Archive for November, 2013

 

via New Study Shows Marijuana\’s Potential to Treat Autoimmune Disorders ~ RiseEarth.

 

▶ Rediscovering Cannabis Oil – Clip from American Drug War 2 – YouTube.

 

From a Facebook post by Cannabis Cures Cancer
116 Medical Studies About the Anti-Cancer Effects of Cannabinoids

Part 2: Studies # 37 – 68:

Brain cancer, Breast cancer, Cancer (all types), Colon cancer, Leukemia, Liver cancer, Lung cancer, Pancreatic cancer, Skin cancer, Stomach cancer, Thymoma, & Thyroid cancer

Part 1: Studies #1 – 36
Part 3: Studies # 69 – 100
& Part 4: The Latest Research (2013):
Studies # 101 – 116
in the Comments below

Collected by CANNABIS CURES CANCERS!
(facebook.com/THeCureForCancers)

BRAIN CANCER:

Nature Medicine
March 2000

Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation

Δ9-Tetrahydrocannabinol, the main active component of marijuana, induces apoptosis of transformed neural cells in culture.
Here, we show that intratumoral administration of Δ9-tetrahydrocannabinol and the synthetic cannabinoid agonist WIN-55,212-2 induced a considerable regression of malignant gliomas in Wistar rats and in mice …
Cannabinoid treatment did not produce any substantial neurotoxic effect in the conditions used.
Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors …
These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.

http://www.nature.com/nm/journal/v6/n3/full/nm0300_313.html

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Biochemical Journal
April 2002

De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis

D9-Tetrahydrocannabinol (THC) and other cannabinoids have been shown to induce apoptosis of glioma cells via ceramide generation.
In the present study, we investigated the metabolic origin of the ceramide responsible for this cannabinoid-induced apoptosis by using two subclones of C6 glioma cells: C6.9, which is sensitive to THC-induced apoptosis; and C6.4, which is resistant to THC-induced apoptosis. …
These findings show that de novo -synthesized ceramide is involved in cannabinoid-induced apoptosis of glioma cells.

http://www.biochemj.org/bj/363/0183/bj3630183.htm

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The Journal of Pharmacology and Experimental Therapeutics
March 2004

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

Abstract

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 addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism … and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure …
We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis …
Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells.
In conclusion, 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.

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

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Cellular and Molecular Life Sciences
September 2006

The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells

Abstract

Recently, we have shown that the non-psychoactive cannabinoid compound cannabidiol (CBD) induces apoptosis of glioma cells in vitro and tumor regression in vivo.
The present study investigated a possible involvement of caspase activation and reactive oxygen species (ROS) induction in the apoptotic effect of CBD. …
The exposure to CBD caused in glioma cells an early production of ROS …
Under the same experimental condition, CBD did not impair primary glia.
Thus, we found a different sensitivity to the anti-proliferative effect of CBD in human glioma cells and non-transformed cells that appears closely related to a selective ability of CBD in inducing ROS production and caspase activation in tumor cells.

http://link.springer.com/article/10.1007%2Fs00018-006-6156-x

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The Journal of Biological Chemistry
March 2007

Cannabinoids Induce Glioma Stem-like Cell Differentiation and Inhibit Gliomagenesis

Abstract

Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis.
However, whether cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB1) and type 2 (CB2) receptors and other elements of the endocannabinoid system.
In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. …
Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. …
Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.

http://www.jbc.org/content/282/9/6854.long

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Expert Review of Neurotherapeutics
January 2008

Cannabinoids as potential new therapy for the treatment of gliomas

Gliomas constitute the most frequent and malignant primary brain tumors.
Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics, e.g., temozolomide, carmustin or carboplatin) for their treatment are only palliative and survival diagnosis is normally 6–12 months.
The development of new therapeutic strategies for the management of gliomas is therefore essential.
Interestingly, cannabinoids have been shown to exert antiproliferative effects on a wide spectrum of cells in culture.
Of interest, cannabinoids have displayed a great potency in reducing glioma tumor growth either in vitro or in animal experimental models, curbing the growth of xenografts generated by subcutaneous or intratecal injection of glioma cells in immune-deficient mice.
Moreover, cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts.
A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.

http://www.expert-reviews.com/doi/abs/10.1586/14737175.8.1.37?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

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Neuropharmacology
January 2008

Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity?

Abstract

Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and inhibiting tumor angiogenesis.
It has also been reported that cannabinoids inhibit tumor cell invasiveness, but the molecular targets of this cannabinoid action remain elusive.
Here we evaluated the effects of cannabinoids on the expression of tissue inhibitors of metalloproteinases (TIMPs), which play critical roles in the acquisition of migrating and invasive capacities by tumor cells.
Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated TIMP-1 expression in mice bearing subcutaneous gliomas …
This cannabinoid-induced inhibition of TIMP-1 expression in gliomas was mimicked by JWH-133, a selective CB2 cannabinoid receptor agonist that is devoid of psychoactive side effects … and was also evident in two patients with recurrent glioblastoma multiforme (grade IV astrocytoma). THC also depressed TIMP-1 expression in cultures of various human glioma cell lines as well as in primary tumor cells obtained from a glioblastoma multiforme patient. …
As TIMP-1 up-regulation is associated with high malignancy and negative prognosis of numerous cancers, TIMP-1 down-regulation may be a hallmark of cannabinoid-induced inhibition of glioma progression.

http://www.sciencedirect.com/science/article/pii/S0028390807001803

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The Journal of Clinical Investigation
May 2009

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells

Abstract

Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure.
Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy.
Our data indicate that THC induced ceramide accumulation … and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3–dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. …
We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo.
These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673842/?report=classic

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Molecular Cancer Therapeutics
January 2010

Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival

Abstract

The cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist Δ9-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma.
It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB1 and CB2 receptors, can modulate the actions of Δ9-THC.
There are conflicting reports, however, as to what extent other cannabinoids can modulate Δ9-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ9-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Δ9-THC.
In the U251 and SF126 glioblastoma cell lines, Δ9-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities.
These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique.
Our results suggest that the addition of cannabidiol to Δ9-THC may improve the overall effectiveness of Δ9-THC in the treatment of glioblastoma in cancer patients.

http://mct.aacrjournals.org/content/9/1/180.long

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PLOS ONE (Public Library of Science)
January 2010

The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas

Abstract

Background

Cannabinoids represent unique compounds for treating tumors, including astrocytomas. Whether CB1 and CB2 receptors mediate this therapeutic effect is unclear.

Principal Findings

We generated astrocytoma subclones that express set levels of CB1 and CB2, and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to ERK1/2. In contrast, cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT. Remarkably, cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB1, CB2 and AKT, but still through a mechanism involving ERK1/2.

Significance

The high expression level of CB1 and CB2 receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics, unless AKT is concomitantly inhibited, or cannabinoids are applied at concentrations that bypass CB1 and CB2 receptors, yet still activate ERK1/2.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008702

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BREAST CANCER:

Proceedings of the National Academy of Sciences of the United States of America
July 1998

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

Abstract
Anandamide was the first brain metabolite shown to act as a ligand of “central” CB1 cannabinoid receptors.
Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro.
Anandamide dose-dependently inhibited the proliferation of … cells …
The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle.
… another endogenous cannabinoid … and the synthetic cannabinoid HU-210 also inhibited … cell proliferation …
These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.

http://www.pnas.org/content/95/14/8375.long

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The Journal of Pharmacology and Experimental Therapeutics
September 2006

Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma

Abstract

Δ9-Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity.
We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids.
Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth … with significantly lower potency in noncancer cells.
The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency.
Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma … and reduced lung metastases … our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB2 …
Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.

http://jpet.aspetjournals.org/content/318/3/1375.long

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Oncogene
May 2008

JunD is involved in the antiproliferative effect of Δ9-tetrahydrocannabinol on human breast cancer cells

Abstract

It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells.
Here we studied the mechanism of Δ9-tetrahydrocannabinol (THC) antiproliferative action in these cells, and show that it involves the modulation of JunD, a member of the AP-1 transcription factor family.
THC activates JunD both by upregulating gene expression and by translocating the protein to the nuclear compartment, and these events are accompanied by a decrease in cell proliferation.
Of interest, neither JunD activation nor proliferation inhibition was observed in human non-tumour mammary epithelial cells exposed to THC. …
In summary, this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.

http://www.nature.com/onc/journal/v27/n37/full/onc2008145a.html

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CANCER (ALL TYPES):

Prostaglandins, Leukotrienes and Essential Fatty Acids
February 2002

Endocannabinoids in the immune system and cancer

Abstract

The present review focuses on the role of the endogenous cannabinoid system in the modulation of immune response and control of cancer cell proliferation.
The involvement of cannabinoid receptors, endogenous ligands and enzymes for their biosynthesis and degradation, as well as of cannabinoid receptor-independent events is discussed.
The picture arising from the recent literature appears very complex, indicating that the effects elicited by the stimulation of the endocannabinoid system are strictly dependent on the specific compounds and cell types considered. …
Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors …
In conclusion, further investigations are needed to elucidate the function of endocannabinoids as immunosuppressant and antiproliferative/cytotoxic agents.
The experimental evidence reviewed in this article argues in favor of the therapeutic potential of these compounds in immune disorders and cancer.

http://www.sciencedirect.com/science/article/pii/S0952327801903552
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Cancer Cell
April 2006

The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells

Summary

One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs.
Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells.
By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes …
Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.

http://www.cell.com/cancer-cell/retrieve/pii/S1535610806000857

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Oncology Reports
April 2007

Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (Review)

Abstract

The medicinal properties of extracts from the hemp plant Cannabis sativa have been known for centuries but only in the 90s membrane receptors for the Cannabis major principle were discovered in mammalian cells.
Later on the endogenous ligands for the cannabinoid receptors were identified and the term ‘endocannabinoid system’ was coined to indicate the complex signaling system of cannabinoid receptors, endogenous ligands and the enzymes responsible for their biosynthesis and inactivation. The ‘endocannabinoid system’ is involved in a broad range of functions and in a growing number of pathological conditions. There is increasing evidence that endocannabinoids are able to inhibit cancer cell growth in culture as well as in animal models.
Most work has focused on the role of endocannabinoids in regulating tumor cell growth and apoptosis and ongoing research is addressed to further dissect the precise mechanisms of cannabinoid antitumor action.
However, endocannabinoids are now emerging as suppressors of angiogenesis and tumor spreading since they have been reported to inhibit angiogenesis, cell migration and metastasis in different types of cancer, pointing to a potential role of the endocannabinoid system as a target for a therapeutic approach of such malignant diseases.
The potential use of cannabinoids to retard tumor growth and spreading is even more appealing considering that they show a good safety profile, regarding toxicity, and are already used in cancer patients as palliatives to stimulate appetite and to prevent devastating effects such as nausea, vomiting and pain.

http://www.spandidos-publications.com/or/17/4/813

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COLON CANCER:

Clinical Cancer Research
December 2008

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

Abstract

Purpose:
Cannabinoids have been recently proposed as a new family of potential antitumor agents.
The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.

Experimental Design:
Cannabinoid receptor expression was investigated in both human cancer specimens and in the … colon cancer cell lines.
The effects of the CB1 agonist … on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-α production were evaluated.

Results:
We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor.
The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the … cells.
The CB2 agonist … also reduced the growth of … cells in a mouse model of colon cancer.

Conclusions:
The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. …

http://clincancerres.aacrjournals.org/content/14/23/7691.long

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Pharmacological Research
August 2009

Cannabinoids in intestinal inflammation and cancer

Abstract

Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer.
Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing.
In vivo, cannabinoids – via direct or indirect activation of CB1 and/or CB2 receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer.
Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.

http://www.sciencedirect.com/science/article/pii/S1043661809000838

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LEUKEMIA:

Leukemia Research
August 2005

Targeting cannabinoid receptors to treat leukemia: Role of cross-talk between extrinsic and intrinsic pathways in Δ9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells

Abstract

Targeting cannabinoid receptors has recently been shown to trigger apoptosis and offers a novel treatment modality against malignancies of the immune system.
However, the precise mechanism of apoptosis in such cancers has not been previously addressed.
In this study, we used human Jurkat leukemia cell lines with defects in intrinsic and extrinsic signaling pathways to elucidate the mechanism of apoptosis induced by Δ9-tetrahydrocannabinol (THC). … THC treatment of wild-type Jurkat cells caused cytochrome c release, and cleavage of caspase-8, -9, -2, -10, and Bid. …
Together, these data suggest that the intrinsic pathway plays a more critical role in THC-induced apoptosis while the extrinsic pathway may facilitate apoptosis via cross-talk with the intrinsic pathway.

http://www.lrjournal.com/article/S0145-2126(05)00061-5/abstract

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FEBS Letters (Federation of European Biochemical Societies)
September 2005

p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells

Abstract

Cannabinoids have been shown to inhibit the growth of a broad spectrum of tumour cells.
However, the molecular mechanisms involved in that effect have not been completely elucidated.
Here, we investigated the possible involvement of mitogen-activated protein kinases (MAPKs) in CB2 receptor-induced apoptosis of human leukaemia cells.
Results show that stimulation of the CB2 receptor leads to p38 MAPK activation …
These findings support a role for p38 MAPK in CB2 receptor-induced apoptosis of human leukaemia cells.

http://www.sciencedirect.com/science/article/pii/S0014579305010057

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Experimental Cell Research
July 2006

The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway

Abstract

Δ9-Tetrahydrocannabinol and other cannabinoids exert pro-apoptotic actions in tumor cells via the CB2 cannabinoid receptor.
However, the molecular mechanism involved in this effect has remained elusive.
Here we used the human leukemia cell line Jurkat—that expresses CB2 as the unique CB receptor—to investigate this mechanism. …
Cannabinoid treatment led to a CB2 receptor-dependent stimulation of ceramide biosynthesis and inhibition of this pathway prevented Δ9-tetrahydrocannabinol-induced mitochondrial hypopolarization and cytochrome c release, indicating that ceramide acts at a pre-mitochondrial level. …
In summary, results presented here show that CB2 receptor activation signals apoptosis via a ceramide-dependent stimulation of the mitochondrial intrinsic pathway.

http://www.sciencedirect.com/science/article/pii/S0014482706001066

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Molecular Pharmacology
September 2006

Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22phox and Nox4 Expression

Abstract

In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis.
Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo. …
The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome c.
It is noteworthy that cannabidiol exposure led to an increase in reactive oxygen species (ROS) production …
Together, the results from this study reveal that cannabidiol … may be a novel and highly selective treatment for leukemia.

http://molpharm.aspetjournals.org/content/70/3/897.long

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LIVER CANCER:

Biochimie
April 2009

Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: Involvement of the transcription factor PPARγ

Abstract

It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines. In the current study, the effects of WIN 55,212-2 (WIN), a synthetic and potent cannabinoid receptor agonist, are investigated in hepatoma HepG2 cells …
WIN induces a clear apoptotic effect which was accompanied by up-regulation of the death-signalling factors … and down-regulation of the survival factors …
Moreover, WIN-induced apoptosis is associated with … mitochondrial depolarisation …
Altogether, the results seem to indicate a potential therapeutic role of WIN in hepatic cancer treatment.

http://www.sciencedirect.com/science/article/pii/S030090840800312X

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LUNG CANCER:

Journal of the Federation of American Societies for Experimental Biology
April 2012

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1

Abstract

… anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. …
Overall, our data indicate that cannabinoids induce … decreased cancer cell invasiveness.

Besides their palliative benefits in cancer therapy, accumulating evidence suggests a potential advance of cannabinoids as anticancer agents.
Accordingly, several investigations revealed antitumorigenic cannabinoid actions, such as inhibition of tumor cell proliferation and angiogenesis , as well as induction of apoptosis and autophagy.
A possible clinical use of cannabinoids for the treatment of highly invasive cancer types is further supported by recent findings showing a decrease of tumor cell invasion by the phytocannabinoids …

Among cannabinoid-based drugs, CBD has raised particular interest due to its lack of adverse psychoactive effects that limit the clinical use of classic cannabinoids.
Besides its beneficial effects on inflammation, pain, and spasticity when used for the treatment of multiple sclerosis, CBD has been reported to exert inhibitory effects on tumor angiogenesis and metastasis and to induce cancer cell apoptosis …
Recently, we were able to demonstrate an anti-invasive action of CBD on human lung and cervical carcinoma cells …
In another study, this anti-invasive pathway was likewise elicited by THC …

Here, we demonstrate for the first time that …
CBD result in a decrease of tumor cell invasion and metastasis. …
Furthermore, to the best of our knowledge, this is the first study on the anti-invasive action of cannabinoids using human primary tumor cells and the first to provide an inhibitor-based antimetastatic mechanism of a cannabinoid in an in vivo model. …

Effect of cannabinoids on the invasiveness of primary NSCLC [non small cell lung cancer] cells

To obtain additional support for the anti-invasive action of cannabinoids, we analyzed tumor cells obtained from surgeries of patients with lung tumors.
Biopsies were taken from brain metastases of one male and one female patient …
After biopsies were taken, NSCLC diagnosis was confirmed.
… all cannabinoids tested exerted significant anti-invasive effects on primary lung tumor cells …

DISCUSSION

Cannabinoids are currently discussed as tools for new anticancer therapies.
Besides a great body of experimental evidence pointing to an antitumorigenic action by these compounds, this notion is particularly supported by the lack of severe adverse side effects of cannabinoids as compared to the generalized toxic actions of conventional chemotherapies.
Furthermore, several substantial side effects of chemotherapeutics, such as emesis and collateral toxicity on noncancerous tissues, have been demonstrated to be even attenuated on treatment with cannabinoids.
Within cannabinoid-based substances, the phytocannabinoid CBD has emerged as a particularly interesting drug due to its lack of adverse psychoactive effects, as well as its considerable antitumorigenic properties.

… To assess the efficacy of cannabinoid-based drugs as systemic anticancer strategies, clinical trials are suggested.

http://www.fasebj.org/content/26/4/1535.long

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PANCREATIC CANCER:

FEBS Letters (Federation of European Biochemical Societies)
March 2006

Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism

Abstract

Cannabinoids (CBs) are implicated in the control of cell survival in different types of tumors, but little is known about the role of CB system in pancreatic cancer.
Herein, we investigated the in vitro antitumor activity of CBs and the potential role of their receptors in human pancreatic cancer cells …
Our results demonstrate that CBs produce a significant cytotoxic effect via a receptor-independent mechanism. …

Introduction

Several findings support the role of cannabinoids (CBs) and their derivatives in cell growth inhibition and apoptosis induction in tumor cells.
The plethora of experimental observations regarding the mechanism involved in the antiproliferative action of cannabinoids is in line with their pleiotropic nature.
… several observations on cancer cells which express both CB1 and CB2 receptors underline the irrelevance of CB receptor status in determining drug response …
δ9-tetrahydrocannabinol (THC)-mediated apoptosis in leukemic cell lines and in human prostate PC-3 cells was independent of the CB receptors.
Moreover, immunohistochemical and functional analyses in mouse models of glioma and skin carcinoma have shown that CBs may exert their antitumor effects by blocking the angiogenic process.

Despite the above mentioned observations, we need to be cautious when envisaging the potential clinical use of new anticancer therapies. … biological responses to CBs critically depend on drug concentration and type of cell examined.

The aim of the present study was to investigate the effect of CBs on the human pancreatic cancer cells …

Discussion

The present study demonstrates in vitro anticancer activity of CB derivatives on the poorly differentiated pancreatic cancer cell line …

http://www.sciencedirect.com/science/article/pii/S0014579306002110

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SKIN CANCER:

The FASEB Journal (Federation of the American Societies for Experimental Biology)
December 2006

Cannabinoid receptors as novel targets for the treatment of melanoma

Abstract

Melanoma causes the greatest number of skin cancer-related deaths worldwide.
Despite intensive research, prevention and early detection are the only effective measures against melanoma, so new therapeutic strategies are necessary for the management of this devastating disease.
Here, we evaluated the efficacy of cannabinoid receptor agonists, a new family of potential antitumoral compounds, at skin melanoma.
Human melanomas and melanoma cell lines express CB1 and CB2 cannabinoid receptors.
Activation of these receptors decreased growth, proliferation, angiogenesis and metastasis, and increased apoptosis, of melanomas in mice.
Cannabinoid antimelanoma activity was independent of the immune status of the animal, could be achieved without overt psychoactive effects and was selective for melanoma cells vs. normal melanocytes.
Cannabinoid antiproliferative action on melanoma cells was due, at least in part, to cell cycle arrest …
These findings may contribute to the design of new chemotherapeutic strategies for the management of melanoma.

http://www.fasebj.org/content/20/14/2633.long

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European Journal of Pharmacology
August 2009

The CB1/CB2 receptor agonist WIN-55,212-2 reduces viability of human Kaposi’s sarcoma cells in vitro

Abstract

Kaposi’s sarcoma is a highly vascularized mesenchymal neoplasm arising with multiple lesions of the skin.
Endogenous cannabinoids have been shown to inhibit proliferation of a wide spectrum of tumor cells.
We studied the effects of cannabinoids on human Kaposi’s sarcoma cell proliferation in vitro.
To do so, we first investigated the presence of the cannabinoid receptors CB1 and CB2 mRNAs in the human Kaposi’s sarcoma cell line … and, subsequently, the effects of the mixed CB1/CB2 agonist WIN-55,212-2 (WIN) on cell proliferation in vitro.
WIN showed antimitogenic effects on Kaposi’s sarcoma cells.
… In view of the antiproliferative effects of cannabinoids on KS-IMM cells, one could envision the cannabinoid system as a potential target for pharmacological treatment of Kaposi’s sarcoma.

http://www.sciencedirect.com/science/article/pii/S0014299909005159

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STOMACH CANCER:

Journal of Surgical Research
July 2009

Abstract

Orally applicable Δ9-tetrahydrocannabinol and its synthetic derivatives have been used as antiemetic drugs during chemotherapy in cancer patients.
However, it is not well known how cannabinoids influence the effects of chemotherapeutic agents on malignant tumors.
In this study, we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect of paclitaxel on gastric cancer cell lines.
In the human gastric cancer cell line, HGC-27, which express cannabinoid receptor 1 (CB1), AEA stimulated proliferation at concentrations under 1 μM, while it strongly suppressed proliferation through the induction of apoptosis at 10 μM. … When AEA was used with paclitaxel, AEA at 10 μM synergistically enhanced the cytotoxic effect of paclitaxel, whereas it showed no significant effect at lower concentrations. …
Our results suggest that cannabinoids could be a good palliative agent for cancer patients receiving paclitaxel.

http://www.journalofsurgicalresearch.com/article/S0022-4804(08)00452-6/abstract

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Journal of Cellular Biology
May 2010

Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells

Abstract

Although cannabinoids are associated with antineoplastic activity in a number of cancer cell types, the effect in gastric cancer cells has not been clarified.
In the present study, we investigated the effects of a cannabinoid agonist on gastric cancer cell proliferation and invasion.
The cannabinoid agonist … inhibited the proliferation of human gastric cancer cells in a dose-dependent manner and that this effect was mediated partially by the CB1 receptor. … Our results open the possibilities in using cannabinoids as a new gastric cancer therapy

http://onlinelibrary.wiley.com/doi/10.1002/jcb.22540/abstract

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THYMOMA:

International Immunopharmacology
May 2008

Abstract

It has been shown that leukemia and glioma cells are sensitive to cannabidiol (CBD)-induced apoptosis, whereas primary monocytes and glia cells are relatively insensitive.
In the current study, the cellular events and sensitivity to CBD-induced apoptosis between murine [mouse] thymocytes and EL-4 thymoma cells were compared.
Cannabidiol markedly induced apoptosis in a time- and concentration-related manner in both cells.
The efficacy of CBD to induce apoptosis was comparable between the 2 types of T cells, whereas CBD induced apoptosis in thymocytes with a slightly greater potency than in EL4 cells. … CBD-mediated apoptosis occurred earlier in EL-4 cells than that in thymocytes.
An increased level of cellular reactive oxygen species (ROS) was detected in both cells with the peak response at 2 h post CBD treatment. …
The results demonstrated that both thymocytes and EL-4 thymoma cells were susceptible to CBD-induced apoptosis and that ROS played a critical role in the apoptosis induction.

http://www.sciencedirect.com/science/article/pii/S1567576908000234

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THYROID CANCER:

Cancer Gene Therapy
December 2007

Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma

Abstract

Anaplastic thyroid carcinoma is the most aggressive type of thyroid malignancies. …
To identify genes involved, we examined gene expression profile …
The most highly expressed gene was cannabinoid receptor 2 (CB2) …
A considerable regression of thyroid tumors generated by inoculation … was observed in nude mice following local administration of JWH133. …
These data suggest that CB2 overexpression may contribute to the regression of human anaplastic thyroid tumor in nude mice …
Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma.

http://www.nature.com/cgt/journal/v15/n2/full/7701101a.html

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Investigational New Dugs
April 2010

A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis

Summary

The active components of Cannabis sativa and their derivatives produce a wide spectrum of effects, some of which may have clinical application.
The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids as agents capable of controlling the decision of cells to survive or die.
We analysed the effects exerted by … (Met-F-AEA), a metabolically stable analogue of anandamide, and observed a growth inhibition in cell lines derived from thyroid carcinomas.
Growth inhibition was associated with a high level of CB1 receptor expression, suggesting that the cytotoxic effect is due to interaction with the CB1 receptor.
This study provides new insights into the mechanism of Met-F-AEA action, and could have significance in providing a basis for the management of thyroid carcinoma.

http://link.springer.com/article/10.1007%2Fs10637-009-9221-0

▶ The Endocannabinoid System – Scientific Understanding of ECS – YouTube.

 

New Ruling Finds Marijuana To Be The Most Medicinal Plant In The World |Higher Perspective.

 

Imagine buying a new TV or even an automobile, spending thousands of hard-earned dollars.  Then, a year or two later, the government decides that your TV or car is illegal, AND GOES TO YOUR HOME TO CONFISCATE IT!!!!  No compensation, no grandfathering in.  If that is not tyranny, what the hell is????

California Begins Confiscating Legally-Purchased Guns – Downtrend.com.

 

▶ The SETH Group – The Action of Cannabinoids in Cancer Cells – YouTube.

via ▶ The SETH Group – The Action of Cannabinoids in Cancer Cells – YouTube.

New Study: Marijuana May Treat Addiction To Hard Drugs | The Weed Blog.

 

5 Ways Marijuana Affects Your Sleep – Leaf Science.

 

Re-posted from a Facebook post by:  CANNABIS CURES CANCERS!
116 Medical Studies About the Anti-Cancer Effects of Cannabinoids

Part 4: The Latest Research (2013):
Studies # 101 – 116:

Brain cancer, Breast cancer, Cancer (all types), Leukemia, Liver cancer, Lung cancer, Prostate cancer

Part 1: Studies # 1 – 36
Part 2: Studies # 37 -68
& Part 3: Studies # 69 -100
in the Comments below

Collected by CANNABIS CURES CANCERS!
(facebook.com/THeCureForCancers)

BRAIN CANCER:

PLoS ONE (Public Library of Science),
January 2013

Abstract

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. …
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) 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. …

Discussion

One of the strategies that are currently under investigation to improve the efficacy of anticancer treatments is the utilization of drug carrier systems facilitating the local delivery of antineoplasic agents.
Among these drug carrier systems, polymeric MPs [microparticles] have drawn much attention owing to their ability to control drug release, improve the therapeutic effect, prolong the biological activity, and decrease the administration frequency of several anti-neoplasic agents.

THC and CBD – two phytocannabinoids with potent anti-cancer activity – can be efficiently encapsulated into biodegradable PCL microspheres .
Our data show that PCL microspheres permit continuous release of these drugs and that its administration every 5 days to tumour-bearing mice reduces the growth of glioma xenografts with similar efficacy than a daily local administration of these cannabinoids in solution. …

Of note, different observations suggest that the doses of THC required to produce its cell death-promoting effect in cancer cells … are higher than the ones required for other actions of this agent …
Thus, reaching effective concentrations of THC at the tumour site using a systemic route of administration may require increasing the doses of THC administered to humans, which would enhance the risk of undergoing the undesired side effects of THC derived from its binding to CB1 receptors present in different brain regions.
Local administration of cannabinoid-loaded MPs can help to circumvent this problem as their administration in the proximity of the tumour would ensure that effective concentrations of THC are reached at the therapeutically relevant site without enhancing acutely the levels of this agent in the brain regions responsible for its pyschoactivity.
In addition, in this study we also found that the anticancer efficacy of the individual treatments with THC-loaded MP (containing approximately 6.15 mg of THC per administration) or CBD-loaded MP (containing approximately 6.7 mg of CBD per administration) is similar to that produced by co-administration of a mixture (1:1) of THC- and CBD-loaded MPs (containing approximately 3.075 mg of THC and 3.75 mg of CBD per administration).
These results are in line with previous observations by our laboratory, and suggest that rather than producing a synergistic effect, the combined administration of sub-maximal doses of THC and CBD could help to reduce the doses of these compounds required to produce their inhibitory effects on tumour growth.

Cannabinoids have been shown to produce a potent anticancer action in different types of tumour xenografts including some of the ones that exhibit a higher resistance to standard chemotherapies such as gliomas, pancreatic adenocarcinomas and hepatocellular carcinomas, three tumour types that are susceptible of being treated with drug-loaded MPs.
This anticancer action of cannabinoids is based on the ability of these compounds to enhance apoptosis, inhibit proliferation of cancer cells and inhibit tumour angiogenesis.
Data presented here confirm that these mechanisms of action are activated in glioma xenografts upon administration of MPs loaded with THC, CBD or the combination of the two types of MPs.
Although additional research should clarify whether a similar effect can be produced in other types of tumour xenografts, and whether MPs loaded with THC, CBD or its combination are equally efficacious in different tumour types and sub-types, these observations strongly support that microencapsulation could be a promising strategy to optimize the utilization of cannabinoids as anticancer agents.

Of interest, we have recently found that the combined administration of THC or THC + CBD (but not CBD, S Torres, M Lorente and G Velasco unpublished observations) with temozolomide synergistically reduces the growth of glioma xenografts.
The findings presented here now provide a rational for the design of novel anticancer strategies based on the use of cannabinoid-loaded MPs in combinational therapies.

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.

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

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Advances in Experimental Biology and Medicine:
Glioma Signaling
2013

Cannabinoid Signaling in Glioma Cells

Abstract

Cannabinoids are a group of structurally heterogeneous but pharmacologically related compounds, including plant-derived cannabinoids, synthetic substances and endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol.
Cannabinoids elicit a wide range of central and peripheral effects mostly mediated through cannabinoid receptors.
There are two types of specific Gi/o-protein-coupled receptors cloned so far, called CB1 and CB2, although an existence of additional cannabinoid-binding receptors has been suggested.
CB1 and CB2 differ in their predicted amino acid sequence, tissue distribution, physiological role and signaling mechanisms.
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 relies on the generation of a pro-apoptotic sphingolipid ceramide and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation or apoptosis.
Increased ceramide levels lead also to ER-stress and autophagy in drug-treated glioblastoma cells.

http://link.springer.com/chapter/10.1007%2F978-94-007-4719-7_11

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Journal of Neuro-Oncology
October 2013

Abstract

To evaluate, through a systematic review of the literature, the antitumoral effects of cannabinoids on gliomas. …
All published studies involving the antitumoral effects (cellular and molecular mechanisms) of cannabinoids were considered for this review. …
All the studies included in this systematic review were experimental (in vivo and/or in vitro), except for one pilot clinical trial phase I/II involving humans.
In all experimental studies included, cannabinoids exerted antitumoral activity in vitro and/or antitumoral evidence in vivo in several models of tumor cells and tumors.
The antitumor activity included: antiproliferative effects (cell cycle arrest), decreased viability and cell death by toxicity, apoptosis, necrosis, autophagy, as well as antiangiogenic and antimigratory effects.
Antitumoral evidence included: reduction in tumor size, antiangiogenic, and antimetastatic effects.
Additionally, most of the studies described that the canabinnoids exercised selective antitumoral action in several distinct tumor models.
Thereby, normal cells used as controls were not affected.
The safety factor in the cannabinoids’ administration has also been demonstrated in vivo.
The various cannabinoids tested in multiple tumor models showed antitumoral effects both in vitro and in vivo.
These findings indicate that cannabinoids are promising compounds for the treatment of gliomas.

http://link.springer.com/article/10.1007%2Fs11060-013-1277-1

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PLOS ONE (Public Library of Science)
October 21, 2013

Cannabidiol, a Non-Psychoactive Cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect

Abstract

In the present study, we found that CBD inhibited U87-MG and T98G cell proliferation and invasiveness in vitro and caused a decrease in the expression of a set of proteins specifically involved in growth, invasion and angiogenesis.
In addition, CBD treatment caused a dose-related down-regulation of ERK and Akt prosurvival signaling pathways in U87-MG and T98G cells and decreased hypoxia inducible factor HIF-1α expression in U87-MG cells.
Taken together, these results provide new insights into the antitumor action of CBD, showing that this cannabinoid affects multiple tumoral features and molecular pathways.
As CBD is a non-psychoactive phytocannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anti-cancer drug in the management of gliomas.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076918

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CANCER (ALL TYPES):

British Journal of Clinical Pharmacology
February 2013

Cannabidiol as potential anticancer drug

Abstract

Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ9-tetrahydrocannabinol (Δ9-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors.
Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization.
However, the clinical use of Δ9-THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive cannabinoid compounds with structural affinity for Δ9-THC, such as cannabidiol (CBD), has substantially increased in recent years.
The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2012.04298.x/full

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Evidence-based Complementary and Alternative Medicine
June 2013

The Medical Necessity for Medicinal Cannabis:
Prospective, Observational Study Evaluating the Treatment in Cancer Patients on Supportive or Palliative Care

Abstract

Background:
Cancer patients using cannabis report better influence from the plant extract than from synthetic products.
However, almost all the research conducted to date has been performed with synthetic products.
We followed patients with a medicinal cannabis license to evaluate the advantages and side effects of using cannabis by cancer patients. …

Results:
… All cancer or anticancer treatment-related symptoms showed significant improvement …
No significant side effects except for memory lessening in patients with prolonged cannabis use were noted. …

Conclusion:
… Although studies with a control group are missing, the improvement in symptoms should push the use of cannabis in palliative treatment of oncology patients.

http://www.hindawi.com/journals/ecam/2013/510392/

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J-STAGE: Biological and Pharmaceutical Bulletin:
The Pharmaceutical Society of Japan
July 2013

Structural Requirements for Potent Direct Inhibition of Human Cytochrome P450 1A1 by Cannabidiol: Role of Pentylresorcinol Moiety

Abstract

Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined.
However, the mechanism underlying this CBD inhibition remains to be clarified.
Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity …
These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.

Discussion

We have recently reported the potent direct inhibition of human CYP1A1 activity by CBD. …
Therefore, CBD and its structurally related compounds which potently inhibit CYP1A1 activity would be expected as a lead compound in anticancer chemotherapy. …

https://www.jstage.jst.go.jp/article/bpb/36/7/36_b13-00183/_html

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Cancer Management and Research
August 30, 2013

Critical appraisal of the potential use of cannabinoids in cancer management

Abstract

Cannabinoids have been attracting a great deal of interest as potential anticancer agents.
Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available.
This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. …
Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated.
Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung.
This work is complemented by an increasing body of evidence from in vivo models. …

Introduction

The cannabinoids are a class of over 60 compounds derived from the plant Cannabis sativa, as well as the synthetic or endogenous versions of these compounds.
Cannabis has been used as a medicinal and recreational drug for many centuries, but its psychoactive properties have led to legal regulations around access and use in most countries.
Despite this, scientific research into both natural and synthetic cannabinoids has continued.
Studies are now being conducted on the potential efficacy of cannabinoids, both natural and synthetic, as anticancer agents and their possible mechanisms of action. …

Role of cannabinoids in cancer

Two therapeutic avenues exist for the development of cannabinoids as anticancer agents.
As antiemetic and analgesic compounds, this class of compounds has been explored in terms of palliative care.
More recently, cannabinoid agonists and antagonists have been screened for potential direct antitumorigenic properties. …

Antitumorigenic properties

Cannabinoids are not yet approved for the treatment of tumor progression, although their antitumorigenic effects have been known for over 30 years.
Cannabinol and Δ8-THC inhibited tumor growth in a mouse model of Lewis lung adenocarcinoma after 20 days of treatment [Journal of the National Cancer Institute, September 1975] …
Since this pioneering study, a vast range of cancer cell and tumor models have been used to evaluate the possible efficacy and mechanisms of cannabinoid antitumor activity.
This work is supported by findings that the endocannabinoid system may be altered during disease states.
Significant levels of the cannabinoid receptor are found in prostate, breast, leukemia, melanoma, and thyroid cell lines, as well as colorectal and hepatocellular carcinoma tissue …

Anticancer actions of specific compounds

Endo- and phytocannabinoids (Δ9-THC, AEA, cannabidiol)

The primary active constituent of cannabis, Δ9-THC, has been investigated in a number of in vitro- and in vivo-based systems.
Overall, some efficacy has been recorded in breast, prostate, glioma, lymphoma, and pancreatic cancer cell lines.
In contrast, there are reports of pro-cancerous activity in breast, bronchial, hepatoma, and lung cell lines.

Results are not clear-cut as to whether Δ9-THC causes pro- or antiproliferative effects in breast cancer cells. …
These results indicate that the role of compounds such as Δ9-THC is not well understood, and its effects are possibly regulated by a range of factors that are yet to be determined. …

In glioma cell lines, almost all studies show that cannabinoids decrease cell proliferation. …
Results showed a consistent decrease in cell viability independent of cell line.
… cannabidiol inhibited cell proliferation …

Δ9-THC shows inhibitory effects in a range of pancreatic cell lines …
When MiaPaCa2 cells were implanted subcutaneously into nude mice and left to form tumors, Δ9-THC (15 mg/kg/day, 15 days) caused a significant reduction in tumor growth.

Both Δ9-THC and AEA [anandamide] … inhibited the growth of lymphoma cell lines …

In contrast to the inhibitory effects documented above, the natural cannabinoids have also shown to increase cell proliferation, although normally these results have been documented in studies investigating smoke mixtures that include natural cannabinoid compounds. …

Overview of potential mechanisms

Effects on tumor growth and development

Cannabinoids affect a range of pathways that regulate cell division and viability; however, the knowledge in this area remains incomplete.
For example, it is still difficult to explain the myriad of results around cell survival that have been reported in the literature.
This is confounded by a lack of understanding of the possible receptors involved and ongoing doubt over their definitive localization.
In addition, the actual mechanisms of cell death remain controversial, with some authors maintaining that autophagy precedes apoptosis and others suggesting that apoptosis is stimulated directly.
Current evidence suggests that the type and stage of the cancer is likely to be important, with hormone-dependent cancers possibly reacting differently to cannabinoid exposure than gliomas (the most studied cancer type in terms of cannabinoid action). …

Effects on invasion and metastasis

Cannabinoids affect a wide range of markers associated with the invasion and metastasis of cancers, including markers of migration, adhesion, invasion, and metastasis itself.
For example, studies on migration have shown that AEA [anandamide] … cannabidiol … Δ9-THC … all decreased migration, or markers of migration, in a wide range of cell lines. …

In terms of migration, cannabidiol … Δ9-THC … have all proven to have direct effects on migration markers.
In breast cancer cells, cannabidiol decreased lung metastasis … Similarly, Δ9-THC … inhibited the epidermal growth factor-induced growth, chemotaxis, and chemoinvasion of the lung cancer cell lines …

All these results suggest that overall the cannabinoids affect multiple cellular signaling pathways, which means they have the potential to decrease cancer development, growth, and metastasis.
However, there are likely to be both cancer- and cannabinoid-specific elements to these effects. …

Effects on angiogenesis

Angiogenesis is critical for tumor development, and many anticancer agents are selected for their antiangiogenic properties.
In vivo models show tumors from cannabinoid-treated animals have a decreased number of sprouting blood vessels, reduced vascular networks, and small, undifferentiated intratumoral blood vessels.
Cannabinoids may produce a dual attack on the development of tumor blood vessels, through the inhibition of proangiogenic regulators, such as vascular endothelial growth factor (VEGF), and through a direct effect on endothelial cells.

A number of experiments have determined that the levels of the major vascularization factors, including VEGF, are downregulated following administration of Δ9-THC …
Δ9-THC decreased VEGF levels in lung cancer cell lines …
and this effect correlated with a decrease in vascularization of … xenoplantation tumors in severe combined immunodeficient mice. …
Overall, cannabinoids appear to have consistent effects on the vascularization pathway, causing a decrease in tumor vascularization in in vivo models.

… Therefore, the cannabinoids show significant potential as antiangiogenic agents, and this may prove key to their success as a clinical therapy …

The future of cannabinoid compounds in cancer treatment

Overall, the cannabinoids may show future promise in the treatment of cancer, but there are many significant hurdles to be overcome.
There is much still to be learned about the action of the cannabinoids and the endocannabinoid system. …
Future research will help clarify the actions of the cannabinoids, and particularly the endocannabinoid signaling pathway, which will be critical in the ongoing development of these compounds.

It is a distinct possibility that the cannabinoids may have a place in the future treatment of cancer. …
The resolution of the conflicting evidence around cannabinoid action will continue to be a research priority in the near future, and it is expected that developing a more robust understanding of the mechanisms of action underlying cannabinoid action will facilitate the acceptance of cannabinoid use in a clinical setting.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770515/?report=classic

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Journal of Drug Targeting
September 21, 2013

Preparation and characterization of Δ9-tetrahydrocannabinol-loaded biodegradable polymeric microparticles and their antitumoral efficacy on cancer cell lines

Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer, AIDS and multiple sclerosis), analgesics, and in the treatment of multiple sclerosis and cancer, among other conditions.
However, despite their high clinical potential, only few dosage forms are available to date.

In this paper, the development of Δ9-tetrahydrocannabinol (THC) biodegradable microspheres as an alternative delivery system for cannabinoid parenteral administration is proposed.
Tetrahydrocannabinol was encapsulated into biodegradable microspheres by the oil-in-water (o/w) emulsion solvent evaporation method. …
The in vitro drug release studies showed that the encapsulated drug was released over a two week period.
As THC has shown therapeutic potential as anticancer drug, the efficacy of the microspheres was tested on different cancer cell lines.
Interestingly, the microspheres were able to inhibit cancer cell proliferation during the nine-day study period.
All the above results suggest that the use of biodegradable microspheres would be a suitable alternative delivery system for THC administration.

http://informahealthcare.com/doi/abs/10.3109/1061186X.2013.809089

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Biochimica et Biophysica Acta (BBA)
(Molecular and Cell Biology of Lipids)
October 2013

The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action

Abstract

Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumour growth in animal models of cancer.
This effect relies, at least in part, on the up-regulation of several endoplasmic reticulum stress-related proteins including the pseudokinase tribbles homologue-3 (TRIB3), which leads in turn to the … stimulation of autophagy-mediated apoptosis in tumour cells.
Here, we took advantage of the use of cells derived from Trib3-deficient mice to investigate the precise mechanisms by which TRIB3 regulates the anti-cancer action of THC.
… we found that tumours generated by inoculation of Trib3-deficient cells in nude mice are resistant to THC anticancer action.
Altogether, the observations presented here strongly support that TRIB3 plays a crucial role on THC anti-neoplastic activity.

http://www.sciencedirect.com/science/article/pii/S1388198113000851

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British Journal of Pharmacology
October 4, 2013

Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy

Abstract

Purpose:

Paclitaxel (PAC) is associated with a chemotherapy-induced neuropathic pain (CIPN) state that can lead to the cessation of treatment in late stage breast cancer patients, even in the absence of alternate therapies. Indeed, to date no one drug or drug class is considered to be effective for reversal of CIPN. We have recently reported that chronic administration of the non-psychoactive and non-toxic cannabinoid, cannabidiol (CBD) prevents the onset of PAC-induced mechanical and thermal sensitivity in a mouse model of CIPN. In this investigation, we sought to discover pathways through which CBD inhibits CIPN and to determine whether the cannabinoid had any unforeseen deleterious effects on nervous system function or chemotherapy efficacy.

Method:

The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed … The effect of CBD on place conditioning and on autoshaping, a conditioned learning and memory task, were determined to determine whether the cannabinoid produced any negative CNS effects. The potential positive or negative interaction of CBD and PAC on breast cancer cell viability was determined …

Results:

Treatment with PAC … produced significant mechanical sensitivity in female … mice that was prevented by administration of CBD … CBD produced no conditioned rewarding effects in comparison to morphine which served as a positive control. … CBD+PAC combinations produce additive to synergistic inhibition of breast cancer cell viability.

Conclusions:

Our data suggest that CBD is protective against PAC-induced neurotoxicity … Furthermore, CBD treatment was devoid of other nervous system effects such as conditioned reward or cognitive impairment. CBD also did not attenuate the efficacy of PAC in inhibiting breast cancer cell viability. Taken together, adjunct treatment with CBD during PAC chemotherapy treatment may be safe and effective in the prevention or attenuation of CIPN.

http://onlinelibrary.wiley.com/doi/10.1111/bph.12439/abstract

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LEUKEMIA:

Anticancer Research
October 2013

Enhancing the Activity of Cannabidiol and Other Cannabinoids In Vitro Through Modifications to Drug Combinations and Treatment Schedules

Abstract

Cannabinoids are the bioactive components of the Cannabis plant that display a diverse range of therapeutic qualities. We explored the activity of six cannabinoids, used both alone and in combination in leukaemic cells.
Cannabinoids were cytostatic and caused a simultaneous arrest at all phases of the cell cycle.
Re-culturing pre-treated cells in drug-free medium resulted in dramatic reductions in cell viability. …
We suggest that the activities of some cannabinoids are influenced by treatment schedules; therefore, it is important to carefully select the most appropriate strategy in order to maximise their efficacy.

http://ar.iiarjournals.org/content/33/10/4373.abstract

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LIVER CANCER:

Cell Death and Disease
May 2, 2013

Involvement of PPARγ in the antitumoral action of cannabinoids on hepatocellular carcinoma

Abstract

Cannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma (HCC) cells.
In this study, we examined whether the PPARγ-activated pathway contributed to the antitumor effect of two cannabinoids, Δ9-tetrahydrocannabinol (THC) and JWH-015, against … HCC cells.
… we demonstrate for the first time that the antiproliferative action of the cannabinoids THC and JWH-015 on HCC, in vitro and in vivo, are modulated by upregulation of PPARγ-dependent pathways.

http://www.nature.com/cddis/journal/v4/n5/full/cddis2013141a.html

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LUNG CANCER:

Molecular Cancer Therapeutics
January 2013

Abstract

The antitumorigenic mechanism of cannabidiol is still controversial.
This study investigates … cannabidiol’s proapoptotic and tumor-regressive action.
In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. …
Moreover, in A549-xenografted nude mice, cannabidiol caused … tumor regression …

http://mct.aacrjournals.org/content/12/1/69.abstract

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SKIN CANCER:

European Journal of Pharmacology
September 13, 2013

Abstract

Cannabinoids are implicated in the control of cell proliferation, but little is known about the role of the endocannabinoid system in human malignant melanoma.
This study was aimed at characterizing the in vitro antitumor activity of anandamide (AEA) in A375 melanoma cells. … Overall, these findings demonstrate that AEA induces cytotoxicity against human melanoma cells in the micromolar range of concentrations through a complex mechanism …

http://www.sciencedirect.com/science/article/pii/S0014299913006481

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PROSTATE CANCER:

British Journal of Pharmacology
January 2013:

Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms

Abstract

BACKGROUND AND PURPOSE:
Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ(9) -tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. …

EXPERIMENTAL APPROACH:
We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS) …

KEY RESULTS:
Cannabidiol (CBD) significantly inhibited cell viability.
Other compounds became effective in cells deprived of serum for 24 h.
Several BDS were more potent than the pure compounds in the presence of serum. …

CONCLUSIONS AND IMPLICATIONS:
These data support the clinical testing of CBD against prostate carcinoma.

http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2012.02027.x/full