Whole or crude marijuana (including marijuana oil or hemp oil) is not that THC and other cannabinoids such as CBD slow growth and/or. Cannabis has been used medicinally for millennia, but has not been approved by the U.S. Food and Drug Administration to treat any medical. Keywords: Cancer, Cannabidiol, Cannabinoids, Cannabis, CBD, . Tumor growth rate has been observed to decrease after a reduction in the.
Growth Tumor Cannabis and Cancer
The lack of effective pain relief by prescription painkillers is leading many cancer patients to try alternative medicine, notably, marijuana. For a number of years, cancer patients have turned to marijuana to treat nausea and vomiting caused by cancer treatments or to alleviate anxiety caused by the disease. Along with the traditional mode of smoking marijuana, the online sale and marketing of marijuana ointments such as creams and oils as smoke-free alternatives are on the rise, fueled by easy access to online drug stores in social media platforms.
Many cancer sufferers prefer using these topical preparations of marijuana to smoking. Some patients believe that applying these ointments directly on the tumor site is unlikely to cause the psychiatric problems seen in marijuana smokers, such as anxiety, paranoia, delusions, and hallucination.
Some of these claims may be true, but there is no robust scientific evidence from studies carried out in humans to suggest that either topical or inhaled marijuana produce these effects in cancer patients. While these findings are encouraging, cancer patients should take these reports with a pinch of salt. Most—if not all—of these were short-term studies that were conducted in a limited number of subjects who had these chemicals administered via a different route than inhalation and at doses that contain higher amounts of CBD and THC than those found in most marijuana ointments sold online.
Some patients believe that applying these ointments directly on the tumor site is unlikely to cause the psychiatric problems seen in marijuana smokers. Numerous animal studies have shown that CBD, THC, or their combination inhibit tumor growth and reduce the risk of cancer cells spreading to distant organs. To my knowledge, none of the data to support these claims were obtained in animals that received these chemicals by topical application or inhalation.
Rather, most preclinical studies conducted in mice administer cannabinoids via injections. I would go so far as to argue that it is dangerous to think that applying marijuana cream or oil on tumors would be of any benefit in reducing chronic pain or inhibiting tumor growth. Aymen Idris on his campaign to raise awareness of the medicinal benefits and harm of marijuana among the general public and to influence politicians to support medical use of cannabis.
Marijuana as a mainstream treatment for cancer has a long way to go, but research on its medicinal benefits has been growing within the scientific community. Many companies and research laboratories, mine included, are currently testing existing and new preparations of marijuana that may one day be used in the clinic to treat cancer pain with fewer side effects than smoking or vaping marijuana.
In addition to signaling through cannabinoid receptors, cannabinoids, in particular anandamide and cannabidiol, have CB receptor-independent effects. AEA has been shown to induce neuroblastoma, lymphoma, and uterine cervix carcinoma cell death through vanilloid receptors [ 51 , 52 ]. It has also been proposed that lipid rafts, membrane domains rich in sphingolipids and cholesterol, mediate AEA effects through CB1 signaling [ 53 , 54 ].
In cholangiocarcinoma, the anti-proliferative and pro-apoptotic action of AEA is facilitated by lipid raft stabilization, ceramide accumulation, and recruitment of FAS and FAS ligand into lipid rafts [ 55 ]. Another cellular protein that may be important in CB receptor-independent cell death induced by endocannabinoids is COX In human neuroblastoma and C6 glioma cells AEA induces apoptosis through a vanilloid receptor mediated increase in intracellular calcium concentration, which activates COX-2, releases cytochrome c and activates caspase 3 [ 52 ].
An important molecule for studying cannabinoid receptor-independent effects is cannabidiol. Cannabidiol is a cannabinoid analog that has no activity at CB1 or CB2 receptors and lacks psychotropic effects. Cannabidiol has been shown to inhibit glioma and breast tumor growth in vitro and in vivo through induction of apoptosis and inhibition of cell migration and angiogenesis, with these effects being independent of CB and TRPV1 receptor activity [ 60 - 62 ].
Cannabidiol reduces the invasiveness of breast cancer cells by inhibiting Id-1, an inhibitor of basic helix-loop-helix transcription factors involved in tumor progression, at the promoter level [ 63 ]. A quinone analog of cannabidiol, HU, a highly specific inhibitor of topoisomerase II, has been reported to have high efficacy against human cancer cell lines in vitro and against tumor grafts in nude mice [ 64 ].
HU also inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and anti-angiogenic cytokines and their receptors [ 65 ]. Cannabinoids have been shown to cause cell cycle arrest in various cancer cell lines. However, CB2-selective antagonists significantly, but not totally, prevent these effects, suggesting a contribution of a CB2 receptor-independent mechanism [ 68 ]. WIN, treatment of LNCaP cells also causes a dose-dependent decrease in the expression of cyclin D1, cyclin D2 and cyclin E, as well as cdk2, cdk4 and cdk6, pRb and its molecular partner, the transcription factor E2F [ 69 ].
WIN, causes a dose-dependent decrease in the protein expression of DP-1 and DP-2, which form heterodimeric complexes with E2F essential for activity [ 69 ]. CB1 also reduces cyclic AMP-dependent protein kinase A signaling leading to down-regulation of the anti-apoptotic factor survivin [ 45 ].
Survivin over-expression is associated with poor clinical outcomes and reduced tumor apoptosis in patients with colorectal cancer [ 73 , 74 ]. Survivin is an attractive target for pharmacological modulation because it is over-expressed in most human tumors but is present in very small amounts in normal adult tissues [ 74 ]. A direct link between CB1 activation and decreased survivin expression has been established through treatment of SW cells with AM, a CB1 receptor agonist [ 19 ].
Activation of CB1 or CB2 receptors has been shown to stimulate de novo synthesis of ceramide in human tumors including glioma, leukemia, and pancreatic, and DLD-1 and HT29 colorectal cancer cells [ 75 - 77 ].
Ceramide is a pro-apoptotic lipid that causes up-regulation of the stress protein p8 and several downstream stress-related genes expressed in the endoplasmic reticulum including ATF-4, CHOP, and TRB3 [ 78 ]. In DLD-1 and HT29 colorectal cancer cells, CB1 and CB2 receptor activation leads to increased ceramide levels, whereas CB1 and CB2 receptor-induced apoptosis is prevented by the pharmacologic inhibition of de novo ceramide synthesis [ 77 ]. A role for Bcl-2 family members, such as Bad, has also been hypothesized in cannabinoid-dependent apoptosis [ 81 ].
Pro-apoptotic effects may rely also on a CB1 receptor-independent stimulation of sphingomyelin breakdown [ 84 ]. A common event in cannabinoid-induced apoptosis is the depolarization of mitochondria via cytochrome c release [ 85 - 87 ].
CB agonists have been reported to be mitochondrial inhibitors, since they decrease oxygen consumption and mitochondrial membrane potential while increasing mitochondrial hydrogen peroxide production, thus inducing apoptosis [ 88 ].
AEA inhibits breast cancer cell proliferation through down-regulation of the prolactin receptor, brca1 gene product, and the high affinity neurotrophins receptor trk [ 89 , 93 ].
The anti-proliferative effect of AEA is proportional to the degree of hormone dependency of the cell lines and the mechanism relies on the inhibition of the cAMP-dependent PKA pathway [ 93 ]. These effects are CB1-mediated [ 91 ]. Similar growth arrest and receptor modulation by AEA are observed in prolactin and nerve growth factor-stimulated DU cells [ 92 - 94 ]. Treatment of LNCaP cells with WIN, results in decreased proliferation, androgen receptor expression, VEGF protein expression, and secreted levels of PSA, a glycoprotein androgen receptor-regulated protein that is a marker of prostate cancer progression [ 46 ].
The antagonistic effect of endocannabinoids on growth factor-induced proliferation has also been reported in glioma [ 95 ]. Cannabinoids have been shown to inhibit tumor growth by lowering vascular density in tumors.
Cannabinoids cause a lower distribution of CDpositive cells, a common angiogenesis marker, in experimental tumor xenografts from glioma, melanoma and nonmelanoma skin cancer, and lung tumor cells [ 32 , 96 - 98 ]. Met-fluoro-anandamide Met-F-AEA , a metabolically stable analog of AEA, has been demonstrated to reduce the sprout number and length of endothelial cell spheroids, inhibit capillary-like tube formation in vitro , and suppress angiogenesis in an in vivo chick chorioallantoic membrane assay [ 99 ].
Furthermore, experimental tumors from animals treated with cannabinoids have been shown to exert a vascular network that is small, undifferentiated, and impermeable giving tumors a paler appearance when compared to controls [ 90 , 96 ]. In addition to the direct inhibition of vascular endothelial cell migration and survival, cannabinoids decrease the expression of proangiogenic factors in tumors.
Several studies have revealed that cannabinoids have an effect on the expression of VEGF, which is one of the major cancer cell-released chemoattractants in tumor neovascularization [ ]. JWH down-regulates connective tissue growth factor and heme oxygenase-1, genes known to be regulated by VEGF, as well as the VEGF-related factors, inhibitor of differentiation-3 Id-3 , midkine, and the angiopoietin receptor tyrosine kinase with immunoglobulin-like and epidermal growth factor EGF -like domains 1 Tie-1 [ , ].
Cannabinoids diminish the expression of angiopoietin-2 Ang-2 and placental growth factor PlGF along with the appearance of narrow capillaries and a decrease of blood vessel size [ 32 ]. JWH down-regulates Ang-2, which supports the formation of mature blood vessels, in gliomas and astrocytomas [ 96 , ].
Angiogenesis involves several proteolytic enzymes. THC down-regulates the proangiogenic factor MMP-2 in human tumor samples from recurrent glioblastoma multiforme and in nude mice xenografted with the C6. THC and methanandamide decrease MMP-2 expression in vitro in cervical cancer cells accompanied by a reduced invasiveness of the cancer cells [ 45 ]. JWH also decreases MMP-2 expression in vivo in glioma xenografts and impairs tumor vasculature [ 96 ].
The effects of cannabinoids on several antiangiogenic factors have also been studied. WIN, and JWH do not have an effect on the expression of thrombospondin-1 and -2, multidomain matrix glycoproteins that inhibit neovascularization, in nude mice xenografted with melanoma carcinoma cells [ 32 ]. The effects of cannabinoids on the expression of TIMP-1, an inhibitor of angiogenesis, are dependent on the specific cancer cell line used [ ].
In human cervical and lung cancer cells, cannabinoids up-regulate TIMP-1 expression and are anti-invasive [ 45 ]. In contrast, THC down-regulates TIMP-1 in glioma cell lines and in human tumor samples from recurrent glioblastoma multiforme patients [ ]. The cannabinoid derivative HU is antiangiogenic through a different mechanism.
HU inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without modulating the expression of pro- and antiangiogenic factors and their receptors [ 65 ]. Tumor cell migration is an important step for the spread of cancer [ ]. As an initial step, the primary tumor has to enter lymphatic or blood vessels. Migration of cancer cells is initiated by paracrine or endocrine chemoattractants but is also affected by neurotransmitters and other factors.
Among the chemoattractants that trigger migration, cell growth, proliferation, and differentiation, EGF and its receptor, EGFR, play a pivotal role. As described earlier, THC action modulates intracellular signaling events downstream of EGFR, such as inhibition of mitogen-activated protein kinases and protein kinase B Akt activity [ 98 ]. The impact of cannabinoids on EGFR activation appears to be cell type specific.
In glioma and lung carcinoma, cannabinoid receptor agonists induce cell proliferation through cannabinoid-induced EGFR signal transactivation [ ]. Human astrocytoma cells have no change in EGFR tyrosine phosphorylation when treated with cannabinoids [ ].
Neurotransmitters also play a role in regulating cell migration [ ]. Cannabinoids have an inhibitory action on norepinephrine-induced cancer cell migration [ ]. The pathways involved in CB1-receptor dependent antimigratory effects have been explored in some depth. Mast cells are a source of chemoattractants and are possible targets of cannabinoids [ ]. Cancer cell migration initiated by mast cells is down-regulated by 2-AG and WIN, in the scratch wound healing assay in a CB1-receptor dependent manner [ ].
Human glioma cell migration is inhibited by cannabidiol in a receptor-independent manner, as evidenced by the failure of cannabinoid receptor antagonists and pertussis toxin to reverse the antimigratory action of cannabidiol [ 61 ].
AM and THC do not affect the basal migration of human cervical and lung cancer cells, implicating a cell type-specific or chemoattractant-dependent regulation of migration by cannabinoids [ 45 ].
Thus, cannabinoids are antimigratory in some cancer cell lines but the underlying signaling pathways are not fully elucidated. The adhesive interaction of tumor cells with the surrounding microenvironment is a critical factor in their growth, migration and metastasis. Matrix proteins such as integrins, cadherins, selectins, and cell adhesion molecules of the immunoglobulin superfamily IgSF CAMs are integral to the adhesion of tumor cells to the extracellular matrix ECM.
Cannabinoids have been shown to have various effects on the adhesion of tumors cells to the ECM. Met-F-AEA selectively reduces the adhesion of human breast cancer cells to the ECM component collagen type IV in a CB1 receptor-dependent manner in vitro , but has no effect on adhesion to fibronectin and laminin [ ].
Met-F-AEA does not affect the expression of integrins but it does decrease their affinity for collagen through suppression of phosphorylation of the focal adhesion kinase FAK and the pro-oncogenic tyrosine kinase Src [ ]. HU does not have a direct effect on FAK phosphorylation in murine neuroblastoma cells [ ]. WIN, blocks the interleukin 1 IL-1 -induced up-regulation of intercellular cell adhesion molecule 1 and vascular cell adhesion molecule 1- two IgSF CAMs- in human glioblastoma and lymphoma cells in a cannabinoid receptor-independent manner [ ].
Cancer cell invasion is one of the crucial events in local spreading, growth, and metastasis of tumors. However, the precise mechanism leading to decreased invasiveness by cannabinoids has not been fully elucidated. Several investigations have provided insight into how cannabinoids may achieve their anti-invasive action. Cannabinoids have been shown to modulate the MMP system, which, in part, leads to their anti-invasive action.
MMPs degrade ECM components, an important function in tumor invasion, metastasis, and angiogenesis [ , ]. Cannabinoids have been shown to have a direct effect on the MMP system.
JWH decreases the expression and activity of MMP-2 in mice xenografted with a rat glioma cell line and human grade IV astrocytoma cells [ 96 ]. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion is prevented by blocking ceramide biosynthesis and by knocking down the expression of the stress protein p8 [ ].
There is a correlation between high cancer invasiveness and decreased TIMP-1 expression; in addition, the anti-invasive action of several drugs has been associated with elevated TIMP-1 levels [ - ].
In glioma cell lines and primary tumor cells from glioblastoma multiforme tissues, TIMP-1 expression is inhibited by cannabinoids [ ]. Instead, the cannabinoid-induced apoptosis is dependent on de novo synthesis of ceramide [ ]. Thus, cannabinoid action on TIMP-1 expression and the subsequent impact on tumorigenesis depends on tumor type. In vivo studies demonstrate that cannabinoids reduce tumor growth and metastasis as well as cell proliferation and angiogenesis in mice. THC decreases tumor size, number of tumor and lung metastases, and inhibits both cell proliferation and angiogenesis in an animal model of metastatic breast cancer [ ].
This inhibition of cell proliferation involves CB2 but not CB1 receptors [ ]. The CB2 agonist JWH reduces the size and number of tumors, number and size of lung metastases, inhibits cell proliferation, and decrease angiogenesis in mice injected with different breast cancer cell lines [ , ]. Cannabidiol reduces tumor growth and size and decreases the number of lung metastases in mice injected with MDA-MB or 4T1 breast cancer cell lines [ 62 , ].
AM reduces the number and size of lung tumor nodules in mice injected with TSA-1 mammary carcinoma cell line through CB1 activity [ ]. Direct injection of the preferential CB2 agonist JWH reduces tumor growth in athymic nude male mice injected with PC-3 prostate carcinoma cells and this reduction of growth is inhibited by the CB2 receptor antagonist SR [ ].
Although many studies have found beneficial effects of cannabinoids in the treatment of cancer, there are several conflicting reports. Systemic administration of THC increases the local tumor size and the number and size of metastasis in mice injected with 4T1 tumor cells into the rear footpads [ ].
This effect may be due to the fact that THC suppresses the anti-tumor immune response, which is mediated by CB2 [ ]. Cannabinoids exert a number of interesting effects that are dependent on the cell line or tumor type. Synthetic cannabinoids and the endocannabinoid system are implicated in inhibiting cancer cell proliferation and angiogenesis, reducing tumor growth and metastases, and inducing apoptosis.
Some studies suggest that abnormal regulation of the endocannabinoid system may promote cancer by fostering physiological conditions that allow cancer cells to proliferate and migrate. For this reason, the endocannabinoid is an attractive target for pharmacological intervention in the treatment of cancer. Modulation of the endocannabinoid system to treat cancer may provide a targeted treatment of cancer, which has been shown in several studies that demonstrated selective action of cannabinoids on tumor cells while not having effects on normal cells.
The complexity of the signaling pathways involved in endocannabinoid action both in normal and malignant tissues offer a significant research obstacle, however, several important pathways have been elucidated. These include modulation of pathways critical to cell proliferation, cell cycle, and apoptosis.
The diversity of receptors and signaling pathways that the endocannabinoid system modulates offers an interesting opportunity for the development of specific molecules to perturb the system selectively, as has already been achieved in the development of agonist and antagonists of the CB1, CB2, TRPV1, and GPR55 receptors.
In addition, recent work has revealed that COX-2, which is involved in the progression of several types of cancer, modulates endocannabinoid tone at sites of inflammation [ ]. The oxygenation of endocannabinoids by COX-2 or other enzymes may also play a critical role in the influence of endocannabinoids on cancer.
Although there is a strong set of data in vitro , in cellular model systems, and in mouse model systems, there is a dearth of clinical data on the effects of cannabinoids in the treatment of cancer in humans. This fact is quite surprising considering the large library of compounds that have been developed and used to study the effects of cannabinoids on cancer in model systems.
Despite the lack of preclinical and clinical data, there is a strong agreement that pharmacological targeting of the endocannabinoid system is emerging as one of the most promising new methods for reducing the progression of cancer. In particular, combination therapy utilizing both traditional chemotherapeutics and molecules targeting the endocannabinoid system may be an excellent next generation treatment for cancer.
National Center for Biotechnology Information , U. Author manuscript; available in PMC Jun 3. Hermanson and Lawrence J. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Cancer Metastasis Rev. See other articles in PMC that cite the published article. Open in a separate window. Structures of compounds used to study the endocannabinoid system. Cannabinoids and Cancer 2.
Conclusions Cannabinoids exert a number of interesting effects that are dependent on the cell line or tumor type. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Biochemistry and pharmacology of endovanilloids. The molecular logic of endocannabinoid signalling.
Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Molecular characterization of a peripheral receptor for cannabinoids. A second endogenous cannabinoid that modulates long-term potentiation.
Pathways and mechanisms of N-acylethanolamine biosynthesis: Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes.
Comparison with synthesis from free arachidonic acid and ethanolamine. Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin.
Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Molecular characterization of human and mouse fatty acid amide hydrolases.
The glyceryl ester of prostaglandin E 2 mobilizes calcium and activates signal transduction in RAW Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo. Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines.
Izzo AA, Camilleri M. Cannabinoids in intestinal inflammation and cancer. Loss of cannabinoid receptor 1 accelerates intestinal tumor growth.
The endogenous cannabinoid system protects against colonic inflammation. Targeting endocannabinoid degradation protects against experimental colitis in mice:
Opinion: Do Not Believe the Hype
The inhibition of tumor growth and progression of several types of cancers It has been shown that THC induces apoptosis in several human cancer cell lines. Cannabis and Cancer Tumor Growth. “We observed that when we treated [ astrocytoma, a type of brain tumor] cells with cannabinoids, the. CannaMD covers the landmark studies that every cancer patient needs to researchers noticed that tumor growth slowed and/or stopped.