Part 2: Studies # 37 – 68:
Brain cancer, Breast cancer, Cancer (all types), Colon cancer, Leukemia, Liver cancer, Lung cancer, Pancreatic cancer, Skin cancer, Stomach cancer, Thymoma, & Thyroid cancer
Part 1: Studies #1 – 36
Part 3: Studies # 69 – 100
& Part 4: The Latest Research (2013):
Studies # 101 – 116
in the Comments below
Collected by CANNABIS CURES CANCERS!
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
Recently, cannabinoids (CBs) have been shown to possess antitumor properties.
Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines.
The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism … and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure …
We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis …
Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells.
In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.
Cellular and Molecular Life Sciences
The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells
Recently, we have shown that the non-psychoactive cannabinoid compound cannabidiol (CBD) induces apoptosis of glioma cells in vitro and tumor regression in vivo.
The present study investigated a possible involvement of caspase activation and reactive oxygen species (ROS) induction in the apoptotic effect of CBD. …
The exposure to CBD caused in glioma cells an early production of ROS …
Under the same experimental condition, CBD did not impair primary glia.
Thus, we found a different sensitivity to the anti-proliferative effect of CBD in human glioma cells and non-transformed cells that appears closely related to a selective ability of CBD in inducing ROS production and caspase activation in tumor cells.
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.
Anandamide dose-dependently inhibited the proliferation of … cells …
The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle.
… another endogenous cannabinoid … and the synthetic cannabinoid HU-210 also inhibited … cell proliferation …
These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.
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
It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells.
Here we studied the mechanism of Δ9-tetrahydrocannabinol (THC) antiproliferative action in these cells, and show that it involves the modulation of JunD, a member of the AP-1 transcription factor family.
THC activates JunD both by upregulating gene expression and by translocating the protein to the nuclear compartment, and these events are accompanied by a decrease in cell proliferation.
Of interest, neither JunD activation nor proliferation inhibition was observed in human non-tumour mammary epithelial cells exposed to THC. …
In summary, this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.
CANCER (ALL TYPES):
Prostaglandins, Leukotrienes and Essential Fatty Acids
Endocannabinoids in the immune system and cancer
The present review focuses on the role of the endogenous cannabinoid system in the modulation of immune response and control of cancer cell proliferation.
The involvement of cannabinoid receptors, endogenous ligands and enzymes for their biosynthesis and degradation, as well as of cannabinoid receptor-independent events is discussed.
The picture arising from the recent literature appears very complex, indicating that the effects elicited by the stimulation of the endocannabinoid system are strictly dependent on the specific compounds and cell types considered. …
Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors …
In conclusion, further investigations are needed to elucidate the function of endocannabinoids as immunosuppressant and antiproliferative/cytotoxic agents.
The experimental evidence reviewed in this article argues in favor of the therapeutic potential of these compounds in immune disorders and cancer.
The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells
One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs.
Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells.
By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes …
Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.
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
Cannabinoids have been recently proposed as a new family of potential antitumor agents.
The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.
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
Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer.
Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing.
In vivo, cannabinoids – via direct or indirect activation of CB1 and/or CB2 receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer.
Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.
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
Cannabinoids have been shown to inhibit the growth of a broad spectrum of tumour cells.
However, the molecular mechanisms involved in that effect have not been completely elucidated.
Here, we investigated the possible involvement of mitogen-activated protein kinases (MAPKs) in CB2 receptor-induced apoptosis of human leukaemia cells.
Results show that stimulation of the CB2 receptor leads to p38 MAPK activation …
These findings support a role for p38 MAPK in CB2 receptor-induced apoptosis of human leukaemia cells.
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
To obtain additional support for the anti-invasive action of cannabinoids, we analyzed tumor cells obtained from surgeries of patients with lung tumors.
Biopsies were taken from brain metastases of one male and one female patient …
After biopsies were taken, NSCLC diagnosis was confirmed.
… all cannabinoids tested exerted significant anti-invasive effects on primary lung tumor cells …
Cannabinoids are currently discussed as tools for new anticancer therapies.
Besides a great body of experimental evidence pointing to an antitumorigenic action by these compounds, this notion is particularly supported by the lack of severe adverse side effects of cannabinoids as compared to the generalized toxic actions of conventional chemotherapies.
Furthermore, several substantial side effects of chemotherapeutics, such as emesis and collateral toxicity on noncancerous tissues, have been demonstrated to be even attenuated on treatment with cannabinoids.
Within cannabinoid-based substances, the phytocannabinoid CBD has emerged as a particularly interesting drug due to its lack of adverse psychoactive effects, as well as its considerable antitumorigenic properties.
… To assess the efficacy of cannabinoid-based drugs as systemic anticancer strategies, clinical trials are suggested.
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.
… several observations on cancer cells which express both CB1 and CB2 receptors underline the irrelevance of CB receptor status in determining drug response …
δ9-tetrahydrocannabinol (THC)-mediated apoptosis in leukemic cell lines and in human prostate PC-3 cells was independent of the CB receptors.
Moreover, immunohistochemical and functional analyses in mouse models of glioma and skin carcinoma have shown that CBs may exert their antitumor effects by blocking the angiogenic process.
Despite the above mentioned observations, we need to be cautious when envisaging the potential clinical use of new anticancer therapies. … biological responses to CBs critically depend on drug concentration and type of cell examined.
The aim of the present study was to investigate the effect of CBs on the human pancreatic cancer cells …
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
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
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.