Br J Clin Pharmacol. Feb;75(2) doi: /j x. Cannabidiol as potential anticancer drug. Massi P(1), Solinas M, Cinquina. Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ9-tetrahydrocannabinol (Δ9-THC). Request PDF on ResearchGate | Cannabidiol as potential anticancer drug | Over the past years, several lines of evidence support an.
as anticancer drug potential Cannabidiol
Importantly, analyses of samples obtained from 2 study patients before and after thc administration indicated that the molecular mechanism of cannabinoid antitumour action—namely, p8 and trib 3 upregulation 35 , 37 , m torc 1 inhibition 37 , stimulation of autophagy and apoptosis 11 , 35 , 37 , inhibition of cell proliferation 11 , decreased vegf signalling 32 , and matrix metalloproteinase 2 downregulation 64 delineated here earlier —also operates in vivo.
Those findings were encouraging and reinforced interest in the potential use of cannabinoids in cancer therapies. However, they also highlighted the need for further research aimed at optimizing the use of cannabinoids in terms of patient selection, combination with other anti-cancer agents, and use of other routes of administration. Administration of endocannabinoids or inhibitors of endocannabinoid-degrading enzymes has been shown to reduce the growth of various tumour xenograft types 95 , 96 and could therefore be a reasonable strategy for targeting cannabinoid receptors for anticancer purposes.
However, as discussed here earlier, the role of the endocannabinoid system, including the endocannabinoid-degrading enzymes, in the control of tumour generation and progression is not well understood. Because enhancing endocannabinoid tone only has mild antitumour effects in mice and because no inhibitor of endocannabinoid degradation has yet been approved for use in humans, clinical studies aimed at analyzing the efficacy of cannabinoids as antitumour agents should be based on the use of plant-derived or synthetic agonists of cannabinoid receptors rather than on endocannabinoids or inhibitors of endocannabinoid degradation.
The long-known therapeutic properties of C. As already mentioned, C. However, pure drugs are more prone to standardization than complex molecular cocktails. Thus, it would be ideal for studies aiming to investigate the anticancer actions of cannabinoids in patients to be performed comparatively with both pure substances and cannabis extracts containing controlled amounts of thc , cbd , and other cannabinoids. The most widely used route of administration for recreational and self-medicating marijuana is smoking.
Although thc and other phytocannabinoids are rapidly absorbed by inhalation, smoking is an unattractive clinical option. Preclinical work in animal models has typically used peri-tumoural administration of cannabinoids. Likewise, in the only clinical trial in which a cannabinoid was assayed as an antitumour agent, thc was administered locally intracranial delivery to patients with glioblastoma multiforme Nevertheless, this route of administration has many obvious limitations.
Currently available cannabis-based medicines are administered as capsules or using an oromucosal spray Preclinical animal models have yielded data indicating that systemic oral or intraperitoneal administration of cannabinoids effectively decreases tumour growth GV, CS, and MG.
Unpublished observations , and so it seems reasonable that future clinical studies with the goal of determining the efficacy of cannabinoids as antitumour agents use oral or oromucosal routes of administration. Two currently ongoing clinical trials could shed some light on these issues. The other is a phase ii trial aimed at evaluating the effect of cbd as single treatment in patients with solid tumours https: Hopefully, in the near future, new clinical trials will start, helping to determine whether cannabinoids can be used, for other than their palliative effects, in the treatment of cancer patients.
It is widely believed that strategies aimed at reducing mortality from cancer should consist of targeted therapies capable of providing the most efficacious and selective treatment for each individual tumour and patient.
Thus, the major focus of anticancer drug development has progressively moved from nonspecific chemotherapies to molecularly-targeted inhibitors. However, despite the huge amount of preclinical literature on how these rationally designed compounds work, their use in clinical practice is still limited.
How do cannabinoid-based medicines fit into this ongoing scenario? Consider glioma, the type of cancer in which the most detailed cannabinoid research has been conducted to date. As discussed here, engagement of a molecular target the cb receptors by a family of selective drugs thc and other cannabinoid agonists inhibits tumour growth in animal models through a well-established mechanism of action that also seems to operate in human patients.
Moreover, cannabinoids potentiate the antitumour efficacy of temozolomide and alk inhibitors in mice harbouring gliomas. However, further research is required to define the precise molecular cross-talk between cannabinoids and chemotherapeutic drugs and to optimize the pharmacology of preclinical cannabinoid-based combination therapies.
With respect to patient stratification, the particular individuals that are potentially responsive to cannabinoid administration should be unequivocally determined. To that end, high-throughput approaches should be implemented to find cannabinoid therapy—associated biomarkers in tumour biopsies or, ideally, in easily acquired fluids containing circulating cancer cells or enhanced levels of resistance factors that might have been released by cancer cells.
Such biomarkers would conceivably relate to cannabinoid pharmacodynamics—namely, expression and activity of cannabinoid receptors and their downstream cell-death-inducing effectors. The approach would be analogous to the biochemical evaluation of estrogen and ErbB2 receptors, which respectively predict benefit from endocrine therapies and trastuzumab in breast cancer.
Predictive markers to define the sensitivity of a particular tumour to cannabinoid-based therapies could also include the status of growth factors, such as mdk in gliomas, and their receptors and signalling partners. To summarize, cannabinoids induce tumour cell death and inhibit tumour angiogenesis and invasion in animal models of cancer, and there are indications that they act similarly in patients with glioblastoma.
Given that cannabinoids show an acceptable safety profile, clinical trials testing them as single drugs or, ideally, in combination therapies in glioblastoma and other types of cancer are both warranted and urgently needed. GW Pharmaceuticals and Cellmid fund part of the research conducted by our laboratory. Likewise, a portion of the data obtained by the authors concerning the antitumoural action of cannabinoids is included in three patent applications presented by GW Pharmaceuticals.
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Interestingly, CBD regulated the expression of key genes involved in the control of cell proliferation and invasion through the downregulation of Id-1 expression, an inhibitor of basic helix-loop-helix transcription factors, whose overexpression in breast cancer cells is responsible for proliferation, migration and invasion. Therefore, the ability of CBD to decrease significantly Id-1 expression in breast cancer cells was associated with its efficacy in reducing tumour aggressiveness.
Four years later , the same group [ 32 ] demonstrated that the observed effect of CBD on Id-1 expression was mediated by the upregulation of the extracellular signal-regulated kinase phosphorylation pERK. Moreover, these authors demonstrated that CBD was effective in reducing the primary tumour mass and the size and number of metastatic foci in vivo. Finally , the excellent paper of Shrivastava et al. These authors showed that CBD induced a concentration-dependent cell death of both oestrogen receptor-positive and oestrogen receptor-negative breast cancer cells with a mechanism independent of CB 1 , CB 2 and TRPV1 receptor activation.
Interestingly, the effective concentrations of CBD in tumour cells have little effect on non tumourigenic, mammary cells. Examining further the cellular mechanism involved in CBD-induced cell death, they found that CBD reduced mitochondrial membrane potential, triggered the translocation of the Beclin2 interacting protein Bid to the mitochondria and the release of cytochrome C to the cytosol and, ultimately, the activation of the intrinsic apoptotic pathway.
Finally, the relationship between CBD-induced apoptosis and autophagic cell death was explored by blocking each form of cell death with specific inhibitors. CBD treatment induced the cleavage of Beclin1 and the subsequent translocation of the cleavage product to the mitochondria where it may induce apoptosis through the enhancement of cytochrome C release [ 34 , 35 ].
As a whole this work highlights the presence of a complex balance between autophagy and mitochondria-mediated apoptosis in CBD-induced breast cancer cell death and strengthens the idea that CBD can be considered as an alternative agent for breast cancer therapy. Figure 3 shows a schematic representation of the signalling pathways associated with the effect of CBD in breast cancer cell proliferation and invasion. Schematic representation of the signalling pathways associated with CBD effects on breast cancer.
CBD also possesses anti-tumoural properties in gliomas, tumours of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy.
After the seminal paper of Jacobsson et al. Interestingly, CBD did not affect viability of non-transformed primary glial cells [ 38 ]. When tumour xenografts were generated in immune-deficient mice, in vivo intratumoural treatment with CBD significantly reduced tumour growth [ 37 ].
The anti-proliferative effect of CBD was cannabinoid and vanilloid receptors independent. More importantly, this paper demonstrated for the first time that the anti-tumour effect of CBD involved the induction of oxidative stress, through increased early production of ROS, depletion of intracellular glutathione and increased GSH-associated enzymatic activity. Accordingly, the CBD anti-proliferative effect was reversed by the anti-oxidant , tocopherol.
In line with this, more recently Torres et al. These effects were not observed with either compound individually, indicating them as a prerogative of combination treatment. Differently from Marcu's data [ 39 ], our recent results Dr.
Valenti, University of Insubria, Varese, pers. Thus, inhibition of these three molecules appears as part of the multiple molecular targets for CBD anti-neoplastic activity [ 41 ]. Further biochemical analysis of glioma tumour tissues excised from nude mice treated in vivo with CBD indicated a significant decrease of activity and content of 5-LOX, as well as a marked stimulation of FAAH and a decrease of AEA content [ 42 ].
Besides cell growth, CBD reduced glioma cell migration [ 43 ] and invasiveness in a Boyden chamber test [ 39 ], at concentrations lower than those required to inhibit cell proliferation.
CBD seems to counteract glioma cell proliferation and invasion through multiple mechanisms, as summarized in Figure 4. Schematic representation of the signalling pathways associated with CBD effects on glioma. They demonstrated that CBD treatment induced apoptosis, through caspase-3 activation in human acute myeloid leukaemia HL cell line, whereas it had no effect on human monocytes from normal individuals.
Later on, McKallip et al. In Jurkat cells, CBD exposure resulted in the activation of caspase-8, -9, and -3, the cleavage of poly ADPribose polymerase and the decrease in full-length Bid, suggesting a possible cross-talk between the intrinsic and extrinsic apoptotic pathways. Moreover, exposure to CBD led to the loss of mitochondrial membrane potential and subsequent release of cytochrome C. Finally, CBD decreased the levels of phospho-p38 mitogen-activated protein kinase [ 45 ], and this effect was blocked by treatment with a CB 2 -selective antagonist or ROS scavenger.
In addition, CBD treatment caused a significant reduction in tumour burden and increased the level of apoptotic tumours in ELbearing mice [ 45 ]. Together, the results suggest that CBD, acting through CB 2 receptors and ROS production, may represent a novel and highly selective treatment for leukaemia.
Moreover, previous evidence indicated that human leukaemias and lymphomas expressed significantly higher levels of CB 2 receptors compared with other tumour cell lines, suggesting that tumours of immune origin may be highly sensitive to the CB 2 -mediated effects of CBD [ 46 ]. Given the poor response of lung cancer to available therapy and its aggressive biological nature, a series of targets and new therapeutic strategies for their treatment are currently being investigated [ 47 — 50 ].
Recently, Ramer et al. Interestingly all these cellular events were blocked by cannabinoids or TRPV1 receptor antagonists. The significant inhibition of A cell invasion following CBD treatment was also accompanied by the downregulation of another important factor involved in the regulation of cell spreading, the plasminogen activator inhibitor PAI-1 [ 52 ]. Additionally , in vivo studies in thymic aplastic nude mice revealed a significant inhibition of A lung metastases following CBD treatment [ 51 ] and a significant downregulation of PAI-1 protein was demonstrated in A xenografts of CBD-treated rats [ 52 ].
It is worth noting that CBD decreased invasiveness in a range of therapeutically relevant concentrations 0. Together, these findings provide a novel mechanism underlying the anti-invasive action of CBD on human lung cancer cells and imply its use as a therapeutic option for the treatment of highly invasive cancers.
Thyroid cancer is the most common endocrine malignancy and Ligresti et al. Later on, Lee et al. The presence of N-acetyl-L-cysteine NAC , a precursor of glutathione, markedly attenuated the induction of apoptosis and restored the diminished levels of cellular thiols.
The observation that CBD induced oxidative stress in thymocytes, EL-4 cells and splenocytes [ 56 ] substantiates the notion that, unlike monocytes, T cells both primary and immortalized, are all sensitive and respond similarly to CBD, with a central role of ROS generation.
Colon cancer is a major cause of morbidity and mortality in Western countries. A recent paper from Izzo's group [ 57 ] demonstrated the chemopreventive effect of CBD in a preclinical animal model of colon cancer based on azoxymethane AOM administration in mice.
In vitro studies, supported the beneficial effect of CBD. In the light of its safety records, these results suggest that CBD might be worthy of clinical consideration in colon cancer prevention. Angiogenesis consists of the formation of new blood vessels from pre-existing ones and represents another promising therapeutic target for cancer therapy.
Surprisingly, so far no study has investigated the effect of CBD on angiogenesis. Our data currently awaiting publication [ 58 ] demonstrated that CBD potently inhibited HUVE cells proliferation, migration and invasion through the induction of endothelial cell cytostasis without triggering apoptosis. Interestingly, CBD also affected endothelial cell differentiation into tubular capillaries as well as the outgrowth of capillary-like structures from HUVEC spheroids in vitro.
In addition, the anti-angiogenic properties of CBD were demonstrated also in vivo , using a matrigel sponge model. Collectively , these preliminary data demonstrate that, besides its well known pro-apoptotic anti-proliferative and anti-invasive actions, CBD may also exert anti-angiogenic effects, thus further strengthening its potential application in cancer therapy.
Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic and perhaps anti-angiogenic properties.
On the basis of these results, evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread. Interestingly , the anticancer effect of this compound seems to be selective for cancer cells, at least in vitro , since it does not affect normal cell lines. The efficacy of CBD is linked to its ability to target multiple cellular pathways that control tumourigenesis through the modulation of different intracellular signalling depending on the cancer type considered.
The most common effect of CBD is the increase in ROS production that seems to be determinant for triggering its beneficial action in all the considered cancer cell types. In some cases lung, leukaemia, colon a clear contribution of these receptors has been demonstrated through the use of specific antagonists, but in other cancer types glioma and breast their relevance appears only marginal or absent. Besides the in vitro data, the efficacy of CBD in reducing tumour growth and, in some cases, metastasization was confirmed in experimental animal models.
However, the potential clinical application of CBD for cancer therapy needs some consideration. Its low toxicity is certainly a good starting point. The route of administration appears more problematic since CBD oral absorption is slow and unpredictable. Interestingly, this range of concentration was demonstrated to be active in inhibiting lung cancer cell invasion [ 52 , 53 ], thus suggesting that in some cases the oral route could be the appropriate choice.
Moreover, oromucosal administration may represent a first choice in the presence of nausea and vomiting. In the light of its safety record and considering that CBD is already currently used in patients with multiple sclerosis, the findings here summarized suggest that CBD might be worthy of clinical consideration for cancer therapy. National Center for Biotechnology Information , U. Br J Clin Pharmacol.
Published online Apr Author information Article notes Copyright and License information Disclaimer. Received Jan 30; Accepted Apr This article has been cited by other articles in PMC.
Open in a separate window. Cannabinoids in the treatment of cancer Cannabinoids are currently used in cancer patients to palliate wasting, emesis and pain that often accompany cancer.
Table 1 Effects of cannabidiol on different types of cancer. CBD and breast cancer In Ligresti et al. CBD and glioma CBD also possesses anti-tumoural properties in gliomas, tumours of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy.
CBD and lung cancer Given the poor response of lung cancer to available therapy and its aggressive biological nature, a series of targets and new therapeutic strategies for their treatment are currently being investigated [ 47 — 50 ].
CBD and endocrine tumours Thyroid cancer is the most common endocrine malignancy and Ligresti et al.
Cannabidiol as potential anticancer drug. Article date: February By: Paola Massi, Marta Solinas, Valentina Cinquina, Daniela Parolaro, in Volume Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ9‐tetrahydrocannabinol (Δ9‐THC). Cannabidiol as potential anticancer drug. Subject: Cancer - PUBLISHED VIA British Journal of Clinical Pharmacology. Author(s): Massi P, Solinas M, Cinquina V.