids ability to limit cell proliferation and to induce tumour-selective cell death may offer a novel strategy in cancer treatment.

This review describes the main properties of cannabinoids in cell death and attempts to clarify the different pathways triggered by these compounds that may help to understand the complexity of respective molecular mechanisms and explore the potential clinical benefit of cannabinoids use in cancer therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/28425013

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Can Marijuana Cure Cancer? Pharmaceutical Company Developing Cannabis Medicine To Treat Brain Cancer

“Can Marijuana Cure Cancer? Pharmaceutical Company Developing Cannabis Medicine To Treat Brain Cancer” http://www.ibtimes.com/can-marijuana-cure-cancer-pharmaceutical-company-developing-cannabis-medicine-treat-2489282

“GW Pharmaceuticals Achieves Positive Results in Phase 2 Proof of Concept Study in Glioma” http://ir.gwpharm.com/releasedetail.cfm?ReleaseID=1010672
 
“Cannabinoid Drug Prolongs the Life of Brain Tumor Patients in Phase II Trials” http://labiotech.eu/gw-pharmaceuticals-brain-tumor/
“Drug Company Claims to Have Marijuana Treatment That Could Increase Lifespan of Brain Cancer Patients” http://www.complex.com/life/2017/02/gw-pharmaceuticals-claims-to-have-treatment-that-could-increase-lifespan-of-brain-cancer-patients
 “GW Pharma’s cannabis-derived combo med helps brain cancer patients” http://www.fiercebiotech.com/biotech/gw-pharma-s-cannabis-derived-combo-med-helps-brain-cancer-patients
“GW pharmaceuticals to develop oncology portfolio after cannabis medication shows promising results” http://www.telegraph.co.uk/business/2017/02/07/gw-pharmaceuticals-develop-oncology-portfolio-cannabis-medication/
“GW Pharma is touting claims that a combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) produced positive survival benefits in a small study of 21 patients with recurrent glioblastoma multiforme, a common form of brain cancer.” https://endpts.com/gw-touts-positive-survival-benefit-in-small-brain-cancer-study-ablynx-files-for-ultra-rare-disease-drug-ok/

“GW Pharmaceuticals Is Set to Benefit as Cannabis Takes on Cancer”  https://www.thestreet.com/story/13996559/1/gw-pharmaceuticals-is-set-to-benefit-as-cannabis-takes-on-cancer.html

“GW Pharmaceuticals Achieves Positive Results In Phase 2 Proof Of Concept Study In Glioma” https://www.clinicalleader.com/doc/gw-pharmaceuticals-phase-proof-of-concept-study-in-glioma-0001

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Quantitative analyses of synergistic responses between cannabidiol and DNA-damaging agents on the proliferation and viability of glioblastoma and neural progenitor cells in culture.

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“Evidence suggests that the non-psychotropic cannabis-derived compound, cannabidiol (CBD), has anti-neoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM).

DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM.

Here we studied the anti-proliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures.

This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system (CNS) toxicity.

We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells.

Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells.

Co-treatment regiments combining CBD and DNA-damaging agents produced synergistic anti-proliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs.

Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells.

Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little-to-no therapeutic window when considering NPCs.”

https://www.ncbi.nlm.nih.gov/pubmed/27821713

“Definition of antineoplastic: inhibiting or preventing the growth and spread of tumors or malignant cells”  http://www.merriam-webster.com/dictionary/antineoplastic

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Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression

Cancer Research: 68 (6)

“Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis.

It has also been reported that these compounds inhibit tumor cell spreading.

Here, we evaluated the effect of cannabinoids on matrix metalloproteinase (MMP) expression and its effect on tumor cell invasion.

Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas generated in mice.

This cannabinoid-induced inhibition of MMP-2 expression in gliomas.

As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity.

As selective CB2 receptor activation to mice has been shown to inhibit the growth and angiogenesis of gliomas, skin carcinomas and melanomas, our observations further support the possibility of finding cannabinoid-based antitumoral strategies devoid of nondesired psychotropic side effects.”

http://cancerres.aacrjournals.org/content/68/6/1945

 

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Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization.

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“Autophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used Δ9-tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the regulatory mechanisms that determine the selective activation of autophagy-mediated cancer cell death.”

http://www.ncbi.nlm.nih.gov/pubmed/27635674

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Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system.

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“Pediatric low-grade gliomas (P-LGG) consist of a mixed group of brain tumors that correspond to the majority of CNS tumors in children.

Notably, they may exhibit spontaneous involution after subtotal surgical removal (STR). In this study, we investigated molecular indicators of spontaneous involution in P-LGG.

CONCLUSIONS:

The P-LGG, which remained stable or that presented spontaneous involution after STR, showed significantly higher CNR1 expression at the time of diagnosis.

We hypothesize that high expression levels of CNR1 provide tumor susceptibility to the antitumor effects of circulating endocannabinoids like anandamide, resulting in tumor involution.

This corroborates with reports suggesting that CNR1 agonists and activators of the endocannabinoid system may represent therapeutic opportunities for children with LGG.

We also suggest that CNR1 may be a prognostic marker for P-LGG.

This is the first time spontaneous involution of P-LGG has been suggested to be induced by endocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/27613640

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Anticancer and antioxidant properties of terpinolene in rat brain cells.

“Terpinolene (TPO) is a natural monoterpene present in essential oils of many aromatic plant species.

Our findings clearly demonstrate that TPO is a potent antiproliferative agent for brain tumour cells and may have potential as an anticancer agent, which needs to be further studied.” http://www.ncbi.nlm.nih.gov/pubmed/24084350

“Three different medicinal cannabis varieties were investigated Bedrocan, Bedrobinol and Bediol. The major components in Bedrocan smoke were Delta(9)-THC, cannabinol (CBN), terpinolene, CBG, myrcene and cis-ocimene in Bedrobinol Delta(9)-THC, CBN and myrcene in Bediol CBD, Delta(9)-THC, CBN, myrcene, CBC and terpinolene.”  http://www.ncbi.nlm.nih.gov/pubmed/20118579

“The sedative effect of inhaled terpinolene in mice and its structure-activity relationships.” http://www.ncbi.nlm.nih.gov/pubmed/23339024

 “Anticancer and antioxidant properties of terpinolene in rat brain cells.”  http://www.ncbi.nlm.nih.gov/pubmed/24084350
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