This article is a far more detailed version of a smaller collection of studies showing the medicinal capabilities of cannabis for treating cancer. With alcohol showing essentially no medical properties beyond application as an anti-septic, cannabis (and in particular a molecules known as cannabinol -CBD- and its more famous brother THC), has numerous medical, industrial, and even ecological benefits (due to its fast growth and ability to protect itself from many pests without genetic modification or pesticides). There are a lot of reasons that cannabis prohibition cannot be rationally maintained.
Now, 123 is a lot of studies, and I can understand that not everyone wants to read through all of the summaries/abstracts (listed along with the title, publication date, and a link to the article). In some cases I shortened the abstract, in others cases I left it to provide a greater understanding of the context.
Taken together, these studies show cannabis as being more effective and less physically detrimental than chemotherapy for treating cancer. We must not forget that there are numerous other studies showing the medical properties of cannabis in regard to other conditions as well, and everyone is encouraged to do further research on their own.
For those with shorter attention spans: at least check out this 6 minute video from South California Labs about CBD: it covers several important studies and is well done, but if you want in-depth coverage and links to peer-reviewed science then I suggest continuing farther down the text.
This library is seperated into 4 parts to make navigation a little easier. The sections are largely based on the type of cancer being treated or investigated, and year of publishing. If you are looking for something specific -with a total of approximately 16,000 words in this document-, I suggest using ctrl+f (or similar on-page search method).
Part 1: Studies # 1 – 36:
Brain cancer, Breast cancer, Cancer (all types), Cervical cancer, Cholangiocarcinoma, Colorectal cancer, Leukemia, Lung cancer, Lymphoma, Prostate cancer, & Rhabdomyosarcoma
Journal of Neuropathology & Experimental Neurology
Arachidonylethanolamide Induces Apoptosis of Human Glioma Cells through Vanilloid Receptor‐1
The anti-tumor properties of cannabinoids have recently been evidenced, mainly with Δ9-tetrahydrocannabinol (THC). However, the clinical application of this drug is limited by possible undesirable side effects due to a broad expression of cannabinoid receptors (CB1 and CB2).
This is particularly important for malignant gliomas, considering their poor prognosis and their location in the brain.
Here we investigated whether the most potent endogenous cannabinoid, arachidonylethanolamide (AEA), could be a candidate.
We observed that AEA induced apoptosis in long-term and recently established glioma cell lines via aberrantly expressed vanilloid receptor-1 (VR1).
In contrast with their role in THC-mediated death, both CB1 and CB2 partially protected glioma against AEA-induced apoptosis.
These data show that the selective targeting of VR1 by AEA or more stable analogues is an attractive research area for the treatment of glioma.
Up-Regulation of Cyclooxygenase-2 Expression Is Involved in R(+)-Methanandamide-Induced Apoptotic Death of Human Neuroglioma Cells
Cannabinoids have been implicated in the reduction of glioma growth. This study investigated a possible relationship between the recently shown induction of cyclooxygenase (COX)-2 expression by the endocannabinoid analog R(+)methanandamide [R(+)-MA] and its effect on the viability of H4 human neuroglioma cells.
Incubation with R(+)-MA for up to 72 h decreased the cellular viability and enhanced accumulation of cytoplasmic DNA fragments in a time-dependent manner. …
As a whole, this study defines COX-2 as a hitherto unknown target by which a cannabinoid induces apoptotic death of glioma cells.
Furthermore, our data show that pharmacological concentrations of celecoxib may interfere with the proapoptotic action of R(+)-MA and anandamide, suggesting that cotreatment with COX-2 inhibitors could diminish glioma regression induced by these compounds.
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, but mechanisms of their antiproliferative action remain elusive.
In the present studies, C6 cells were exposed to a synthetic cannabinoid …which produced down-regulation of the Akt and Erk signalling pathways prior to appearance of any sign of apoptosis.
We hypothesized that cannabinoid-induced cell death may be mediated by a Bcl-2 family member—Bad … treatment further resulted in mitochondrial depolarization and activation of caspase cascade. Thus, 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.
Journal of Neurochemistry
Cannabinoid receptors in human astroglial tumors
In animal models, cannabinoids are reported to inhibit the growth of tumors, including gliomas.
These effects have been claimed to be mediated via cannabinoid receptors 1 and 2 (CB1, CB2).
To elucidate a possible relevance for treatment of human gliomas, we investigated receptor subtype expression in surgical material of solid human astrocytomas, gliomas and cultivated glioma cells …
In normal brain, cultivated glioma cells and solid tumors, CB1 … was expressed to a much greater extent than CB2, which in some samples was even undetectable.
Expression of both receptor subtypes was unrelated to malignancy, varied between patients, and was not significantly increased in relation to normal brain tissues. In normal brain, CB1 protein was localized on astroglial and other cell types; in gliomas, it was found on astroglial/glioma cells.
CB2 protein was detected on microglial cells/macrophages but rarely on astroglial cells. Functionally, CB1 receptor agonists … slightly reduced proliferation of glioma cells in vitro, but did not induce apoptosis.
We conclude that cannabinoid therapy of human gliomas targets not only receptors on tumor, but also on other cell types.
Therefore, complex and potential side-effects should be considered carefully.
Journal of Neuroscience Research
High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells
Cannabinoids bind to two G-protein-coupled receptors, CB1 and CB2, expressed by neurons and cells of the immune system, respectively.
Glioma cells (astrocyte-derived brain tumor cells) express cannabinoid receptors, and numerous in vitro and in vivo studies performed in rodents have concluded that apoptosis could be induced by cannabinoids in these cells.
Whether this also applies to human cells is controversial; we, therefore, assessed the effect of cannabinoids on human glioma cell viability with the human astrocytoma cell line U373MG.
We report here that U373MG human glioma cells are sensitive only to high concentrations of cannabinoids (>5 μg/ml for Δ9-THC). … suggesting that cannabinoid receptors are functional in U373MG cells. …
CB1 is expressed in U373MG cells and is involved in cannabinoid-induced cell death …
In addition, as already reported, some cannabinoids may have modest proproliferative properties in U373MG cells. Human U373MG glioma cells are sensitive only to very high, pharmacologically irrelevant concentrations of cannabinoids, so it seems unlikely that cannabinoids would constitute promising molecules for treating malignant astrocytoma; they do not induce glioma cell death at doses that could be applied safely to humans.
Δ9-Tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells
Δ9-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G1 arrest …
Hence, it is suggested that Δ9-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.
Brain Research Bulletin
Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans
The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality.
Glioblastoma are characterized particularly by fast growth and a dependence on blood vessel formation for survival. Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The distribution of CB1 and CB2 receptors in glioblastoma and associated endothelial vessels is still unknown.
The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation.
Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth.
Molecular Cancer Therapeutics
Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells
Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically.
Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available.
Clearly, effective and nontoxic therapies are urgently required.
Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated …
Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells.
The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion.
These effects seemed to occur as the result of an inhibition of the Id-1 gene …
CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness.
Molecular Cancer Therapeutics
Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer
Cannabinoids have been reported to possess antitumorogenic activity.
Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis.
We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue.
We have also observed that the breast cancer cell lines … express CB1 and CB2 receptors.
Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems.
Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. …
In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the … transgenic mouse model system. …
These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.
CANCER, ALL TYPES:
Pharmacokinetics and Pharmacodynamics of Cannabinoids
Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant.
However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues.
Additionally, there is evidence for nonreceptor-dependent mechanisms.
Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today.
The pharmacokinetics of THC vary as a function of its route of administration.
Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15–30 minutes, and taper off within 2–3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30–90 minutes, reach their maximum after 2–3 hours and last for about 4–12 hours, depending on dose and specific effect.
At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences.
The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure.
Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome.
The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial.
They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs.
Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.
Expert Opinion on Therapeutic Targets
Cannabinoid receptor systems: therapeutic targets for tumour intervention
The past decade has witnessed a rapid expansion of our understanding of the biological roles of cannabinoids and their cognate receptors.
It is now certain that Δ9-tetrahydrocannabinol, the principle psychoactive component of the Cannabis sativa plant, binds and activates membrane receptors …
Synthesis of numerous cannabinomimetics has also greatly expanded the repertoire of cannabinoid receptor ligands with the pharmacodynamic properties of agonists, antagonists and inverse agonists.
Collectively, these ligands have proven to be powerful tools both for the molecular characterisation of cannabinoid receptors and the delineation of their intrinsic signalling pathways.
Much of our understanding of the signalling mechanisms activated by cannabinoids is derived from studies of receptors expressed by tumour cells; hence, this review provides a succinct summary of the molecular pharmacology of cannabinoid receptors and their roles in tumour cell biology.
Moreover, there is now a genuine expectation that the manipulation of cannabinoid receptor systems may have therapeutic potential for a diverse range of human diseases. Thus, this review also summarises the demonstrated antitumour actions of cannabinoids and indicates possible avenues for the future development of cannabinoids as antitumour agents.
Mini-Reviews in Medicinal Chemistry
Cannabinoids and Cancer
Marijuana has been used in medicine for millennia, but it was not until 1964 that Δ9- tetrahydrocannabinol (Δ9-THC), its major psychoactive component, was isolated in pure form and its structure was elucidated.
Shortly thereafter it was synthesized and became readily available.
In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth.
The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found.
In spite of the promising results from these early studies, further investigations in this area were not reported until a few years ago, when almost simultaneously two groups initiated research on the antiproliferative effects of cannabinoids on cancer cells: Di Marzos group found that cannabinoids inhibit breast cancer cell proliferation, and Guzmans group found that cannabinoids inhibit the growth of C6 glioma cell.
Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.
A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells
… We have reported that a new cannabinoid anticancer quinone, cannabidiol hydroxyquinone (HU-331), is highly effective against tumor xenografts in nude mice. …
The ability of cannabinoids to cause endothelial cell apoptosis was assayed …
Immunostaining with anti-CD31 of tumors grown in nude mice served to indicate inhibition of tumor angiogenesis.
HU-331 was found to be strongly antiangiogenic, significantly inhibiting angiogenesis at concentrations as low as 300 nM. HU-331 inhibited angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors.
A significant decrease in the total area occupied by vessels in HU-331-treated tumors was also observed.
These data lead us to consider HU-331 to have high potential as a new antiangiogenic and anticancer drug.
Molecular Cancer Therapeutics
HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor
Anthracyclines, a large group of quinonoid compounds, are used to treat some forms of cancer.
Although highly effective in cancer therapy, the mechanism of action of these compounds is not specific; they act on cancer and other cells by numerous mechanisms.
A new anticancer quinone (HU-331) was synthesized from cannabidiol.
It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice.
In this study, we investigated its mode of action and present evidence on its unique mechanism. …
HU-331–caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species …
The cannabinoid quinone HU-331 is a highly specific inhibitor of topoisomerase II, compared with most known anticancer quinones.
It might represent a new potent anticancer drug.
Dialogues in Clinical Neuroscience
Cannabinoids in health and disease
Cannabis sativa L. preparations have been used in medicine for millenia. …
Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value.
However, their use is highly restricted. … the therapeutic value of cannabinoids is too high to be put aside.
Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, Alzheimer’s disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds.
In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable – instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and – in cases where it is impossible to separate the desired clinical action and the psychoactivity – just to monitor these side effects carefully.
Cannabinoids for Cancer Treatment: Progress and Promise
Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival.
In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer.
Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy.
Antineoplastic and apoptotic effects of cannabinoids. N-acylethanolamines: protectors or killers?
The proapoptotic and antineoplastic properties of cannabinoids … were analyzed.
Cannabinoids enhanced apoptotic and necrotic processes in many types of tumour cells and tissues.
Involvement of different types of receptors and signaling pathways in mediating the proapoptotic effects of cannabinoids are discussed.
The evidences in favour of both proapoptotic, pronecrotic and protective, antiapoptotic effects of cannabinoids … are evaluated.
The conclusion is made on promising of cannabinoids as potential anticancer agents.
The Journal of Pharmacy and Pharmacology
Cannabinoid receptor ligands as potential anticancer agents–high hopes for new therapies?
The endocannabinoid system is an endogenous lipid signalling network comprising arachidonic-acid-derived ligands, cannabinoid (CB) receptors, transporters and endocannabinoid degrading enzymes.
The CB(1) receptor is predominantly expressed in neurons but is also co-expressed with the CB(2) receptor in peripheral tissues.
In recent years, CB receptor ligands, including Delta(9)-tetrahydrocannabinol, have been proposed as potential anticancer agents.
This review critically discusses the pharmacology of CB receptor activation as a novel therapeutic anticancer strategy in terms of ligand selectivity, tissue specificity and potency.
Intriguingly, antitumour effects mediated by cannabinoids are not confined to inhibition of cancer cell proliferation; cannabinoids also reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and attenuate inflammatory processes. …
The role of the endocannabinoid system in tumourigenesis is still poorly understood and the molecular mechanisms of cannabinoid anticancer action need to be elucidated.
The development of CB(2)-selective anticancer agents could be advantageous in light of the unwanted central effects exerted by CB(1) receptor ligands.
Probably the most interesting question is whether cannabinoids could be useful in chemoprevention or in combination with established chemotherapeutic agents.
Trends in Pharmacological Sciences
The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities
The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease.
Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland).
It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).
Cannabinoids in the treatment of cancer
Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer.
While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB1 and CB2) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids, discuss their potential mechanisms of action, as well as explore controversies surrounding the results.
The Journal of Pharmacology and Experimental Therapeutics
Antitumorigenic Effects of Cannabinoids beyond Apoptosis
According to the World Health Organization, the cases of death caused by cancer will have been doubled until the year 2030.
Apart from their proapoptotic and antiproliferative action, recent research has shown that cannabinoids may likewise affect tumor cell angiogenesis, migration, invasion, adhesion, and metastasization.
This review will summarize the data concerning the influence of cannabinoids on these locomotive processes beyond modulation of cancer cell apoptosis and proliferation.
The findings discussed here provide a new perspective on the antitumorigenic potential of cannabinoids. …
Apart from regulating tumor cell growth and apoptosis, other antitumorigenic mechanisms of cannabinoids are currently emerging as a focus of research work.
Therefore, the present review focuses on the impact of cannabinoids on tumor neovascularization, tumor cell migration, adhesion, invasion, and metastasization.
Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1
Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects.
Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion.
… we found a cannabidiol-driven impaired invasion of human cervical cancer … and human lung cancer cells … Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of … lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls.
Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.
Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1
Δ9-Tetrahydrocannabinol, the active agent of Cannabis sativa, exhibits well-documented antitumor properties, but little is known about the possible effects mediated by endogenous cannabinoids on human tumors.
In the present study, we analyzed the effect of arachidonyl ethanolamide (AEA) on cervical carcinoma (CxCa) cell lines.
The major finding was that AEA induced apoptosis of CxCa cell lines … whereas AEA binding to the classical CB1 and CB2 cannabinoid receptors mediated a protective effect. Furthermore, unexpectedly, a strong expression of the three forms of AEA receptors was observed in ex vivo CxCa biopsies.
Overall, these data suggest that the specific targeting of VR1 by endogenous cannabinoids or synthetic molecules offers attractive opportunities for the development of novel potent anticancer drugs.
CHOLANGIOCARCINOMA (Bile duct cancer):
The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration.
Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma.
The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers.
We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells.
Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors.
THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis.
Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.
International Journal of Cancer
The cannabinoid δ9-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells
Deregulation of cell survival pathways and resistance to apoptosis are widely accepted to be fundamental aspects of tumorigenesis.
As in many tumours, the aberrant growth and survival of colorectal tumour cells is dependent upon a small number of highly activated signalling pathways, the inhibition of which elicits potent growth inhibitory or apoptotic responses in tumour cells.
Accordingly, there is considerable interest in therapeutics that can modulate survival signalling pathways and target cancer cells for death.
There is emerging evidence that cannabinoids, especially Δ9-tetrahydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival.
Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells. …
These data suggest an important role for CB1 receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.
Blood: Journal of the American Society of Hematology
Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease
Cells of the immune system express high levels of CB2 receptors. …
If CB2 receptor agonists can induce apoptosis in transformed immune cells, it could lead to development of a novel class of anticancer agents.
In the current study, we investigated this possibility by using both murine (mouse) and human leukemia and lymphoma lines as well as primary acute lymphoblastic leukemia (ALL) cells. …
We demonstrate that ligation of CB2 receptors can induce apoptosis in a wide range of cancers of immune-cell origin. Furthermore, we demonstrate that THC can inhibit the growth of murine lymphoma cells in vivo by inducing apoptosis and cure approximately 25% of the mice bearing the tumor.
Together, the current data suggest that CB2 agonists that are devoid of psychotropic effects may constitute a novel and effective modality to treat malignancies of the immune system.
Leukemia & Lymphoma
γ-Irradiation Enhances Apoptosis Induced by Cannabidiol, a Non-psychotropic Cannabinoid, in Cultured HL-60 Myeloblastic Leukemia Cells
Two non-psychotropic cannabinoids, cannabidiol (CBD) and cannabidiol-dimethylheptyl (CBD-DMH), induced apoptosis in a human acute myeloid leukemia (AML) HL-60 cell line. …
A dose dependent increase of apoptosis was noted, reaching 61 and 43% with 8 μg/ml CBD and 15 μg/ml CBD-DMH, respectively, after a 24 h treatment.
Prior exposure of the cells to γ-irradiation (800 cGy) markedly enhanced apoptosis, reaching values of 93 and 95%, respectively.
Human monocytes from normal individuals were resistant to either cannabinoids or γ-irradiation.
Caspase-3 activation was observed after the cannabinoid treatment, and may represent a mechanism for the apoptosis.
Our data suggest a possible new approach to treatment of AML.
Blood: Journal of the American Society of Hematology
Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway
Δ9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis.
THC causes cell death in vitro through the activation of complex signal transduction pathways.
However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear.
We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines … to establish further the mechanism of cell death. …
We have shown that THC is a potent inducer of apoptosis, even at 1 × IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug.
These effects were seen in leukemic cell lines … as well as in peripheral blood mononuclear cells.
Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin.
One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes …
Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.
Journal of the National Cancer Institute
Antineoplastic activity of cannabinoids
Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD).
Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth.
Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size.
CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days.
Delta9-THC, delta8-THC, and CBN increased the mean survival time … whereas CBD did not. … delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly.
Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent … inhibition (80-20%, respectively) …
CBD was active only in high concentrations.
Biochemical and Biophysical Research Communications
December 7, 2007
Cannabinoid receptor agonists are mitochondrial inhibitors: A unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death
Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Δ-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis.
In rat heart mitochondria, all three ligands caused significant decreases in oxygen consumption and mitochondrial membrane potential.
THC and HU 210 caused significant increases in mitochondrial hydrogen peroxide production, whereas AEA was without significant effect.
All three ligands induced biphasic changes in either mitochondrial complex I activity and/or mitochondrial complex II–III activity.
These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors.
FEBS Letters (Federation of European Biochemical Societies)
Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma
In this study, treatment with cannabinoid receptor ligands caused a decrease in viability of MCL cells, while control cells lacking CB1 were not affected.
Interestingly, equipotent doses of the CB1 antagonist … and the CB1/CB2 agonist anandamide inflicted additive negative effects on viability.
Moreover, treatment with the CB1/CB2 agonist … caused a decrease in long-term growth of MCL cells in culture. Induction of apoptosis … contributed to the growth suppressive effect …
Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.
Cannabinoid Receptor-Mediated Apoptosis Induced by R(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma
We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB1 and CB2).
In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated.
Induction of apoptosis after treatment with the synthetic agonists … was dependent on both cannabinoid receptors … Taken together, these results suggest that concurrent ligation of CB1 and CB2 … induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation.
Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected.
The present data suggest that targeting CB1/CB2 may have therapeutic potential for the treatment of mantle cell lymphoma.
International Journal of Cancer
Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation
Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL).
In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type …
A majority of the lymphomas expressed higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid tissue.
With the exception of MCL, which uniformly overexpresses both CB1 and CB2, the levels of cannabinoid receptors within other lymphoma entities were highly variable, ranging from 0.1 to 224 times the expression in reactive lymph nodes. …
In functional studies using MCL … chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide analog … induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors, but not in BL.
In vivo treatment … caused a significant reduction of tumor size … in mice xenografted with human MCL.
Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.
Molecular Cancer Research
Potentiation of Cannabinoid-Induced Cytotoxicity in Mantle Cell Lymphoma through Modulation of Ceramide Metabolism
Ceramide levels are elevated in mantle cell lymphoma (MCL) cells following treatment with cannabinoids.
Here, we investigated the pathways of ceramide accumulation in the MCL cell line …
Furthermore, this is the first study were the cytotoxic effect of a cannabinoid is enhanced by modulation of ceramide metabolism.
Cannabinoid Receptor as a novel target for the treatment of prostate cancer
Here we show that expression levels of both cannabinoid receptors, CB1 and CB2, are significantly higher in CA-human papillomavirus-10 (virally transformed cells derived from adenocarcinoma of human prostate tissue) … than in human prostate epithelial … (virally transformed cells derived from normal human prostate tissue) cells. …
Our results suggest that WIN-55,212-2 or other non–habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.
Molecular Cancer Therapeutics
Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma
Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies …
Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma.
Our study shows that treatment with the cannabinoid receptor agonists HU210 and Δ9-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis. … Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo.
These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.
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
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.
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.
The Journal of Pharmacology and Experimental Therapeutics
Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines
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.
Cellular and Molecular Life Sciences
The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells
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.
The Journal of Biological Chemistry
Cannabinoids Induce Glioma Stem-like Cell Differentiation and Inhibit Gliomagenesis
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.
Expert Review of Neurotherapeutics
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.
Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity?
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.
The Journal of Clinical Investigation
Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
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.
Molecular Cancer Therapeutics
Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival
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.
PLOS ONE (Public Library of Science)
The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas
Cannabinoids represent unique compounds for treating tumors, including astrocytomas. Whether CB1 and CB2 receptors mediate this therapeutic effect is unclear.
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.
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.
Proceedings of the National Academy of Sciences of the United States of America
The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation
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.
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.
The Journal of Pharmacology and Experimental Therapeutics
Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma
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.
JunD is involved in the antiproliferative effect of Δ9-tetrahydrocannabinol on 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.
CANCER (ALL TYPES):
Prostaglandins, Leukotrienes and Essential Fatty Acids
Endocannabinoids in the immune system and cancer
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.
The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells
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.
Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (Review)
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.
Clinical Cancer Research
Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells
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.
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.
The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. …
Cannabinoids in intestinal inflammation and 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.
Targeting cannabinoid receptors to treat leukemia: Role of cross-talk between extrinsic and intrinsic pathways in Δ9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells
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.
FEBS Letters (Federation of European Biochemical Societies)
p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells
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.
Experimental Cell Research
The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway
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.
Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22phox and Nox4 Expression
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.
Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: Involvement of the transcription factor PPARγ
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.
Journal of the Federation of American Societies for Experimental Biology
Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1
… 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… all cannabinoids tested exerted significant anti-invasive effects on primary lung tumor cells …
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.
FEBS Letters (Federation of European Biochemical Societies)
Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism
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. …
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.
The present study demonstrates in vitro anticancer activity of CB derivatives on the poorly differentiated pancreatic cancer cell line …
The FASEB Journal (Federation of the American Societies for Experimental Biology)
Cannabinoid receptors as novel targets for the treatment of melanoma
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.
European Journal of Pharmacology
The CB1/CB2 receptor agonist WIN-55,212-2 reduces viability of human Kaposi’s sarcoma cells in vitro
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.
Journal of Surgical Research
Pharmacological Synergism Between Cannabinoids and Paclitaxel in Gastric Cancer Cell Lines
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.
Journal of Cellular Biology
Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells
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
A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells
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.
Cancer Gene Therapy
Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma
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.
Investigational New Dugs
A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis
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.
Part 3: Studies # 69 – 100:
Brain cancer, Breast cancer, Cancer (all types),
Colon cancer, Liver cancer, Oral cancer, Pancreatic cancer, Prostate cancer & Skin cancer
FEBS Letters (Federation of European Biochemical Societies)
Δ9-Tetrahydrocannabinol induces apoptosis in C6 glioma cells
Δ9-Tetrahydrocannabinol (THC), the major active component of marijuana, induced apoptosis in C6.9 glioma cells, as determined by DNA fragmentation and loss of plasma membrane asymmetry. …
THC … induced apoptosis in several transformed neural cells but not in primary astrocytes or neurons. …
Results thus show that THC-induced apoptosis in glioma C6.9 cells may rely on a CB1 receptor-independent stimulation of sphingomyelin breakdown
Hypothesis: cannabinoid therapy for the treatment of gliomas?
Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer.
Current therapeutic strategies for the treatment of glioblastoma multiforme are usually ineffective or just palliative.
During the last few years, several studies have shown that cannabinoids—the active components of the plant Cannabis sativa and their derivatives—slow the growth of different types of tumours, including gliomas, in laboratory animals. Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition.
In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death.
Journal of Neuro-Oncology
Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells
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, Δ9-tetrahydrocannabinol Δ9-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy.
We discovered that Δ9-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2.
Δ9-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2.
The effects of Δ9-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation. The same concentration of Δ9-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 Δ9-THC.
Cannabinoids and Gliomas
Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances—the endocannabinoids—that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients.
In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis.
Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts.
On the basis of these preclinical findings, a pilot clinical study of Δ9-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run.
The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.
Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression
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, but the molecular targets of this cannabinoid action remain elusive.
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 …
THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression … experiments proved that down-regulation of this MMP plays a critical role in THC-mediated inhibition of cell invasion.
Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knocking-down the expression of the stress protein p8.
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.
Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosis
Gliomas, one of the most malignant forms of cancer, exhibit high resistance to conventional therapies.
Identification of the molecular mechanisms responsible for this resistance is therefore of great interest to improve the efficacy of the treatments against these tumors.
Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the ability of these compounds to induce apoptosis of tumor cells.
By analyzing the gene expression profile of two sub-clones of C6 glioma cells with different sensitivity to cannabinoid-induced apoptosis, we found a subset of genes with a marked differential expression in the two sub-clones. Furthermore, we identified the epidermal growth factor receptor ligand amphiregulin as a candidate factor to mediate the resistance of glioma cells to cannabinoid treatment. Amphiregulin was highly overexpressed in the cannabinoid-resistant cell line, both in culture and in tumor xenografts. Moreover, in vivo silencing of amphiregulin rendered the resistant tumors xenografts sensitive to cannabinoid antitumoral action.
Amphiregulin expression was associated with increased extracellular signal-regulated kinase (ERK) activation, which mediated the resistance to THC by blunting the expression of p8 and TRB3—two genes involved in cannabinoid-induced apoptosis of glioma cells.
Our findings therefore identify Amphirregulin as a factor for resistance of glioma cells to THC-induced apoptosis and contribute to unraveling the molecular bases underlying the emerging notion that targeted inhibition of the EGFR pathway can improve the efficacy of antitumoral therapies.
May – June 2010
Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas
Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer.
During the last years, several studies have demonstrated that cannabinoids induce apoptosis of glioma cells and inhibit angiogenesis of gliomas in vivo.
As the effects of cannabinoids rely on CB1 and CB2 receptors activation, the aim of the present study was to investigate both receptors protein expression in cellular membrane homogenates of human glial tumors using specific antibodies raised against these proteins. …
The present results demonstrate opposite changes in CB1 and CB2 receptor protein expression in human gliomas. These changes may be of interest for further research about the therapeutic effects of cannabinoids in glial tumors.
Molecular Cancer Therapeutics
A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma
Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease.
Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells.
Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment.
Combined administration of THC and TMZ enhanced autophagy … supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination.
Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts.
Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors.
Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM.
Child’s Nervous System (ChNS): official journal of the International Society for Pediatric Neurosugery
Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas—possible role of Cannabis inhalation
Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1).
The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression.
We report two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case.
During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period.
Neither patient received any conventional adjuvant treatment.
The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression.
We advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later.
Further research may be appropriate to elucidate the increasingly recognized effect of cannabis/cannabinoids on gliomas.
Id-1 is a Key Transcriptional Regulator of Glioblastoma Aggressiveness and a Novel Therapeutic Target
Glioblastoma (GBM) is the most common form of primary adult brain tumors.
A majority of GBMs grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable.
It is, therefore, essential to discover master regulators that control GBM invasiveness and target them therapeutically. We demonstrate here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of GBM cell lines and primary GBM cells.
Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathological grades in patient biopsies. Id-1 knockdown dramatically reduces GBM cell invasion that is accompanied by profound morphological changes and robust reduction in expression levels of “mesenchymal” markers, as well as inhibition of self-renewal potential and down-regulation of glioma stem cell markers.
Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human GBM. Furthermore, we show that a non-toxic compound, cannabidiol, significantly down-regulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal.
Additionally, cannabidiol significantly inhibits the invasion of GBM cells through an organotypic brain slice and glioma progression in vivo.
Our results suggest that Id-1 regulates multiple tumor-promoting pathways in GBM, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of GBM patients.
Δ9-Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer Cells through Cdc2 Regulation
It has been proposed that cannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation, and survival in different manners depending on the cell type and its physiopathologic context.
However, little is known about the effect of cannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that Δ9-tetrahydrocannabinol (THC), through activation of CB2 cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. …
Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC.
We also analyzed by real-time quantitative PCR the expression of CB1 and CB2 cannabinoid receptors in a series of human breast tumor and nontumor samples.
We found a correlation between CB2 expression and histologic grade of the tumors.
There was also an association between CB2 expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor …
Importantly, no significant CB2 expression was detected in nontumor breast tissue.
Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.
Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition
ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies.
Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse.
The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies.
The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors.
We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse.
We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors.
Our results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis.
Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway.
We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2.
Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.
Molecular Cancer Therapeutics
Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy
Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated.
Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation.
Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. …
We showed that CBD induces endoplasmic reticulum stress … In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells.
Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent.
Breast Cancer Research and Treatment
Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis
Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression.
Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required.
Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers.
We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity pro-file, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture.
Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells.
Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo.
We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression.
Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2.
Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis.
Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer.
The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.
Journal of Controlled Release
Poly-ε-caprolactone microspheres as a drug delivery system for cannabinoid administration: Development, characterization and in vitro evaluation of their antitumoral efficacy
Cannabinoids show promise for the treatment of various medical conditions such as emesis, anorexia, pain, cancer, multiple sclerosis, Parkinson’s disease and glaucoma.
The objective of the present work was to assess the feasibility of developing cannabinoid loaded poly-ε-caprolactone (PCL) microparticles prepared by the oil-in-water emulsion–solvent evaporation technique as a suitable dosage form for their administration.
Cannabidiol (CBD) dissolved in the polymeric matrix of the microspheres was slowly released in vitro within 10 days.
In vitro cell viability studies demonstrated the antitumoral activity of CBD released from microparticles.
After 4 and 7 days of incubation, CBD in microspheres significantly inhibited the growth of MDA-MB-231 cells by 60% as compared to the 50% attained with free drug.
The results suggest that PCL microparticles could be an alternative delivery system for long-term cannabinoid administration, showing potential therapeutic advantages over free drug.
November 15, 2012
Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration
Cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, has been reported to possess diverse biological activities, including anti-proliferative effect on cancer cells.
Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), few studies have investigated whether CBDA itself is biologically active.
Results of the current investigation revealed that CBDA inhibits migration of the highly invasive MDA-MB-231 human breast cancer cells …
The data presented in this report suggest for the first time that as an active component in the cannabis plant, CBDA offers potential therapeutic modality in the abrogation of cancer cell migration, including aggressive breast cancers.
CANCER (ALL TYPES):
Journal of Molecular Medicine
Control of the cell survival/death decision by cannabinoids
Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral 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 in recent years.
One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells.
The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined.
Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage.
In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo.
Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation.
Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis.
The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson’s disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors.
Pharmacology & Therapeutics
Cannabinoids and cell fate
Cannabinoids recently have been shown to control the cell survival/death decision.
Thus, cannabinoids induce growth arrest or apoptosis in a number of transformed neural and non-neural cells in culture. In addition, cannabinoid administration induces regression of malignant gliomas in rodents by a mechanism that may involve sustained ceramide generation and extracellular signal-regulated kinase activation.
In contrast, most of the experimental evidence indicates that cannabinoids may protect normal neurons from toxic insults, such as glutamatergic overstimulation, ischaemia, and oxidative damage.
Regarding immune cells, low doses of cannabinoids may enhance proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis.
The potential therapeutic applications of these findings are discussed.
Mini-Reviews in Medicinal Chemistry
Involvement of Cannabinoids in Cellular Proliferation
The endogenous canabinoid system (ECS) is involved in the regulation of an important number of central and peripheral physiological effects.
Among all these functions, the control of the cellular proliferation has become a focus of major attention as opening new therapeutic possibilities for the use of cannabinoids as potential antitumor agents.
The capacity of endogenous and synthetic cannabinoids to induce apoptosis of different tumoral cells in culture and in vivo, the mechanism underlying and the potential therapeutic applications are discussed in this review.
Harm Reduction Journal
Cannabis and tobacco smoke are not equally carcinogenic
More people are using the cannabis plant as modern basic and clinical science reaffirms and extends its medicinal uses. Concomitantly, concern and opposition to smoked medicine has occurred, in part due to the known carcinogenic consequences of smoking tobacco.
While chemically very similar, there are fundamental differences in the pharmacological properties between cannabis and tobacco smoke. Cannabis smoke contains cannabinoids whereas tobacco smoke contains nicotine.
Available scientific data, that examines the carcinogenic properties of inhaling smoke and its biological consequences, suggests reasons why tobacco smoke, but not cannabis smoke, may result in lung cancer.
Handbook of Experimental Pharmacology
Effects on cell viability
Cannabinoids are known to control the cell survival/death decision, leading to different outcomes that depend on the nature of the target cell and its proliferative or differentiation status.
Cannabinoids induce growth arrest or apoptosis in a number of transformed cells in culture. They do so by modulating key cell signalling pathways involved in the control of tumour cell fate.
The best-characterised example is cannabinoid-induced apoptosis of glioma cells, which occurs via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition.
In addition, cannabinoid administration inhibits the angiogenesis and slows the growth of different types of tumours in laboratory animals. By contrast, most of the experimental evidence indicates that cannabinoids protect normal neurons and glial cells from apoptosis as induced by toxic insults such as glutamatergic overstimulation, ischaemia and oxidative damage.
It is therefore very likely that cannabinoids regulate cell survival and cell death pathways differently in tumour and non-tumour cells.
Regarding immune cells, cannabinoids affect proliferation and survival in a complex and still obscure manner that depends on the experimental setting.
The findings reviewed here might set the basis for the use of cannabinoids in the treatment of cancer and neurodegenerative diseases.
Journal of Pain and Symptom Management
Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain
This study compared the efficacy of a tetrahydrocannabinol: cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer.
In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial.
Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59).
The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo … whereas the THC group showed a nonsignificant change. Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]).
The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. …
This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.
British Journal of Pharmacology
The endocannabinoid system and cancer: therapeutic implication
The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others).
The main active ingredient of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), produces its effects through activation of CB1 and CB2 receptors.
CB1 receptors are expressed at high levels in the central nervous system (CNS), whereas CB2 receptors are concentrated predominantly, although not exclusively, in cells of the immune system.
Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors.
The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer.
This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems.
The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed.
Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients.
In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted.
The Journal of Pain: Official Journal of the American Pain Society
Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial
Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge.
Nabiximols (Nabiximols is the US Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, UK], which does not yet have an INN), a novel cannabinoid formulation, is undergoing investigation as add-on therapy for this population.
In a randomized, double-blind, placebo-controlled, graded-dose study, patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose (1–4 sprays/day), medium dose (6–10 sprays/day), or high dose (11–16 sprays/day). Average pain, worst pain and sleep disruption were measured daily during 5 weeks of treatment; other questionnaires measured quality of life and mood.
A total of 360 patients were randomized; 263 completed… A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall … and specifically in the low-dose … and medium-dose … groups. …
Adverse events were dose-related and only the high-dose group compared unfavorably with placebo.
This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials.Nabiximols, a novel cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain.
Journal of Molecular Medicine
Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer
Colon cancer affects millions of individuals in Western countries.
Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis.
Thus, we investigated its possible chemopreventive effect in the model of colon cancer …
Cannabidiol-reduced ACF, polyps and tumours …
In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation …
It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.
Cell Death & Differentiation
Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide.
When these tumors are in advanced stages, few therapeutic options are available.Therefor, it is essential to search for new treatments to fight this disease.
In this study, we investigated the effects of cannabinoids – a novel family of potential anticancer agents – on the growth of HCC.
We found that Δ9-tetrahydrocannabinol (Δ9-THC, the main active component of Cannabis sativa) … reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB2 receptor. …
In vivo studies revealed that Δ9-THC … reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically or pharmacologically inhibited in those tumors.
Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC.
Cannabinoids Inhibit Cellular Respiration of Human Oral Cancer Cells
The primary cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-tetrahydrocannabinol (Δ8-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on … human oral cancer cells. … This epithelial cell line … is highly resistant to anticancer drugs. …
A rapid decline in the rate of respiration was observed when Δ9-THC or Δ8-THC was added to the cells. The inhibition was concentration-dependent, and Δ9-THC was the more potent of the two compounds.
Conclusions and Implications:
These results show the cannabinoids are potent inhibitors of … cellular respiration and are toxic to this highly malignant tumor.
Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes
Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease.
The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer.
We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue…. cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. …
Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells.
Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue.
In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress–related genes …
These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.
FEBS Letters (Federation of European Biochemical Societies)
Δ9-Tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism
The effect of Δ9-tetrahydrocannabinol (THC), the major psycho-active component of marijuana, in human prostate cancer cells PC-3 was investigated.
THC caused apoptosis in a dose-dependent manner. Morphological and biochemical changes induced by THC in prostate PC-3 cells shared the characteristics of an apoptotic phenomenon.
First, loss of plasma membrane asymmetry … Second, presence of apoptotic bodies and nuclear fragmentation …
Third, presence of typical ‘ladder-patterned’ DNA fragmentation.
Central cannabinoid receptor expression was observed in PC-3 cells … However, several results indicated that the apoptotic effect was cannabinoid receptor-independent …
British Journal of Cancer
Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2
We have previously shown that cannabinoids induce growth inhibition and apoptosis in prostate cancer PC-3 cells, which express high levels of cannabinoid receptor types 1 and 2 (CB1 and CB2).
In this study, we investigated the role of CB2 receptor in the anti-proliferative action of cannabinoids and the signal transduction triggered by receptor ligation.
The human prostate cancer cell lines … were used for this study. Cell proliferation was measured … In vivo studies were conducted by the induction of prostate xenograft tumours in nude mice.
We found that the anandamide analogue … as well as JWH-015, a synthetic CB2 agonist, exerted anti-proliferative effects in PC-3 cells. …Downregulation of CB2 expression reversed the effects of JWH-015, confirming the involvement of CB2 in the pro-apoptotic effect of cannabinoids.
Further analysing the mechanism of JWH-015-induced cell growth inhibition, we found that JWH-015 triggered a de novo synthesis of ceramide, which was involved in cannabinoid-induced cell death …
In vivo treatment with JWH-015 caused a significant reduction in tumour growth in mice.
This study defines the involvement of CB2-mediated signalling in the in vivo and in vitro growth inhibition of prostate cancer cells and suggests that CB2 agonists have potential therapeutic interest and deserve to be explored in the management of prostate cancer.
The Journal of Clinical Investigation
Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors
Nonmelanoma skin cancer is one of the most common malignancies in humans.
Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB1 and CB2), we studied the potential utility of these compounds in anti–skin tumor therapy.
Here we show that the CB1 and the CB2 receptor are expressed in normal skin and skin tumors of mice and humans.
In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected.
Local administration of the mixed CB1/CB2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells.
This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors … These results support a new therapeutic approach for the treatment of skin tumors.
Cancer Prevention Research
A Population-Based Case-Control Study of Marijuana Use and Head and Neck Squamous Cell Carcinoma
Cannabinoids, constituents of marijuana smoke, have been recognized to have potential antitumor properties. However, the epidemiologic evidence addressing the relationship between marijuana use and the induction of head and neck squamous cell carcinoma (HNSCC) is inconsistent and conflicting.
Cases (n = 434) were patients with incident HNSCC disease from nine medical facilities in the Greater Boston, MA area between December 1999 and December 2003. Controls (n = 547) were frequency matched to cases on age (±3 years), gender, and town of residence, randomly selected from Massachusetts town books. A questionnaire was adopted to collect information on lifetime marijuana use (decade-specific exposures) and associations evaluated …
After adjusting for potential confounders (including smoking and alcohol drinking), 10 to 20 years of marijuana use was associated with a significantly reduced risk of HNSCC [head and neck squamous cell carcinoma] …
Among marijuana users moderate weekly use was associated with reduced risk …The magnitude of reduced risk was more pronounced for those who started use at an older age … However, for the subjects who have the same level of smoking or alcohol drinking, we observed attenuated risk of HNSCC among those who use marijuana compared with those who do not.
Our study suggests that moderate marijuana use is associated with reduced risk of HNSCC [head and neck squamous cell carcinoma].
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