Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein.

“Cannabinoids were shown to induce apoptosis of glioma cells in vitro and tumor regression in vivo…

… we suggest that the increase of proapoptotic Bad activity is an important link between the inhibition of survival pathways and an onset of execution phase of cannabinoid-induced glioma cell death.” http://www.ncbi.nlm.nih.gov/pubmed/15451022

“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.”  http://www.ncbi.nlm.nih.gov/pubmed/15275820

http://www.thctotalhealthcare.com/category/gllomas/

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THC Gives Cancer Cells the Munchies Too

“…THC and other cannabinoids are actively being investigated for various useful clinical purposes, including the treatment of cancer through the inhibition of tumor growth.

A new study by Salazar et al. in The Journal of Clinical Investigation demonstrates that THC causes tumor cells to begin to degrade themselves from the inside (a process called autophagy, i.e. “self-eating”). Although autophagy has been shown to promote cell survival in some cases and cell death in others, the authors show that in this case it causes cancer cells to undergo programmed cell death (apoptosis). Thus, THC activates a series of events within cancer cells, inhibiting tumor growth.”

More: http://scienceblogs.com/scientificactivist/2009/04/02/thc-gives-cancer-cells-the-mun/

“Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673842/

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Stimulation of ALK by the growth factor midkine renders glioma cells resistant to autophagy-mediated cell death

“Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, promotes cancer cell death via autophagy stimulation.

We find that activation of the tyrosine kinase receptor ALK by its ligand midkine interferes with the signaling mechanism by which THC promotes autophagy-mediated glioma cell death.”

 http://www.ncbi.nlm.nih.gov/pubmed/21593591

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Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

“Treatment with cannabinoid-loaded microparticles activates apoptosis and inhibits tumor angiogensis. The aim of the present study was therefore to evaluate the antitumor efficacy of biodegradable polymeric microparticles allowing the controlled release of the phytocannabinoids THC and CBD. Our findings show that administration of cannabinoid-loaded microparticles reduces the growth of glioma xenografts supporting that this method of administration could be exploited for the design of cannabinoid-based anticancer treatments.

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

Δ9-Tetrahydrocannabinol (THC), the main active component of the hemp plant Cannabis sativa, exerts a wide variety of biological effects by mimicking endogenous substances – the endocannabinoids – that bind to and activate specific cannabinoid receptors. So far, two G protein–coupled cannabinoid-specific receptors have been cloned and characterized from mammalian tissues: CB1, abundantly expressed in the brain and at many peripheral sites, and CB2, expressed in the immune system and also present in some neuron subpopulations and glioma cells. One of the most active areas of research in the cannabinoid field is the study of the potential application of cannabinoids in the treatment of different pathologies. Among these therapeutic applications, cannabinoids are being investigated as anti-tumoral agents. Thus, cannabinoid administration curbs the growth of several types of tumor xenografts in rats and mice including gliomas. Based on this preclinical evidence, a pilot clinical trial has been recently run to investigate the anti-tumor action of THC on recurrent gliomas. The mechanism of THC anti-tumoral action relies on the ability of this compound to: (i) promote the apoptotic death of cancer cells (ii) to inhibit tumour angiogenesis and (iii) to reduce the migration of cancer cells.

Conclusions

Data presented in this manuscript show for the first time that in vivo administration of microencapsulated cannabinoids efficiently reduces tumor growth thus providing a proof of concept for the utilization of this formulation in cannabinoid-based anti-cancer therapies.”

Full text: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054795

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Cannabinoid signaling in glioma cells

“Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas. Cannabinoids exert anti-proliferative action in tumor cells. Induction of cell death by cannabinoid treatment…”

 http://www.ncbi.nlm.nih.gov/pubmed/22879071

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Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells

Journal of Neuro-Oncology

“Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM).

We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cell lines and in primary human glial cultures, the normal cells from which GBM tumors arise. The influence of a plant derived cannabinoid agonist, Delta(9)-tetrahydrocannabinol Delta(9)-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy.

We discovered that Delta(9)-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2. Delta(9)-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2. The effects of Delta(9)-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation.

The same concentration of Delta(9)-THC that significantly inhibits proliferation and increases death of human GBM cells has no significant impact on human primary glial cultures. Evidence of selective efficacy with WIN 55,212-2 was also observed but the selectivity was less profound, and the synthetic agonist produced a greater disruption of normal cell morphology compared to Delta(9)-THC.”

https://www.ncbi.nlm.nih.gov/pubmed/16078104

https://link.springer.com/article/10.1007%2Fs11060-004-5950-2

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Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.

“The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9-tetrahydrocannabinol (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action.”

“CONCLUSIONS:

Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.”

http://www.ncbi.nlm.nih.gov/pubmed/17934890

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Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

“Marijuana and its derivatives have been used in medicine for many centuries, and currently there is a renewed interest in the study of the therapeutic effects of cannabinoids…”

“Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines…”

“…the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.”

“In conclusion, a cannabinoid-based therapeutic strategy for neural diseases devoid of undesired psychotropic side effects could find in CBD a valuable compound in cancer therapies along with the perspective of evaluating a synergistic effect with other cannabinoid molecules and/or with other chemotherapeutic agents as well as with radiotherapy. Whatever the precise mechanism underlying the CBD effects, the present results suggest a possible application of CBD as a promising, nonpsychoactive, antineoplastic agent.”

http://jpet.aspetjournals.org/content/308/3/838.full

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A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

“One of the most devastating forms of cancer is glioblastoma multiforme (grade IV astrocytoma), the most frequent class of malignant primary brain tumours. Current standard therapeutic strategies for the treatment of glioblastoma multiforme (surgical resection and focal radiotherapy) are only palliative…”

“The hemp plant Cannabis sativa L. produces approximately 60 unique compounds known as cannabinoids, of which Δ9-tetrahydrocannabinol (THC) is the most important owing to its high potency and abundance in cannabis. Δ9-Tetrahydrocannabinol exerts a wide variety of biological effects by mimicking endogenous substances – the so-called endocannabinoids – that bind to and activate specific cell surface receptors. cannabinoids have been proposed as potential antitumoral agents owing to their ability to inhibit the growth and angiogenesis of various types of tumour xenografts in animal models.”

“Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration… Cannabinoid delivery was safe and could be achieved without overt psychoactive effects…. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360617/

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Cannabinoids Curb Brain Tumor Growth, First-Ever Patient Trial Shows

“Madrid, Spain: THC administration decreases recurrent glioblastoma multiforme (GBM) tumor growth in humans, according to the findings of the first-ever clinical trial assessing cannabinoids’ anti-tumor action.

Investigators at Complutense University in Spain administered THC intratumorally in nine patients diagnosed with recurrent GBM, an extremely rapid and lethal form of brain tumor. Patients in the study had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumor progression. THC treatment was associated with reduced tumor cell proliferation in two subjects, authors reported.

Investigators did not determine whether THC positively impacted patients’ survival, though they did conclude that cannabinoid therapy does not facilitate cancer growth or decrease patients’ life expectancy. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks, and two patients survived for approximately one year. Survival for GBM patients following diagnosis is typically six to twelve months.

Researchers speculated that newly diagnosed glioma patients may respond more favorably to cannabinoid-based therapies.

Investigators also reported that THC demonstrated significant anti-proliferative activity on human GBM cells in culture.

“The fair safety profile of THC, together with its possible anti-proliferative action on tumor cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids,” investigators concluded.

In 2005, investigators at the California Pacific Medical Center Research Institute in San Francisco reported that THC selectively decreases the proliferation of malignant cells and induces cell death in human GBM cell lines. Healthy cells in the study were unaffected by THC administration.

Separate preclinical studies indicate that cannabinoids and endocannabinoids can stave off tumor progression and trigger cell death in other cancer cell lines, including breast carcinoma, prostate carcinoma, colectoral carcinoma, skin carcinoma, and pancreatic adenocarcinoma.”

http://norml.org/news/2006/07/13/cannabinoids-curb-brain-tumor-growth-first-ever-patient-trial-shows

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