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New research shows - with cautious optimism - that cannabis can kill or slow the development of cancer cells.

Medical cannabis is well known to cancer patients. A large number of Israelis receive it as part of their palliative care for dealing with the symptoms of the disease, as cannabis has been found to be effective in relieving chronic pain, nausea and loss of appetite.


Scientists from the Technion-Israel Institute of Technology in Haifa have been researching completely different possibilities for the use of cannabis by cancer patients – as an active treatment against the development of the disease itself. A precedent-setting study examined how dozens of strains of cannabis affect the development and growth of hundreds of types of cancer cells.


This study is one of the first signs of a new approach to the use of cannabis in cancer treatment, which examines whether the plant can help in delaying the development of cancerous growths – or even eliminate them completely.


The preliminary results, which were found in the first few weeks of the research, show that cannabis is quite possibly effective in treating brain and breast cancers.
Dr. David Meiri, an assistant professor in the biology department at the Technion, is leading the cancer research team. Meiri, the head of Technion’s Laboratory of Cancer Biology and Cannabinoid Research who did postdoctoral work at the Ontario Cancer Institute in Toronto, opened his lab in the Technion about a year ago.


Meiri specializes in studying the cytoskeleton of cells, which is a critical component of the processes of division and movement of cancer cells, and of all cells in general. Meiri told Haaretz that he searched for all sorts of materials that affect the structure of the cell in his research in Toronto, and found cannabis. The deeper he went into the field, the more he realized there was a huge vacuum and lack of scientific knowledge about the effects of cannabis.


There are very few studies on cannabis and brain cancer, he noted. Meiri approached this in two ways: Whether cannabis is capable of keeping cancer cells from becoming virulent, and at the same time studying how far cannabis can go in fighting the cancer cells themselves – and possibly destroy them.
The connection between the cannabis plant and the various cancers is an interesting question in its own right, but it also produces an almost unlimited statistical expanse for study. Today, scientists are examining some 50 different varieties of the plant produced in Israel, and studying its effects on some 200 different types of cancer cells.


Another variable has to be taken into account: the way the cannabis is applied, which can significantly affect its effectiveness. Even if we take the most basic separation between the varieties of the plant, we still do not know how the way it is ingested affects the cell, says Meiri. Take, for example, cannabis extract produced using ethanol compared to that produced using carbon dioxide, since there are differences between the cells of various forms of cancer – so the research potential is infinite – and that is what Meiri says attracts him to the subject.

The research project is part of a joint research agreement between the Technion and Cannabics Pharmaceuticals, an emerging American drug company, signed last week. As its name infers, Cannabics is interested in drugs based on cannabis and sells cannabis capsules for cancer patients. Cannabics will provide the various strains of the plants for the research. The company is traded over the counter in the United States.
Cannabics Pharmaceuticals focuses on the development and commercialization of advanced drugs, therapies, food supplements and administration routes based on the wide range of active ingredients found in diverse and unique strains of the Cannabis plant.


The collaborative research project is meant to develop a diagnostic system that screens the anti-cancer properties of cannabis-based active ingredients. This system will be harnessed to explore different types of cancer cells treated with a multitude of cannabinoid combinations.


“There is a large body of scientific data which indicates that cannabinoids specifically inhibit cancer cell growth and promote cancer cell death,” explained Meiri. “In addition to active cannabinoids, cannabis plants also contain a multitude of other therapeutic agents, such as terpenoids and flavonoids that are usually present in small quantities, but can have beneficial therapeutic effects, especially as synergistic compounds to cannabinoids.”


Cannabics’ current flagship product is Cannabics SR an patent-pending medical cannabis capsule designed specifically for cancer patients as a palliative care treatment. Cannabics is now preparing to launch its line of SR products in eligible states of the U.S. and EU markets under existing medical cannabis regulatory pathways, while simultaneously launching a formal clinical study in order to establish the unique medical benefits of its SR capsules.


The company is expected to start another study at the Rambam Medical Center in Haifa soon, which is intended on examining the effect of cannabis capsules on the loss of appetite and weight loss in cancer patients.

“Cannabinoid based anticancer medicine could be a potent therapy without the side effects related to chemotherapy,” said Dr. Eyal Ballan, the chief scientist of Cannabics. Everyone is waiting and hoping for significant results from the research, he said.
A miracle cure or dangerous drug?


The medical discourse over the cannabis plant moves between two extremes: those who view it as a miracle drug and attribute numerous medical qualities – sometimes based only on anecdotal and not scientific evidence – and those who still see it as a dangerous and illegal drug with harmful effects in all cases. Obviously, both sides are exaggerating, but the real question is where the truth falls – and close to which side.
From 1850 through 1937 cannabis – which has over 400 active ingredients – was used as a medicinal herb and was accepted in conventional medicine. Before that it was used in many cultures for thousands of years, such as in Chinese medicine, in which it is used to treat over 100 illnesses.


The change in the attitude toward the use of the plant started in the early 1900s, and culminated in the late 1930s in the United States with its complete legal ban.


Drug companies have also shown very little interest in the plant and ingredients, both because of its status as a controlled substance, but also because it is very hard to patent drugs from a natural plant, and it would be possible only to patent the various new forms of treatment. But things have changed in recent years and some drug companies, as well as scientists, have shown renewed interest in both the drug and treatments based on cannabis.


The whole field of cannabis research is almost virgin territory from a scientific perspective, and there are relatively few experts in it today. Given all the changes in the field, it is doubtful whether an institution like the Technion would have been interested in such research even just a few years ago.


The real question for Meiri is how realistic are all these high expectations for cannabis as a cancer treatment? He would prefer to be asked the question in another year, and not at the initial stages of his research. But he is certainly pleased that the work has started off well.


Meiri and his colleagues have succeeded in causing brain cancer cells to “commit suicide,” or apoptosis, a form of “programmed cell death.” This is something a group of Spanish researchers has seen in the past, and Meiri has been able to reproduce it.


One of the characteristics of cancer cells is their ability to evade the cell’s mechanisms of death, and it seems cannabis somehow succeeds in putting this mechanism back into operation, even if the researchers still do not understand how, says Meiri. They have succeeded in producing similar results in breast cancer cells, and from there he wants to continue on to the other types of cancer.


The preliminary results have given Meiri a reason for cautious optimism, but not much more than that. He certainly has not become a marijuana missionary.


“Many businesspeople deal with and say things about cannabis. It seems some of them are overdoing it. I think it is now the turn of science to put things in order and find out how it helps, who it helps and exactly how it does so,” he says.


Even if it helps with five or six types of cancer, it will be a success, but he doesn’t want to put the cart before the horse, says Meiri.

Written by by Ido Efrati


Source: www.haaretz.com

Image by Clarita

Posted in Case Studies

Abstract

Cannabinoids - the active components of Cannabis sativa and their derivatives - exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?

 

Author 

Guzmán M.

Nat Rev Cancer. 2003 Oct;3(10):745-55.

[PubMed - indexed for MEDLINE]
Posted in Case Studies

Allergic asthma is a complex inflammatory disorder characterized by airway hyper-responsiveness, elevated serum IgE, recruitment of eosinophils into the lung and mucus hypersecretion by goblet cells [111]. Murine models of allergic airway disease, employing ovalbumin (OVA) as an aeroallergen, indicated that CD4+ Th2 cells (IL-4, IL-5 and IL-13) played a pivotal role in the pathophysiology of the allergic airway response [112]. Intraperitoneal administration of THC or cannabinol (CBN) in OVA-sensitized and challenged A/J mice led to attenuation of serum IgE, IL-2, IL-4, IL-5 and IL-13 mRNA expression and decreased allergen-induced mucus production, indicating that cannabinoid-based compounds may represent a novel class of therapeutic agents for the treatment of allergic airway diseases [113]. While most studies have shown that cannabinoids, such as THC, facilitate a Th1 to Th2 cytokine switch, as discussed previously, it is surprising that cannabinoids can also suppress allergic asthma triggered primarily by Th2 cytokines. It is possible that THC may affect other cells such as DCs and B cells directly in this model. Previous findings indicated that aerosolized THC was capable of causing significant bronchodilatation with minimal systemic side effects, but had a local irritating effect on the airways [114]. Further bronchodilator effects of cannabinoids administered orally or by aerosol to asthmatic patients have also been reported [115,116]. Similarly, endogenous cannabinoids have been shown to regulate airway responsiveness. In rodent lungs, a Ca2+-activated mechanism for the biosynthesis of anandamide was observed and CB1 receptors were found predominantly on axon terminals of airway nerves, indicating that endocannabinoids may regulate bronchial smooth muscle tone [117]. It was reported that activation of CB1 receptors by locally released anandamide may participate in the control of bronchial contractility. Blocking of AEA-induced CB1 activity can enhance capsaicin-induced bronchospasm. However, the authors further suggested that the effects of AEA may depend on the state of the bronchial muscle. During capsaicin-evoked bronchospasm, AEA may reduce the muscle contraction, whereas AEA may cause bronchoconstriction in the absence of vagus nerve-constricting tone [117].

Cannabidiol has been shown to be effective in protecting endothelial function and integrity in human coronary artery endothelial cells (HCAECs). The study demonstrated that CBD reversed the harmful effects of high glucose on HCAECs by inhibiting [118]:

  • Reactive oxygen species production by mitochondria
  • NF-κB activation
  • Transendothelial migration of monocytes
  • Monocyte–endothelial adhesion in HCAECs

In a different experiment, HCAECs were stimulated with TNF-α in order to mimic the inflammatory processes during atherosclerosis, and the effect of different CB2 receptor agonists on the activated cells was studied. It was demonstrated that activation of cells with TNF-α led to increased expression of CB2 and activation of Ras, p38, MAPK, JNK and AKT pathways. In addition, proliferation and migration was markedly increased in activated cell populations. The use of CB2 agonists JWH-133 and HU-308 inhibited all activated pathways in a dose-dependent manner, establishing a novel use for these cannabinoid compounds [119].

Experimental autoimmune uveoretinitis (EAU), is a CD4+ T-cell-mediated autoimmune disease, which can be induced in rodents by challenge with retinal antigens or their peptides [120]. In a recent study, it was observed that the CB2-selective agonist JWH-133 had a high in vivo immunosuppressive effect in EAU model. EAU was strongly inhibited when the CB2 was engaged and the effects of CB2 engagement appeared to be mediated predominantly through downregulation of T-cell function with a less-marked effect on antigen presentation [121]. An impaired T-cell-proliferative response in leukocytes from JWH-133-treated mice was also accompanied by marked reductions in cytokine production. A more recent study showed that JWH-133 (10 nM–5 μM) suppressed IL-12p40 and enhanced IL-10 production in mouse macrophages induced by LPS [122]. As IL-12p40 is critical for the development of EAU and IL-10 could suppress EAU [123,124], the authors suggested that this may also be one of the possible mechanisms responsible for the effect of JWH-133 on EAU.

Insulin-dependent Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting in destruction of insulin-producing pancreatic β cells, a process that is assumed to be mediated mainly by CD4 Th1 and CD8 T lymphocytes [125]. In rodents, T1D is induced by administration of multiple low doses of streptozotocin (MLDSTZ). This model is used for studying autoimmune processes associated with pancreatic β-cell pathogenesis. A study performed by Li et al. indicated that Δ9-THC could exert a transient attenuation of MLDSTZ-induced autoimmune diabetes. Δ9-THC treated (150 mg/kg) CD-1 mice exhibited reduced hyperglycemia and a significant decrease in the loss of pancreatic insulin. MLDSTZ-induced insulitis was also significantly attenuated by decreases in CD3+ inflammatory cells in the pancreatic islets and in mRNA expression for IL-12, IFN-γ and TNF-α. It was suggested that in this model, the autoimmune component was most effectively modulated by Δ9-THC treatment [126]. Similarly, CBD treatment has been shown to significantly inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in nonobese diabetes-prone (NOD) female mice. CBD-treated mice exhibited significant reduction of plasma levels of the proinflammatory cytokines IFN-γ and TNF-α, whereas production of the Th2-associated cytokines IL-4 and IL-10 was increased when compared with untreated control mice, thus shifting the immune response from Th1 to Th2 dominance [127]. A recent study indicated that treatment of 11–14-week-old female NOD mice, either in a latent diabetes stage (after 14 weeks) or with initial symptoms of diabetes (appearing up to 14 weeks) with CBD for 4 weeks, could lead to sustained inhibition of insulitis [128]. CBD treatment inhibited specific destruction of the islets and reduced the infiltrates by mononuclear cells into the islets, thus preventing diabetes. Furthermore, cannabinoids have also been demonstrated to possess additional beneficial effects in animal models of diabetes. It has been reported that rats treated with CBD for periods of 1–4 weeks experienced significant protection from diabetic retinopathy [129]. Cannabinoids have also been shown to alleviate neuropathic pain associated with the disease. Mice injected with a cannabis receptor agonist experienced a reduction in diabetic-related tactile allodynia compared with nontreated controls [130]. Thus, cannabinoids can be considered useful for controlling T1D due to their anti-inflammatory properties.

Future perspective

It is becoming increasingly clear that cannabinoid receptors and their endogenous ligands play a crucial role in the regulation of the immune system. Exogenous cannabinoids have been shown to suppress T-cell-mediated immune responses by primarily inducing apoptosis and suppressing inflammatory cytokines and chemokines. Such observations indicate that targeting cannabinoid receptor–ligand interactions may constitute a novel window of opportunity to treat inflammatory and autoimmune disorders. As CB2 receptors are primarily expressed on immune cells, targeting CB2 may result in selective immunomodulation without overt toxicity. The future challenges for the use of cannabinoids as anti-inflammatory drugs include synthesis of cannabinoid receptor agonists that are nonpsychoactive with anti-inflammatory activity and then identifying their mode of action. Although current studies suggest that cannabinoids are useful therapeutic agents in the treatment of various inflammatory disorders, further evaluation of the mechanisms that account for their anti-inflammatory properties is necessary. Such studies may involve the use of cannabinoid receptor-knockout mice and use of receptor-specific compounds. While most studies have focused on the effect of cannabinoids on cytokines, apoptosis and Th1 cell functions in the past, additional investigations on their effect on Th17 cells, DCs, NK cells, B cells and Fox-P3+ regulatory T cells is critical as such cells play an important role in the regulation and mediation of inflammatory or autoimmune disease response. Whether endocannabinoids and cannabinoid receptors play a critical role during normal inflammatory response also requires further consideration. Moreover, cannabinoid receptor signaling and effect of cannabinoids on adhesion molecules, co-stimulatory molecules and chemokines require further study in order to increase our understanding of cannabinoids and their intricate effects on immune system disorders. Overall, cannabinoids have exhibited significant potential to be used as novel anti-inflammatory agents and specific targeting of CB2 receptors holds the promise of mediating immunosuppressive effects without exerting psychotropic side effects.

Executive summary

  • Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 (CB1 and CB2).
  • The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties.
  • Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells.
  • Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways.
  • Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis.

Acknowledgments

This work was supported in part by NIH grants R01AI053703, R01ES09098, R01AI058300, R01DA016545, R01HL058641 and P01AT003961. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Glossary

Cannabinoids
Active components extracted from Cannabis sativa that act through cannabinoid receptors
Cannabinoid receptors
G-protein-coupled receptors that mediate the action of cannabinoids
Cytokines
Signaling proteins synthesized and secreted by immune cells upon activation
Autoimmune diseases
Disorders in which the immune system starts recognizing an individual’s own cells as foreign and mounts a reaction, leading to tissue injury
Inflammation
A defense mechanism that results from the action of activated immune cells in response to foreign antigens. Sometimes, response to self antigens can trigger severe tissue injury

Footnotes

 

For reprint orders, please contact moc.ecneicserutuf@stnirper

 

 

Financial & competing interests disclosure

No writing assistance was utilized in the production of this manuscript.

 

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