Studies on Cannabinoids in Cancer
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Studies on Cannabinoids in Cancer
Studies on Cannabinoids in Cancer
There is a growing amount of evidence supporting the claim that certain compounds found in Cannabis plants may inhibit tumor growth.
Overview
There have been many studies performed to determine the efficacy of cannabinoids at treating cancer tumors.
The studies have mostly been conducted on animals and in vitro, though there are an increasing amount of studies performed on human subjects.
The safest and most effective method of administration is by ingesting concentrated oils orally.
Smoking cannabis releases harmful carcinogens and tar, damaging the lungs.
Topical ointments are used by some to treat melanoma skin cancer or localized cancers.
Cannabinoids have been shown to have anti-tumor effects in four key areas:
Antimetastatic :
Cannabinoids have been shown to mitigate the spread of cancerous cells by shutting off the mitochondria in tumor cells.
Breast cancer tumors have had their growth inhibited by cannabinoids with higher CBD concentrations.
Cannabinoids have been shown to induce programmed cell death in cancerous cells while leaving healthy cells unharmed.
Synthetic cannabinoids like JWH-133 have also proven to be effective at treating human cancer cells.
Cannibinoids induce Cancer-Cell Apoptosis while Protecting Healthy Cells.
Antiangiogenic :
Prevents the formation of new blood vessels to and from the cancerous tumors.
Certain ratios 1:1 THC to CBD are more effective, for other tumors, higher CBD is more effective.
For instance, Glioma brain caner requires higher concentrations of the lipid THC, due to the fatty blood-brain barrier.
Breast Cancer may have more CBD receptors.
Decarboxylation- removing the acid group from THC-A, isolating THC can be achieved by heating up the cannabis oils.
Potentially each patient, based on their type of cancer, will require a unique ratio of cannabinoids.
Antiproliferative:
Cannabinoids may prevent the spread of cancer cells to nearby organs.
Apoptotic:
Cannabinoids have been shown to induce programmed cell death.
This is particularly important since cannabinoids are able to destroy cancer cells, instead of simply reducing or preventing the spread.
References
[1]
Citation Linkwww.ncbi.nlm.nih.govAbstract BACKGROUND AND PURPOSE: The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities.These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183).This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs.EXPERIMENTAL APPROACH: A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose.KEY RESULTS: A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells.The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds.Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoidreceptors.Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain.Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart.CONCLUSIONS AND IMPLICATIONS: These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.
Sep 7, 2016, 5:03 AM
[2]
Citation Linkwww.ncbi.nlm.nih.govAbstract 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 profile, 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.
Dec 29, 2016, 9:12 PM
[3]
Citation Linkwww.ncbi.nlm.nih.govAbstract BACKGROUND: Cannabinoids bind to cannabinoid receptors CB(1) and CB(2) and have been reported to possess anti-tumorigenic activity in various cancers.However, the mechanisms through which cannabinoids modulate tumor growth are not well known.In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB(2) may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12.This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.METHODOLOGY/PRINCIPAL FINDINGS: We observed high expression of both CB(2) and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis.We further found that CB(2)-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays.Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis.In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells.Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.CONCLUSIONS/SIGNIFICANCE: This study provides novel insights into the crosstalk between CB(2) and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis.Furthermore, these studies indicate that CB(2) receptors could be used for developing innovative therapeutic strategies against breast cancer.
Sep 13, 2016, 6:34 AM
[4]
Citation Linkjpet.aspetjournals.orgAbstract ∆9-tetrahydrocannabinol (THC) exhibits anti-tumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity.We investigated the anti-tumor 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 (IC50 between 6.0 and 10.6 μM), with significantly lower potency in non- cancer 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 subcutaneous injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells, and reduced lung metastases deriving from intra-paw injection of MDA-MB-231 cells.Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated.At least for MDA-MB- 231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: 1) direct or indirect activation of cannabinoid CB2 and vanilloid TRPV1 receptors; and 2) cannabinoid/vanilloid receptor-independent elevation of intracellular Ca2+ and reactive oxygen species.Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.
Sep 13, 2016, 6:38 AM
[5]
Citation Linkmolecular-cancer.biomedcentral.comBackground 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.Results 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.Conclusions Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.
Sep 13, 2016, 6:48 AM
[6]
Citation Linkwww.ncbi.nlm.nih.govAbstract Breast cancer is a very common disease that affects approximately 1 in 10 women at some point in their lives.Importantly, breast cancer cannot be considered a single disease as it is characterized by distinct pathological and molecular subtypes that are treated with different therapies and have diverse clinical outcomes.Although some highly successful treatments have been developed, certain breast tumors are resistant to conventional therapies and a considerable number of them relapse.Therefore, new strategies are urgently needed, and the challenge for the future will most likely be the development of individualized therapies that specifically target each patient's tumor.Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity.Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture.Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer.This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.
Sep 13, 2016, 6:49 AM
[7]
Citation Linkpnas.orgABSTRACT 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 MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 M and 83–92% maximal inhibition at 5–10 M. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 M anandamide.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.A stable analogue of anandamide (R)-methanandamide, another en- dogenous cannabinoid, 2-arachidonoylglycerol, and the syn- thetic cannabinoid HU-210 also inhibited EFM-19 cell pro- liferation, whereas arachidonic acid was much less effective.These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [3H]CP 55,940 to EFM-19 mem- branes with an order of potency identical to that observed for the inhibition of EFM-19 cell proliferation.Moreover, anan- damide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A.Cell proliferation was ar- rested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1–0.5 M) doses of anandamide.Anandamide suppressed the levels of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin- induced response, i.e., the expression of the breast cancer cell susceptibility gene brca1.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.
Sep 13, 2016, 6:50 AM
[8]
Citation Linkwww.ncbi.nlm.nih.govAbstract Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1).This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action.In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase.Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM.ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls.ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient.In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody].Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.
Sep 13, 2016, 6:53 AM
[9]
Citation Linkwww.ncbi.nlm.nih.govAbstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available.Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC.We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients.Furthermore, we have shown that the treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells.We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2.In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion.In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%).These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist-mediated effects on tumor growth and metastasis.Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2.Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity.These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.
Sep 13, 2016, 6:54 AM
[10]
Citation Linkwww.ncbi.nlm.nih.govAbstract 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 by stable transduction with antisense Id-1.It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer.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 at the promoter level.Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1.In conclusion, 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.
Dec 29, 2016, 9:13 PM
[11]
Citation Linkwww.ncbi.nlm.nih.govAbstract 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.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.
Sep 7, 2016, 5:05 AM
[12]
Citation Linkicrs.coThe International Cannabis Research Society carries out many of the studies surrounding cannabinoid efficacy at cancer treatment.
Jul 29, 2016, 10:03 PM
[13]
Citation Linkywqaugeunhowzrcj.public.blob.vercel-storage.comA graph of CBD's effectiveness at inhibiting tumor invasiveness.
Sep 7, 2016, 5:08 AM
[14]
Citation Linkywqaugeunhowzrcj.public.blob.vercel-storage.comA photograph from this study [10]
Sep 7, 2016, 5:08 AM
[15]
Citation Linklinkedin.comThe story of Donna Esposito, who cured her cancer with cannabinoids.
Jul 28, 2016, 3:54 AM
[16]
Citation Linkywqaugeunhowzrcj.public.blob.vercel-storage.comCannabinoids are Antimetastatic.
Aug 4, 2016, 3:20 AM
[17]
Citation Linkyoutube.comA video of Dr. Cristina Sanchez, of University of Madrid.
Aug 4, 2016, 3:23 AM
[18]
Citation Linkwww.ncbi.nlm.nih.govUsing the CB2 agnoist, JWH-133 (a synthetic cannabinoid), mice were injected with brain tumor glioma C6 cells and administered JWH-133.The study "showed that selective activation of the CB(2) receptor signaled apoptosis via enhanced ceramide synthesis de novo.These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects."The full version is available on this web page.
Jul 29, 2016, 10:01 PM
[19]
Citation Linkjpet.aspetjournals.org"Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines" The antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists.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.
Jul 29, 2016, 11:13 PM
[20]
Citation Linkywqaugeunhowzrcj.public.blob.vercel-storage.comAn image from the following study, published in 2003:
Jul 29, 2016, 11:49 PM