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An inhibition of autophagy prevents apoptosis induced by cannabinoids, while an inhibition of apoptosis prevents only cell death but not the autophagy 39 , 41 , 42 , It has been shown that cannabinoids induce process of autophagy in cancer cell lines such as glioma, melanoma, hepatic, and pancreatic cancer 39 , 41 , 42 , Moreover, some additional mechanisms have been demonstrated to contribute to the process of an induction of cell death by cannabinoids in certain cell lines.
Similar results have been obtained in prostate carcinoma cells Table S1 Cannabinoids devoid of psychoactive properties also exhibit anticancer potential. They do not affect CB receptors directly and their exact mechanism of action is still not fully elucidated.
Another interesting explanation is that CBD can prevent the degradation of anandamide AEA and subsequently leads to increased endocannabinoid concentration by acting as an inhibitor of fatty acid amide hydrolase FAAH 52 , This notion raises the possibility that the observed actions of CBD can be, in fact, partially the result of an elevated level of AEA.
These observations are in line with the described earlier relations between endocannabinoids and cancer development. Most of the research implicates that the action of CBD and other cannabinoids devoid of psychoactive properties is not linked to a direct activation of the CB receptors.
However, there are reports suggesting that CBD can induce apoptosis in cancer cells partially via direct or indirect activation of CB2 receptor Recent studies have shown that CBD reduces cancer cell viability in many cancer types such as neuroblastoma, glioblastoma, melanoma, leukemia, colorectal, breast, lung, or prostate cancer Table S1 41 , 50 , 51 , 54 , 56 , 57 , 58 , The mechanism of the immunomodulatory effects of cannabinoids is still not fully elucidated.
Research has been focused mainly on the CB2 receptor, mostly due to its expression primarily in cells of the immune system. CB1 receptors have been noticed in the T lymphocytes and it is proposed that their activation may be connected with the cytokine biasing induced by cannabinoids The highest level of CB2 expression has been observed in B cells, followed by NK cells, monocytes, polymorphonuclear neutrophils, and T cells It has been shown that the expression level of CB2 correlates with the cell activation state and with the presence of immune modulators The immune system is postulated to be involved in the control of growth and development of many types of cancer.
One of the key regulators of the antitumor immune response is cytokines profile. It is postulated that a Th1 response is crucial for an effective immune response against many tumors Phytocannabinoids with high affinity for CB2 receptors, such as THC, exhibit modulatory effects on both cellular and humoral immunity. Nonpsychotropic cannabinoids with low affinity for CB receptors have also been proven to exhibit immunomodulatory action. Most of the studies indicate that cannabinoids exhibit immunosuppressive action The most extensively examined immunomodulatory effects of cannabinoids in context of cancer are regarding the changes in the activity of T cells.
It has also been proposed that cannabinoids can affect T cells by the induction of apoptosis 73 , Another possibility is that cannabinoids effects on immune cells are at least partially induced indirectly via other suppressive mechanisms such as release of cortisone The effects on the Th17 cells subsets have not been fully described to date. Interestingly, CB receptors seem to take part in the modulation of those phenomena Indeed, there are reports indicating the suppression of anticancer immune response by THC.
It has been demonstrated that THC suppresses host immune reactivity against cancer in murine lung cancer model Lewis lung carcinoma, 3LL and line 1 alveolar cell carcinoma L1C2 , leading to the increase in the tumor growth CB2 receptors antagonists also blocked the effects of THC administration. Similar results were obtained in the study of mouse mammary carcinoma.
It has been demonstrated that THC exposure leads to the significant increase in the 4T1 carcinoma growth and metastasis due to the inhibition of the specific antitumor immune response Observed effects were mediated by CB2 receptors It is possible that tumors originating from tissues of low CB receptors expression would be significantly less sensitive to cannabinoids anticancer action and, eventually, due to THC immunosuppressive properties, such tumors may find a favorable environment for growth and development.
It is also possible that anticancer properties of cannabinoids may be compensated by their immunosuppressive action, finally leading to promotion of the tumor growth. Chronic inflammation has been associated with the development of neoplasia; therefore, reducing inflammation may, to some extent, contribute to the prevention of carcinogenesis.
Viability of noncancerous cells seems to remain unchanged or sometimes even elevated by cannabinoids 34 , 35 , 36 , 39 , On the other hand, cannabinoids can trigger apoptotic cell death in some types of nontransformed cells, especially those of high proliferative properties such as endothelial cells The cellular response to cannabinoids relies on different mechanisms in cancerous and noncancerous cells.
It has been demonstrated in vitro that cannabinoids can exhibit a stimulatory activity in nanomolar concentration and an inhibitory activity in micromolar concentration biphasic response , which significantly exceeds concentrations usually detected in blood of marijuana smokers Concentration of THC used in described experiment corresponded to its serum concentration obtained by smoking or oral administration of THC Besides the above described proapoptotic effect in cancer cells, cannabinoids exhibit some other important and potentially valuable properties.
It has been demonstrated that they can inhibit angiogenesis by blocking an activation of the vascular endothelial growth factor VEGF pathway.
Cannabinoids have also been shown to reduce spontaneous and induced metastases in animal models and to inhibit an invasiveness of cancer cells in vitro breast, lung, cervical cancer, and glioma 86 , 87 , 88 , 89 , These effects are partially connected with a modulation of the activity of extracellular proteases and their inhibitors 86 , The pharmacological inhibition of ceramide biosynthesis and the expression of p8 protein lead to the prevention of the mentioned effects The studies conducted to date indicate that antiangiogenic and antimetastatic characteristics of CB receptor agonists, similar to their antiproliferative effects, rely on the stimulation of ceramide biosynthesis and a modulation of pathways involving p8 protein.
Cannabinoids that are not agonists of CB receptors CBD , have also been shown to exhibit such properties. Increased levels of FAAH substrates e. Data collected to date regarding anticancer effects of cannabinoids are almost completely limited to preclinical studies conducted on cell lines and animal models. The first experiment that was conducted on human subjects was a pilot clinical study on nine terminal patients with recurrent glioblastoma who were resistant to the standard therapy Patients received THC intratumorally.
This way of administration was safe and patients did not exhibit any overt psychoactive effects. In some patients the tumor growth rate decreased. Changes observed upon THC administration in two patients can be connected with anticancer effect of THC according to previous preclinical studies decreased cell proliferation, occurrence of apoptosis Despite these interesting observations, it is not possible to draw significant conclusions from the study on a group of nine.
This shows a need for further clinical trials, which could help to assess the dosage and the potential interaction of cannabinoids with other substances. These studies are currently ongoing or have ended recently, but the results have not been published to date. Cannabis plants produce a substantial amount of cannabinoids and other secondary metabolites.
It has been demonstrated that extracts of Cannabis exhibit stronger effects on the subjects with spasticity than pure THC Some cannabinoids have been demonstrated to attenuate psychoactive effects of THC or smoked marijuana 13 , Pure cannabinoids are more convenient for study and to a subsequent standardization as a medical preparation, but still Cannabis extracts with specified amounts of cannabinoids seem to be valuable aim for further studies, also as potential anticancer agents.
An interesting idea is a combination of cannabinoids with conventional anticancer drugs, which can exhibit synergistic potential. The promising results from studies on animal models of glioblastoma treated with THC and temozolomide have led to, mentioned above, clinical trial of this chemotherapeutic agent and Sativex 94 , Similar observations from the study on pancreatic adenocarcinoma showed that gemcitabine administered with cannabinoids synergistically inhibited cancer cell growth To date, Cannabis or its preparations have found an application in a palliative medicine due to its analgesic and antiemetic effects, an attenuation of the side effects of chemotherapy or a capacity to treat spasticity in multiple sclerosis.
We are still initial stages of incorporating Cannabis products in the clinical care. There is still a lack of profound safety and efficacy clinical trials and it is very difficult or even impossible to assess the potential benefits and risk of using cannabinoids in many cases. Many aspects wait for an elucidation: The most common way of using recreational marijuana is smoking, which is unsuitable way of an administration from a medical point of view.
Another important issue is the lack of easy accessible biomarkers showing the responsiveness of patients to a cannabinoid treatment. Moreover, antitumor effects of cannabinoids have to overcome their known immunosuppressive effects which can be potentially protumorigenic.
The interactions between cannabinoids and classical cytotoxic agents have to be precisely defined. These observations lead us to the conclusion, that further profound studies are doubtlessly needed to verify the idea of introducing cannabinoids into the cancer treatment.
National Center for Biotechnology Information , U. Journal List Cancer Med v. Published online Feb Author information Article notes Copyright and License information Disclaimer. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This article has been corrected. This article has been cited by other articles in PMC. Abstract To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Introduction Nowadays, we observe an increasing public and scientific interest in the medical applications of Cannabis plants. Endocannabinoid system and cancer Despite numerous studies conducted during the last decade, there are still inconsistent data regarding the exact role of cannabinoid system in cancer development.
Open in a separate window. Cannabinoids and the immune system The mechanism of the immunomodulatory effects of cannabinoids is still not fully elucidated. Selectivity and stimulation of viability Viability of noncancerous cells seems to remain unchanged or sometimes even elevated by cannabinoids 34 , 35 , 36 , 39 , Inhibition of angiogenesis and metastasis Besides the above described proapoptotic effect in cancer cells, cannabinoids exhibit some other important and potentially valuable properties.
Anticancer effects of cannabinoids in clinical trials Data collected to date regarding anticancer effects of cannabinoids are almost completely limited to preclinical studies conducted on cell lines and animal models. There are some drugs available that are derived from cannabis, for example Sativex, used for multiple sclerosis and Nabilone, used sometimes for sickness caused by chemotherapy.
These go through the same processes as any other medicine to be licensed in the UK as a prescribable drug. There has been a lot of interest in cannabinoids. Deltatetrahydrocannabidiol and cannabidiol have been studied to see if they could have any role in the treatment of cancer. Most of the scientific research has been done in a laboratory.
Scientists have found that different cannabinoids can:. Some studies have looked at whether using cannabis may increase the risk of developing cancer. These have produced different results. Some research has shown that using cannabis may protect against cancer. But other studies have shown an increased risk of cancer. It is still unclear whether using cannabis has any anti-cancer effects.
But there is some evidence that the chemicals in cannabis might help with symptoms such as nausea and pain. But these studies have had mixed results when used in clinical trials. Because of the mixed results, the general feeling of experts is that there needs to be more research into the chemicals found in cannabis and their possible benefit.
Cannabis, particularly cannabis oil, is a popular topic. Cannabis oil is only one of a number of treatments people might come across. It can be sold in the UK as long as it is sold as a food supplement and the sellers are not making any claim about its medicinal properties. There are a number of examples where people say that using CBD oil has had a dramatic effect on their health. But these are individual stories and not based on clinical research trials.
If you are thinking of using CBD oil, we suggest you talk to your healthcare team. If you are looking for information online you want to be sure that it is accurate and up to date. You can read more about finding quality information on our website. Back to Complementary therapies explained You might be thinking about what you can do to look after yourself.
Some people find complementary therapies lift their spirits and help them relax and cope with stress. Surgery is the main treatment for brain tumours. But some tumours cannot be removed because they are too difficult to reach, or the risk of damaging the brain is too high. We want to make sure we're there when you're diagnosed, through treatment, and beyond.
Because life with cancer is still life, and we'll help you live it. What's happening near you? Find out about support groups, where to get information and how to get involved with Macmillan where you are. Share experiences and get support about any types of cancer treatment, including chemotherapy, radiotherapy, surgery, biological or hormonal therapies, transplants, and clinical trials. Thanks We rely on a number of sources to gather evidence for our information. We thank all those people who have provided expert review for the information on this page.
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The current state and future perspectives of cannabinoids in cancer biology
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