Table S1 CBD inhibits Id1 expression in lung metastatic foci. .. O is more active than CBD at inhibiting cell proliferation, invasion and Id1 expression. CBD was able to inhibit Id-1 expression at the mRNA and protein USA) through the National Institute of Drug Abuse, and O was obtained from Organix, Inc. . cancer metastasis that CBD was more potent than THC at inhibiting . CBD inhibits cell proliferation and invasion of 4T1 cells (mammary. A61K31/00 Medicinal preparations containing organic active ingredients 3A- C provides data indicating that CBD inhibits the expression of Id-1 gene at .. O- CBD analog is more potent than CBD at inhibiting cancer cell growth and The percentage relative proliferation/viability and invasion were calculated as.
and than inhibiting invasion expression O-1663 cell at CBD more is active proliferation, Id1
For any compound used in the method of the disclosure, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 e.
Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. Compositions and formulations of one or more compounds disclosed herein can be used in combination with THC or a THC derivative to treat a disorder or disease in a subject. Examples of such disorders or diseases which can be treated include cancer and other cell proliferative disorders, such as chronic pancreatitis, psoriasis, neoplasms, angiomas, endometriosis, obesity, age-related macular degeneration, retinopathies, restenosis, scaring, fibrogenesis, fibrosis, cardiac remodeling, pulmonary fibrosis, scleroderma, and failures resulting from myocardial infarction, keloids, fibroid tumors and stenting.
In another embodiment, a method of treating cancer in a subject comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition consisting essentially of one or more compounds disclosed herein and a pharmaceutically acceptable carrier.
In general, provided herein are methods for treating cancer by administering to a subject a therapeutically effective amount of a composition consisting essentially of a combination of one or more compounds disclosed herein and THC or a derivative of THC. Examples of THC derivatives, includes, but are not limited to: The methods include using a pharmaceutical composition that includes a combination of one or more compounds disclosed herein and THC or a THC derivative.
In a further embodiment, the disclosure demonstrates a role for the compounds disclosed herein, in inhibiting cell proliferation by activating CB 2 receptors. Exemplary agents include cannabinoids and derivatives arising there from, such as cannabidiol and derivatives therefrom.
While these publications provide general information about Id-1, it is understood that they do not propose or describe the methods provided herein.
In a certain embodiment, the compounds disclosed herein can be used alone or in combination with one or more additional therapeutic agents, such as THC. In a further embodiment, the compound disclosed herein can be used in combination with THC or a derivative thereof in a defined ratio based on weight. In a particular embodiment, the disclosure provides a composition for treating cancer in a subject, the composition comprising a compound disclosed herein and THC or a derivative thereof, such as tetrahydrocannabivarin THCV.
In another embodiment, the disclosure provides a method for treating a disease or disorder in a subject, such as cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound disclosed herein and THC or a THC derivative.
In another embodiment, a compound disclosed herein can be used to treat a disease or disorder that would be benefited by modulating the activity of serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors. In yet a further embodiment, a compound disclosed herein can be used to treat a disease or disorder that would be benefited by activating 5-HT receptors.
In another embodiment, a compound disclosed herein can be used as an antidepressant, anxiolytic, or neuroprotective agent. In yet a further embodiment, a compound disclosed herein, can be used to relieve convulsion, inflammation, anxiety, and nausea. In a certain embodiment, a compound disclosed herein can be used alone or combined with THC or a derivative thereof to treat a neurodegenerative disease or disorder, including, but not limited to, Alzheimer's Disease, Parkinson's Disease, age related dementia, Huntington's Disease, and amyotrophic lateral sclerosis.
In another embodiment, a compound disclosed herein can be used alone or combined with THC or a derivative thereof to treat pain or pain associated with a disease or disorder, including, but not limited to, pain associated with cancer, pain associated with arthritis, headaches, post-operative pain, fibromyalgia, and undiagnosed pain. It should be understood that the administration of an additional therapeutic agent with a compound of the disclosure encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
In addition, administration of an additional therapeutic agent in combination with a compound disclosed herein also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein. In yet a further embodiment, a compound disclosed herein can be combined with one or more classes of therapeutic agents, including, but not limited to, alkylating agents, cancer immunotherapy monoclonal antibodies, anti-metabolites, mitotic inhibitors, anti-tumor antibiotics, topoisomerase inhibitors, photosensitizers, tyrosine kinase inhibitors, anti-cancer agents, and chemotherapeutic agents.
In yet another embodiment, the additional therapeutic agent is an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, methotrexate, fluorouracil, hydroxyurea, mercaptopurine, cisplatin, daunorubicin, doxorubicin, etoposide, vinblastine, vincristine, temozolomide, and pacitaxel. In a particular embodiment, a pharmaceutical composition for treating a cell proliferative disorder includes a compound disclosed herein and one or more therapeutic agents selected from the group comprising: THC, paclitaxel, temozolomide, methotrexate, fluorouracil, hydroxyurea, mercaptopurine, cisplatin, daunorubicin, doxorubicin, etoposide, vinblastine, vincristine and pacitaxel.
For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container s comprising one of the separate elements to be used in a method described herein.
Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. For example, the container s can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container s optionally have a sterile access port for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein. A set of instructions will also typically be included.
A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.
A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. These other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' Desk Reference PDR or as otherwise determined by one of ordinary skill in the art.
On the first day of treatment the media was replaced with vehicle control or drug in RPMI and 0. The media with the appropriate compounds were replaced every 24 h. To quantify cell proliferation, the 3-[4,5-dimethylthiazolyl]-2,5-diphenyl tetrasodium bromide MTT assay was used Chemicon, Temecula, Calif.
When just the confidence limits of the IC 50 values overlapped significant differences were determined using unpaired Student's t-test. Bonferroni-Dunn post-hoc analyses were conducted when appropriate. Cells were grown in 6 well culture dishes and were treated with compounds of the disclosure every 24 hours for three days.
The labeled cells were analyzed by flow cytometry. Cell Flow Cytometry in combination with PI and annexin staining was used to quantify the percentage of cells undergoing apoptosis in control and treatment groups.
PI staining was used to distinguish necrotic cells from those undergoing apoptosis. Cells were cultured and treated in 6-well dishes. After the cells were washed twice with cold PBS, lysis buffer was added. The cell lysate was collected and the protein content was determined by using Bradford reagent. After which, proteins were then electroblotted onto an Immobilon membrane Millipore, Billerica, Mass. Alternatively, the primary antibody was anti-Id-1 and an appropriate secondary antibody was used.
Band intensity values were obtained after background subtraction directly from the Fluorchem using AlphaeaseFC software San Leandro, Calif. As a normalization control for loading, blots were stripped and re-probed with mouse alpha-tubulin Abcam, Cambridge, Mass.
On the third day, the cells were harvested and centrifuged at rpm for 5 minutes. The pellet was re-suspended in 0. The next day the cells were pelleted and re-suspended in 0. The cells were finally suspended in PBS 0. U cells were plated onto 6 well dishes and received drug treatments for three days. The next day, the cells were trypsinized, washed with PBS, and the fluorescent intensity was measured using a FACS and cell quest pro software. Lysed cells were centrifuged and supernatants harvested.
In this model, cancer cells have direct access to the blood stream resulting in a significant enhancement of lung metastasis and reduced variability in the number of metastases formed as compared to orthotopic models. Two days after i. Multiple viability assays in a 96 well format were run for each compound and the average percent inhibition of cell viability was calculated and transformed to fraction affected Fa i.
The rank order of potencies for the antiproliferative effects of the cannabinoids in MDA-MB cells was: The data demonstrates that cannabidiol CBD is an effective inhibitor of human breast cancer cell aggressiveness, invasiveness, and therefore metastasis. Invasion is an important step towards breast cancer cell metastasis. Therefore, the effects of several cannabinoids were tested on their ability to modulate the migratory and invasiveness activity of the most aggressive human breast cancer cell line, MDA-MB, in a reconstituted basement membrane in a Boyden chamber.
All three compounds tested, i. As was observed with the cell aggressiveness and invasiveness experiments, the most potent inhibitor out of the group of compounds, e. The ability of CBD to regulate the expression of key genes that control breast cancer cell aggressiveness and invasiveness was determined. A potential candidate protein that could mediate the effects of CBD on both phenotypes was the helix-loop-helix protein Id The compounds used included: The data demonstrates that CBD is an effective inhibitor of Id It also appears that the opened tetrahydropyran ring in CBD is only partially responsible for its activity, since Abn-CBD and did not inhibit Id One potential key structure is the classical cannabinoid aliphatic side chain: CP55, has an opened tetrahydropyran ring similar to CBD.
The data suggests that a general structural component of CBD, responsible for Id-1 inhibition, is the combination of the opened tetrahydropyran ring and the classical cannabinoid aliphatic side chain. The ectopic Id-1 gene, which is not under the control of the endogenous promoter, was introduced in the cells using the pLXSN retroviral vector.
Western blotting confirmed the down-regulation of Id-1 expression in this control cell line FIG. To determine if this effect was due to the inhibition of transcription, a construct was used that contained the Id-1 promoter fused to a luciferase reporter in a PGL-3 basic vector.
Treatment with CBD resulted in a significant inhibition of luciferase activity. This effect was time-dependent with the greatest inhibition occurring on day 3. These findings correlated to the data obtained when the expression of the Id-1 protein was assessed by Western analysis. While CBD has been shown to inhibit breast cancer metastasis in vivo, pharmacological analysis to determine potency and efficacy has not performed.
The 4T1 intravenous i. In comparison to orthotopic models, when 4T1 cells are injected i. This model is therefore highly suited for the analysis of drug potency and efficacy, including the assessment of survival. One day after i. Based on the robust inhibition of lung tumor formation produced by CBD, it was predicted that treatment with the drug would increase survival in tumor bearing mice. A survival study was carried out FIG. Id-1 was a key factor whose expression needed to be down-regulated in order to observe the effects of CBD on the reduction of breast cancer cell aggressiveness in vitro.
Treatment with CBD produced a significant down-regulation of Id-1 expression; CBD also produced a significant down-regulation of Ki67 demonstrating its ability to reduce tumor cell proliferation in metastatic foci FIG.
Immunohistochemical detection of Id-1 and Ki67 was performed in lung tissues of vehicle and CBD treated mice. Nuclei were stained with hematoxylin. The intensity of the immunohistochemical IHC detection of Id-1 was then graded from 0 to 4. It was found that CBD treated cells had significantly higher amounts of grade 0, grade 1, grade 2 cells, while vehicle had higher amounts of grade 3 and grade 4 cells FIG. When the data was presented as a statistical analysis, CBD treated cells averaged around 1 and vehicle treated cells averaged around 2.
The percentage of Ki67 positive cells per lung metastatic foci was then evaluated. This suggested the compound could be effective at inhibiting the growth of secondary tumors even after their initial establishment in lung. To determine whether CBD could inhibit the formation of lung tumor foci in more advanced stages of metastasis, mice were treated at a time point where visual lung metastatic foci were already formed as shown at day seven in FIG.
Mice were injected i. The mice were then treated with CBD. CBD dose-dependently reduced the growth of established lung metastatic foci and reduced the formation of new metastatic foci FIG.
The compounds of the disclosure were effective in inhibiting tumor formation in an in-vivo model. It was found that mice treated with CBD showed a significant reduction in the number of lung metastatic foci in comparison to mice treated with vehicle alone.
Visible lung metastases were then counted and measured by using a dissecting microscope. CBD was found to inhibit the formation of metastatic foci in later stages of metastatic progression in mice which were injected with 4T1 cells. As 1 mm 3 tumors were first detected using a dissecting scope on day 7 FIG. It was found that CBD can enhance the ability of Paclitaxel to inhibit the viability of 4T1 breast cancer cells. The inhibitory values from the concentration response curves were then used to calculate combination index CI values at multiple combination ratios FIG.
From which, the data was also used to calculate i IC50 values, the slope of the curve m and a goodness of fit value r. Quantitative Western analysis was performed to examine whether CBD would downregulate Id-1 protein expression in cell lines for breast, prostate, salivary gland, head and neck, and glioblastoma cell lines.
It was determined that treatment of cells with CBD 1. Two commonly used CB 1 and CB 2 receptors agonists were chosen to study the effect of cannabinoid treatment on the growth of three human glioblastoma multiforme GBM cell lines. The IC 50 value was 0. IC 50 values are reported in pM. Treatment periods were shortened to three days during experiments with additional agonists since significant effect were observed at this time point.
Three groups of cannabinoid compounds were chosen for a broader analysis of antiproliferative activity in the single GBM cell line, SF SF cells were treated with a range of concentrations of multiple cannabinoid agonists, and the corresponding IC 50 values were calculated.
Cell proliferation was assessed using the MTT assay. The rank order of potencies was: Again, CBD was one of the most potent compounds tested. Invasion is also an important step towards brain cancer progression. The disclosure also provides methods and compositions for the treatment of brain cancer progression. Therefore, the ability of CBD to reduce the growth and invasiveness activity of glioblastoma muliforme GBM cancer cells was tested.
Multiple glioblastoma muliforme GBM cell lines were treated for three days. CBD was also able to significantly reduce the invasiveness of U cells.
To determine whether CBD could inhibit GBM cell invasion through intact brain tissue, an organotypic brain slice assay was utilized. On the third day, the cells were harvested and transferred to the top of a 0.
After three days, GFP-labeled cells that successfully invaded through the slice are visualized using an inverted microscope and we found that CBD was highly effective at inhibiting invasion of U cells through the organotypic brain slice FIG.
In one of the five mice treated with CBD, no tumor cells were observed in any of the brain regions analyzed. Id-1 gene expression was downregulated in all cell lines FIG. From which, the data was also used to calculate i IC 50 values, the slope of the curve m and a goodness of fit value r. In addition to uncontrolled cell growth, a hallmark phenotype of aggressive GBM tumor cells is their ability to migrate away for the primary tumor of origin and invade into neighboring CNS tissue. Non-psychoactive cannabinoids, compounds that do not interact efficiently with CB 1 and CB 2 receptors, can modulate the actions of THC.
The inhibitory properties of the combination were the result of activation of CB 2 receptors and a corresponding increase in oxygen radical formation. The signal transduction mechanisms associated with the effects of the combination treatment were different from those observed with the individual compounds.
The most pronounced synergistic activity was observed with U cells, therefore, this cell lines was used to determine the mechanism of action for the combination effect.
It has been suggested that non-psychoactive cannabinoid constituents can either potentiate or inhibit the actions of THC.
The disclosure demonstrates that of the non-psychoactive cannabinoids, CBD is a far superior inhibitor of GBM cell growth. Significant reductions in ERK activity have been shown to lead to induction of apoptosis. The large reduction in GBM cell growth and ERK activity, observed in the presence of the combination treatment of THC and CBD, suggested there would be a corresponding modulation of the cell cycle and programmed cell death.
When administered separately, THC 1. Albeit, the magnitude of these effects was reduced compared to those observed with the combination treatment. Caspases play a primary role in the regulation of programmed cell death. Therefore, multiple caspase pathways were evaluated to determine mechanisms by which the combination treatment increased apoptosis. The concentrations of the individual cannabinoids THC and CBD were next increased in order to attempt to match levels of apoptosis produced by the combination treatment.
The purpose of these experiments was to determine whether the compounds alone recruited similar pathways as compared to the combination of THC and CBD. This finding was not simply an issue of the treatment concentration used since continuing to increase levels of THC did not produce a greater induction of apoptosis.
Again, the combination treatment produced a profound down regulation of p-ERK. A wide range of cannabinoids inhibit the proliferation of human GBM cells. Overall, CBD was the most potent inhibitor tested. This synergistic activity occurred in two of three GBM cell lines tested.
The synergistic inhibition of GBM cell growth was in part the result of a greater amount of apoptosis being produced in presence of the combination compared to administration of THC alone.
The reduction of ERK activity was specific for the combination treatment indicating that all the effects observed were not simply due to an increase in potency of THC upon co-application with CBD. The specific reduction in ERK activity, observed in the presence of the combination treatment, may be one of the primary mechanisms leading to the synergistic increase in inhibition of GBM cell growth and the induction of apoptosis.
THC was also effective at inhibiting the invasiveness of U cells. However, there was no suggestion of a synergistic interaction upon addition of CBD. The disclosure demonstrates that the synergistic inhibitory effects of combination treatment are the result of CB 2 receptor activation and production of oxygen radicals.
Depending on the cancer cell line and compound used, studies have linked the inhibitory activity of cannabinoids to activation of CB 1 , CB 2 , vanilloid VR1 receptors, and the production of oxygen radicals. Importantly, the induction of apoptosis in the presence of the combination treatment was significantly greater than that observed with THC alone.
Apoptosis produced by the combination of THC and CBD was greatly dependent on the production of oxidative stress and resulted in the activation of both extrinsic and extrinsic caspase pathways. The data presented here show that the synergistic activity of the combination treatment is due in part to a specific convergence of distinct pathways controlled by the individual compounds.
Combinations, compared to individual drug treatments with specific cannabinoid-based compounds may represent a significant improvement for the treatment of patients with GBM.
These synergistic effects may also be present in additional cancers. With the discovery of a specific molecular mechanism potentially explaining the synergistic effects, additional combination treatments may able to be refined in order to further improve antitumor activity.
The previous data suggest key structural requirements of CBD impart the ability to inhibit Id-1 expression. It was also shown that classical CB 1 and CB 2 receptor agonists e. THC do not target Id CB 2 selective cannabinoid agonists, having limited activity at CB 1 receptors psychoactivity , but sharing structural similarities with CBD were developed to modulate Id-1 expression more effectively than CBD.
Moreover, these novel CBD based analogs would not only effectively target Id-1 but would also have the advantage of targeting two distinct cannabinoid antitumor pathways leading to enhanced antitumor activity. In the first screen, a candidate compound O was found to be as potent as CBD.
In the second screen, a candidate compound O was found to be 2. The structure of O and O are almost identical with the exception of one R group.
Breast Cancer Res Treat. Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Int J Biol Sci. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol.
On the effects of CP and other cannabinoid receptor agonists in C6 and U cell lines. O, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms. Anticancer activity of anandamide in human cutaneous melanoma cells. Combined antiproliferative effects of the aminoalkylindole WIN55, and radiation in breast cancer cells. J Pharmacol Exp Ther. Hu T, Li C. Role of human epidermal growth factor receptor 2 in gastric cancer: Tumour cannabinoid CB 1 receptor and phosphorylated epidermal growth factor receptor expression are additive prognostic markers for prostate cancer.
The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Maycotte P, Thorburn A. Autophagy and cancer therapy. Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin A and gemcitabine. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: Gene network exploration of crosstalk between apoptosis and autophagy in chronic myelogenous leukemia.
Nat Rev Mol Cell Biol. The mammalian unfolded protein response. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death. Matrix metalloproteinases in stem cell regulation and cancer. Matrix metalloproteinase 9 expression and prognosis in colorectal cancer: Prognostic significance of matrix metalloproteinase-2 in gynecological cancer: Prognostic value of matrix metalloproteinase 9 expression in breast cancer patients: Asian Pac J Cancer Prev.
Prognostic significance of MMP-7 expression in colorectal cancer: Antiangiogenic activity of the endocannabinoid anandamide: Cannabidiol inhibits angiogenesis by multiple mechanisms. Cannabinoids inhibit angiogenic capacities of endothelial cells via release of tissue inhibitor of matrix metalloproteinases-1 from lung cancer cells. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule Ramer R, Hinz B.
Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases Decrease in ICAM-1 expression on gastric cancer cells is correlated with lymph node metastasis.
Expression of intercellular adhesion molecule-1 and prognosis in colorectal cancer. Enhanced expression of ICAM-1 in a murine fibrosarcoma reduces tumor growth rate. Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM Int J Biochem Cell Biol.
Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. ID1 promotes breast cancer metastasis by SA9 regulation. Inhibitor of differentiation 4 ID4: Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis.
J Biochem Mol Biol. TRPV1 mediates cellular uptake of anandamide and thus promotes endothelial cell proliferation and network-formation. AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma.
A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. CCL3-CCR5 axis regulates intratumoral accumulation of leukocytes and fibroblasts and promotes angiogenesis in murine lung metastasis process. Cannabinoid receptor as a novel target for the treatment of prostate cancer.
Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma.
Cannabinoid CB1 receptor is expressed in chromophobe renal cell carcinoma and renal oncocytoma. Cannabinoid CB1 receptor is downregulated in clear cell renal cell carcinoma. Cannabinoids receptor type 2, CB2, expression correlates with human colon cancer progression and predicts patient survival.
Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Inhibition of glioma growth in vivo by selective activation of the CB 2 cannabinoid receptor. Distinctive pattern of cannabinoid receptor type II CB2 expression in adult and pediatric brain tumors. Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas. Association between cannabinoid CB 1 receptor expression and Akt signalling in prostate cancer. High tumour cannabinoid CB1 receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer.
Expression of the cannabinoid type I receptor and prognosis following surgery in colorectal cancer. Expression and functional relevance of cannabinoid receptor 1 in Hodgkin lymphoma.
CB2 receptor activation inhibits melanoma cell transmigration through the blood-brain barrier. Int J Mol Sci. Cannabinoid receptor-2 immunoreactivity is associated with survival in squamous cell carcinoma of the head and neck. Br J Oral Maxillofac Surg. Deltatetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. Alteration of endocannabinoid system in human gliomas. Cannabinoid receptor type 1 immunoreactivity and disease severity in human epithelial ovarian tumors.
Am J Obstet Gynecol. Bagavandoss P, Grimshaw S. Temporal and spatial distribution of the cannabinoid receptors CB1, CB2 and fatty acid amide hydroxylase in the rat ovary. Localisation and function of the endocannabinoid system in the human ovary. Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: J Exp Clin Cancer Res. Overexpression of Snail induces epithelial—mesenchymal transition and a cancer stem cell—like phenotype in human colorectal cancer cells.
Snail and slug mediate radioresistance and chemoresistance by antagonizing pmediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. 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 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.
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. 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. 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. We investigated the antitumor activities of other plant cannabinoids, i. 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 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. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.
Molecular Cancer Therapeutics November 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.
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.
It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells. 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. 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 These results were confirmed in vivo in various mouse model systems. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis. 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: We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors.
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. Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer. 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.
US20130209483A1 - Cannabidinoid derivatives - Google Patents
5A-C demonstrates that CBD decreases Id-1 expression and Ki staining .. more potent than CBD at inhibiting cancer cell growth and invasion, and Id-1 (B ) MDA-MB cells were treated with CBD or O CBD Supplementary active compounds can also be incorporated into the compositions. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to the active components of marijuana and their derivatives, inhibit cell cycle . We show that CBD inhibits human breast cancer cell proliferation and invasion . Conclusions and implications: O prolonged survival in advanced. is given in repeated doses to increase cell proliferation and induce subsequent BRAIN CANCER. It is estimated that more than 23, individuals will be newly .. O , , 10 mg/kg. CBD; mg/kg. O (i.p.). Decreased tumor .. that CBD inhibited Id-1 expression which occurred coincident.