Figure S1 CBD produces a dose-dependent reduction of metastatic spread to the Figure S6 O produces a significant inhibition of advanced stage breast CBD reduced breast cancer metastasis in advanced stages of the disease as the .. in some mice, the tumour did adapt over time and began to progress again. Advanced · Journal list · Help Keywords: Cancer, Cannabidiol, Cannabinoids, Cannabis, CBD, The activation of each of them leads to an inhibition of adenylyl to inhibit the growth of prostate cancer cells in dose‐dependent .. to be a key regulator of the metastatic potential of breast cancer In addition, the palliative effects of cannabinoids include inhibition of nausea and emesis . Endogenous cannabinoids which are produced in our body include lipid . JWH-O15 inhibits hormone sensitive breast cancer metastasis by . The submaximal doses of Δ9-THC and CBD in combination with TMZ.
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Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents. Nowadays, we observe an increasing public and scientific interest in the medical applications of Cannabis plants.
In the USA, marijuana is now allowed for medical applications in 24 states and the District of Columbia. Furthermore, during the last decade, we have collected a great pool of evidence from preclinical and clinical studies that Cannabis and cannabinoids have a therapeutic potential in many medical fields, and can even display some anticancer characteristics. This class of molecules can be divided into three main groups: Phytocannabinoids are secondary metabolites of Cannabis plants.
Action of THC in human organism relies on mimicking endogenous agonists of CB receptors—endocannabinoids 3. Another phytocannabinoid which gains medical attention is cannabidiol CBD. It has low affinity for cannabinoid receptors and acts independently of them.
They have been proposed to be classified as CB receptors, but their exact role in endocannabinoid signaling is still under discussion 3.
Endocannabinoids are part of the endocannabinoid system, which is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in their metabolism. To date, two cannabinoid receptors CB1 and CB2 have been identified in mammalian tissues 5 , 6. Its high expression has been observed in these areas of central nervous system, that are engaged in the modulation of motor behavior, memory, learning, emotions, perception, and endocrine functions 3 , 8.
CB2 receptors have been found in immune cells, but their presence was revealed also in nervous system 10 , In addition to its neuromodulatory function, endocannabinoid system has been shown to play other important functions such as control of the energy metabolism, immunity, cardiovascular tone, and reproduction 12 , According to the contribution of the endocannabinoid system in a regulation of such variety of processes, its pharmacological modulation becomes promising therapeutic strategy.
To date, cannabinoids have been exploited in the palliative medicine. Nabilone THC synthetic analogue is allowed for the treatment of nausea and vomiting induced by chemotherapy, and sleep disorders. Dronabinol synthetic THC is approved also for nausea and vomiting due to chemotherapy and for the treatment of weight loss associated with AIDS. Medical Cannabis in the form of marijuana dried flowers and leafs is illegal in the USA at the federal level according to the Controlled Substances Act as a Schedule I substance, but some states have legalized it for medical purposes Besides palliative properties of cannabinoids, it has been shown in wide range of in vitro and animal models, that they also exhibit anticancer effects 7 , 15 , 16 , Despite numerous studies conducted during the last decade, there are still inconsistent data regarding the exact role of cannabinoid system in cancer development.
The upregulated expression of CB receptors and the elevated levels of endocannabinoids have been observed in a variety of cancer cells skin, prostate, and colon cancer, hepatocellular carcinoma, endometrial sarcoma, glioblastoma multiforme, meningioma and pituitary adenoma, Hodgkin lymphoma, chemically induced hepatocarcinoma, mantel cell lymphoma , but it is not always correlated with the expression level of these receptors in tissue of origin 7 , 11 , 18 , Furthermore, concentration of endocannabinoids, expression level of their receptors, and the enzymes involved in their metabolism frequently are associated with an aggressiveness of cancer.
This implies that an overactivation of endocannabinoid system might be protumorigenic and plays an essential role in the development of cancer 20 , On the other hand, there are reports indicating that an activation of the cannabinoid receptors can impair cancer development and hence endocannabinoid signaling can be antitumorigenic.
Furthermore, it has been shown that silenced expression of CB1 receptor leads to an acceleration of intestinal adenoma growth, whereas activation of this receptor attenuates its growth in murine model The elevated level of endocannabinoids has been shown to reduce the development of precancerous lesions in mouse colon On the other hand, there are reports that have indicated that under certain circumstances, cannabinoids can be protumorigenic 31 , 32 , It has been shown that CB1 and CB2 receptor agonists stimulate apoptotic cell death in glioma cells by induction of de novo synthesis of ceramide, sphingolipid with proapoptotic activity 34 , If this response fails, ER stress can lead to activation of intrinsic apoptosis pathway The known mechanisms responsible for the induction of apoptosis by cannabinoids.
It has been demonstrated that process of autophagy is upstream of apoptosis in mechanism of cell death induced by cannabinoids. 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 Natural and synthetic cannabinoids, as well as those found endogenously, have been reported to affect the cell proliferation rate in cell lines derived from the central nervous system.
In another study that aimed to determine the possible in vitro antiproliferative effect of CBD, a non-psychoactive cannabinoid, two glioma cell lines of human origin were used U87 and U The antiproliferative effect of CBD was also shown to be correlated to induction of apoptosis. The significant antitumor activity of CBD suggested its possible application as an antineoplastic agent. A significant antitumor action in glioma xenografts was observed.
Moreover, tumours that are resistant to TMZ treatment were also shown to be responsive to the combination. This formulation also increased the autophagy and the mechanism was confirmed by pharmacological or genetic inhibition of this process, which resulted in the prevention of cell death.
When comparison of CB2 receptor expression in paraffin-embedded sections from primary brain tumours of paediatric and adult patients was made, their expression was found to be high in most glioblastomas and to correlate with tumour grade. High CB2 immunoreactivity was also observed in some benign paediatric astrocytic tumours, such as subependymal giant cell astrocytoma. Thus, these tumours might be vulnerable to cannabinoid treatment. To determine the potential of cannabinoids as a new therapeutic choice in the management of ErbB2-positive breast tumours a study was conducted by which their antitumor potential was examined in a clinically relevant model of ErbB2-driven metastatic breast cancer the MMTV-neu mouse.
A series of human breast tumours were used to analyse the expression of cannabinoid targets. A group of researchers investigated the antitumor potential of numerous plant cannabinoids i. Amongst the tested compounds, CBD was found to be the most powerful growth inhibitor in cancer cells, with IC 50 values between 6.
The researchers concluded that CBD and cannabis extract enriched in this natural cannabinoid may serve as an encouraging choice in non-psychoactive antineoplastic strategy. It inhibited cell growth as well as tumour metastasis, particularly in the case of a highly malignant human breast carcinoma cell line. The mechanism of antineoplastic action of CBD in human breast carcinoma included activation of CB2 and TRPV1 receptors and initiation of oxidative stress, all of which contribute to apoptosis induction.
In another study, the down-regulation of Id-1 in aggressive human breast cancer cells was reported with CBD and to occur in a dose-dependent fashion. The compound O was found to be the most potent of all the tested derivatives in inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. The study suggested the potential use of cannabinoids in the treatment of patients with metastatic breast cancer, and proposed a framework for using these lead compounds for the synthesis of novel cannabinoid analogs.
They also reported that these effects were produced via activation of CB2 cannabinoid receptors. Normal human mammary epithelial cells, in terms of their proliferation pattern, were less affected by the cannabinoid used, which is quite encouraging; these findings may lead to an innovative approach for the treatment of breast cancer.
CRC, also known as bowel cancer, is regarded as the third most common cancer worldwide both in men and women, with 50, deaths and , new cases estimated to have occurred in CBG is a safe and non-psychotropic cannabinoid and interacts with specific targets involved in carcinogenesis.
The effect of CBG against colon tumorigenesis was investigated by a group of researchers; mouse models of colon cancer were employed to assess the in vivo antineoplastic effect of CBG. The in vivo growth and development of colon carcinogenesis was also retarded.
The inhibitory role of CBG in tumoural cell growth has a close association to reactive oxygen species overproduction. Notably, the action against CRC cells was rather selective. CBG was hypothesized to be a worthy anti-CRC curative and preventive therapeutic agent, keeping in line with the safety profile of Cannabis -derived cannabinoids. In another study, CBD was investigated for its possible chemopreventive effect in an experimental model of colon cancer and its likely mechanism of action evaluated in CRC cell lines.
The azoxymethane AOM -induced colon cancer mouse model was used to study the effect. It was concluded from the findings that CBD exerts an in vivo chemopreventive effect and retards cell proliferation via numerous mechanisms worthy of clinical consideration in colon cancer prevention.
A study conducted on CRC investigated related expression and the underlying molecular mechanism of apoptotic activity associated with CB1 and CB2 up-regulation. The receptor expression was studied in cell lines of colon cancer DLD-1 and HT29 as well as human cancer specimens.
CB1 expression was found to be high in normal human colonic epithelium, while CB2 expression was significantly high in tumour tissue. Activation of these receptors, especially CB2 triggered apoptosis and elevated ceramide level in the cell lines investigated. Pharmacologic inhibition of new ceramide synthesis inhibited apoptosis. In another study, CBD-rich C. The results showed that proliferation in tumour cells was reduced by CBD, but it did not show a similar response in normal cells.
AOM-induced polyps, preneoplastic lesions and tumour progression in a xenograft model of colon cancer was reduced by CBD in vivo. It was, thus, concluded that CB1 and CB2 receptor activation by CBD was responsible for attenuation of colon carcinogenesis and inhibition of colorectal cancer cell proliferation. Those study results might well help in designing novel therapeutic strategies for the management of HCC.
Survival rate in lung cancer patients is low, leading to a demand for design of new approaches that will allow for better management of the disease. Cannabinoid-based antitumor therapies represent new strategies and many studies have reported their antiproliferative potential. Moreover, when studied in vivo , it resulted in suppression of subcutaneous tumour growth and metastasis in severely immunodeficient mice.
Numerous studies have reported on the antitumor potential of cannabinoids in various lymphoma tumours. Another research group reported expression of CB2 receptors after examination of numerous human leukaemia and lymphoma cell lines, including Jurkat, Molt-4 and Sup-T1. The results suggest that CB2 receptors may represent possible targets for apoptosis induction and that selective CB2 agonists bearing minimal or no psychotropic effects may serve as novel anticancer agents.
Pancreatic cancer is classified as one of the most fatal cancer types. Cannabinoid exposure has been shown to cause apoptosis of pancreatic tumour cells, and this effect was found to rely on CB2 receptor and ceramide-dependent up-regulation of the stress regulation protein p8 and ATF-4 and TRB3 stress—related genes.
Prostate cancer is amongst the most prevalent cancers diagnosed in men, and it has been quite a challenge to develop novel therapeutic strategies for its management. The results suggested the possible development of cannabinoid receptor agonists for the treatment of prostate cancer.
Another study revealed the expression of cannabinoid receptors in prostate tissue and PC-3 cells human prostate cancer cell line.
Structures of the cannabinoid analogues and synthetic cannabinoids are presented in Figure 5. Cannabinoids were used for the palliative treatment of cancer long before its medicinal use in oncology was recognized. The possible use of THC in oncology might be accompanied by certain limitations, especially its side effects at the central nervous system level, which include hallucinations, somnolence, dysphoria, abnormalities in thoughts and perception, and depersonalization.
Their development, therefore, will demand more advanced studies focusing on the underlying anticancer mechanisms as well as the pros and cons of their possible use in treating different cancer types.
A perplexing situation has arisen from reports of the cancer cell growth-stimulating properties of cannabinoids at low doses in vitro. Studies have shown that there are numerous proteins capable of existing in more than one subcellular location.
Moreover, additional activities have been reported for identical proteins found in different locations within the cell. Such differential localization profiles may be illustrative of a new mechanism through which cells can exploit a partial sum of genomic information to elicit complex behavioural and biological phenotypes. Cancer prognosis can be negatively affected by dysregulation of translocation.
Apart from change in cellular localization, the functions of such moonlighting proteins can vary based on changes in redox state of cell, oligomeric state of the protein, and temperature or variations in cellular concentration of a substrate, ligand, cofactor or product. Proteins with dual characteristics relevant to anticancer action of cannabinoids include the following: Notwithstanding the fact that the observed effects of cannabinoids are multifaceted, complicated and contradictory in some instances, formidable evidence exists to advocate that cannabinoids might present useful alternatives in our pursuit for new chemotherapeutic agents.
Development of new anticancer therapies is the need of the hour; however, their introduction to and potential application in clinic should be made with great caution and systematically. The anticancer value of this ancient remedy can only be fully exploited if future research is directed towards drawing a realistic correlation between the significant in vitro findings and results obtained from clinical trials run in parallel.
A decent safety profile and palliative effects of cannabinoids in cancer patients make them useful candidates for clinical trials. The anticancer mechanism of bioactive principles from C. Moreover, a deep understanding of the multiple functions of some proteins involved in these pathways can also help in optimizing the use of cannabinoids as potential anticancer agents. Identification of cannabinoid receptors has triggered researchers to validate the underexplored pharmacological prospects of this prehistoric remedy.
These efforts have provided momentous evidence of the promise of cannabinoids in the quest for the treatment of numerous neoplastic brutalities involving brain, breast, colon, liver, pancreas, lung, blood and prostate, among others. Psychoactive effects associated with cannabis utilization pose serious hurdles against its therapeutic application, so that extensive research is required in standardization of its pharmacokinetic parameters. In order to identify the real potential of cannabinoid-based therapeutics and their anticancer mechanism for the management of various types of cancer, detailed clinical studies are still a prerequisite to ascertaining their safe utility as anticancer agents.
We would also like to acknowledge Mr. No funds of any sort or magnitude were availed from any organization or institute. Journal of Exploratory Research in Pharmacology 2: March 22, Accepted: June 22, Published online: Abstract Cannabis has been used medicinally for centuries and numerous species of this genus are undoubtedly amongst the primeval plant remedies known to humans.
Keywords Cannabis sativa , Cannabinoids, Psychoactive agents, Cancer therapy. Introduction Cannabis Cannabis in both its pure and altered forms has been beneficial for human use since antiquity. Table 1 Cannabinoids action against various tumours. Type Study model Action [Reference] Breast carcinoma In vitro Cell cycle arrest [ 47 , 55 , 56 ] Colorectal carcinoma In vivo mouse ; in vitro Apoptosis; reduced cell proliferation [ 45 , 50 — 52 ] Glioma In vivo mouse, rat ; in vitro Decreased tumour size; apoptosis [ 39 , 40 , 49 , 57 ] Lung carcinoma In vivo mouse ; in vitro Decreased tumour size; inhibition of cell growth [ 38 ] Lymphoma In vivo mouse ; in vitro Decreased tumour size; apoptosis [ 53 ] Neuroblastoma In vitro Apoptosis [ 48 , 49 ] Skin carcinoma In vivo mouse ; in vitro Decreased tumour size; apoptosis [ 41 ] Prostate carcinoma In vitro Apoptosis [ 46 , 47 , 54 ] Uterus carcinoma In vitro Inhibition of cell growth [ 58 , 59 ].
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The current state and future perspectives of cannabinoids in cancer biology
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