cannabis%20and%20cancer%20review%202012 by Independent Drug Monitoring Unit

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Cannabinoids & Cancer

12th April 2012

Cannabinoids and Cancer Overview Scientific study into the relationship between cannabinoids and cancer can be divided into three broad phases1, initially there were attempts to provide epidemiological evidence proving a link between cannabis use and cancer risk in order to provide evidence justifying international prohibition, the second phase was investigating potential therapeutic benefits from symptomatic relief e.g. nausea, vomiting resulting from chemotherapy and cachexia – a generalised wasting syndrome. Most recently research has focussed on more direct effects of endocannabinoids on the development and potential treatment of cancer, with effects of THC and CBD including reducing proliferation and blood-supply to tumours, and direct anti-tumour activity via cell-suicide (apoptosis). The use of cannabinoids in treating the side effects of cancer chemotherapy has been very widely-studied, and a number of clinical studies have taken place investigating the use of THC and synthetic cannabinoids as anti-emetic agents. Two preparations have been licensed for use in clinical treatment either in the UK or elsewhere, including dronabinol (synthetic THC) and Nabilone (a novel synthetic cannabinoid). Research into direct anti-tumour activity of cannabinoids and the mechanisms by which such activity is exerted has exploded since I last reviewed this field in 2003, with nearly 600 new studies published. Cancer Risk Lung Cancer: Cannabis is overwhelmingly used via smoking, in the UK the vast majority of cannabis is consumed in hand-rolled cigarettes mixed with tobacco, less commonly in neat-herbal cannabis reefers and pipes, with around 5% taken in food and drink. In recent years there has been an increase in the use of vapourisers and some patients prescribed Sativex® via sublingual spray. Smoking would therefore be expected to result in a highly significant increase in the risk of lung and other cancers. Hashibe et al2 observed “marijuana smoke contains several of the same carcinogens and cocarcinogens as the tar from tobacco, raising concerns that smoking of marijuana may be a 3 risk factor for tobacco-related cancers” and Grendelmeier noted “Cannabis and tobacco smoke contain a similar mix of irritant and toxic chemicals. Therefore, there are reasons to suspect, that cannabis and tobacco have similar side effects.” Investigating

the properties of cannabis smoke and the effects of acetaldehyde content on DNA, Singh et al4 reported “these results provide evidence for the DNA damaging potential of cannabis smoke, implying that the consumption of cannabis cigarettes may be detrimental to human health with the possibility to initiate cancer development.” Hart et al5 concluded “concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients”

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In a 2004 review of adverse effects of cannabis on health, Kalant6 stated “Chronic inflammatory and precancerous changes in the airways have been demonstrated in cannabis smokers, and the most recent case-control study shows an increased risk of 7 airways cancer that is proportional to the amount of cannabis use” Hall et al noted “There have been case reports of upper-respiratory-tract cancers in young adults who smoke cannabis, but evidence from a few epidemiological cohort studies and case-control studies is inconsistent” Case studies include a 26 year old male with significant

cannabis exposure with small-cell lung cancer8 Lebeau & Genot9 reported the case history of a 22 year old male who presented with bronchial mucoepidermoid carcinoma and a history of heavy cannabis and tobacco use since age 11, concluding “The oncogenic role of cannabis smoke should be envisaged, and emphasis placed on the possible synergic effects of multiple addiction, in this case 10 tobacco and cannabis” Tashkin concluded in 2005: “regular marijuana smoking produces a number of long-term pulmonary consequences, including chronic cough and sputum, histopathologic evidence of widespread airway inflammation and injury and immunohistochemical evidence of dysregulated growth of respiratory epithelial cells, that may be precursors to lung cancer. The THC in marijuana could contribute to some of these injurious changes through its ability to augment oxidative stress, cause mitochondrial dysfunction, and inhibit apoptosis. On the other hand, physiologic, clinical or epidemiologic evidence that marijuana smoking may lead to chronic obstructive pulmonary disease or respiratory cancer is limited and inconsistent.” A French review of adverse cannabis effects11 noted “Numerous case-control studies have investigated the role of cannabis in the incidence of some types of cancer. Its role has not been ruled out, but it is not possible to determine whether the risk is distinct from that of the tobacco with which it is often smoked.”

Berthiller et al12 reported on the results of three epidemiological studies in North Africa, reporting “Adjusting for country, age, tobacco smoking, and occupational exposure, the odds ratio (OR) for lung cancer was 2.4 (95% confidence interval [CI]: 1.63.8) for ever cannabis smoking… The risk of lung cancer increased with increasing jointyears, but not with increasing dose or duration of cannabis smoking” and concluding “cannabis smoking may be a risk factor for lung cancer. However, residual confounding by tobacco smoking or other potential confounders may explain part of the increased risk.” In a study of cancer risk factors in Tunisia, Voirin et al13 reported “The odds ratio for the past use of cannabis and lung cancer was 4.1 (95% CI: 1.9-9.0) after adjustment for age, tobacco use, and occupational exposures. No clear dose-response relationship was observed between the risk of lung cancer and the intensity or duration of cannabis use. This study suggests that smoking cannabis may be a risk factor for lung cancer.” In a case

control study involving 79x lung cancer patients and 324x age-matched controls in New Zealand, Aldington et al14 reported “The risk of lung cancer increased 8% (95% confidence interval (CI) 2-15) for each joint-yr of cannabis smoking, after adjustment for confounding variables including cigarette smoking, and 7% (95% CI 5-9) for each pack-yr of cigarette smoking, after adjustment for confounding variables including cannabis smoking. The highest tertile of cannabis use was associated with an increased risk of lung cancer (relative risk 5.7 (95% CI 1.5-21.6)), after adjustment for confounding variables including cigarette smoking. In conclusion, the results of the present study indicate that long-term cannabis use increases the risk of lung cancer in young 15 adults” In a similar study of head and neck cancers the same team concluded “Cannabis use did not increase the risk of head and neck cancer; however,

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because of the limited power and duration of use studied, a small or longer-term effect cannot be excluded.”

Hashibe et al16 reviewed a number of studies claiming an association between cannabis use and increased cancer risk, concluding “sufficient studies are not available to adequately evaluate marijuana impact on cancer risk. Several limitations of previous studies include possible underreporting where marijuana use is illegal, small 17 sample sizes, and too few heavy marijuana users in the study sample” Melamede concluded “While chemically very similar, there are fundamental differences in the pharmacological properties between cannabis and tobacco smoke. Cannabis smoke contains cannabinoids whereas tobacco smoke contains nicotine. Available scientific data, that examines the carcinogenic properties of inhaling smoke and its biological consequences, suggests reasons why tobacco smoke, but not cannabis smoke, may result in 18 lung cancer.” In a critical review, Quoix concluded “The role of cannabis as a risk factor of lung cancer is difficult to assess as most cannabis smokers are also tobaccosmokers but recent epidemiological studies suggest that cannabis is not carcinogenic” Quoix & Lemarie19 concluded “The specific impact of smoking cannabis is difficult to assess precisely as, in most cases, it is mixed with tobacco. However, despite important differences with tobacco smoke, cannabis exposure doubles the risk of developing lung cancer.”

Other Cancers: In a study matching 369x testicular cancer patients with 979x agematched controls, Daling et al20 reported “An association was observed between marijuana use and the occurrence of nonseminoma [testicular germ cell tumors].” In a smaller study Trabert et al21 stated “The finding of an association between frequent marijuana use and TGCTs, particularly among men with nonseminoma, was consistent with the findings of a previous report.”

Zhang et al22, studying Kaposi’s Sarcoma, noted “Our results indicate that Delta(9)-THC can enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. Thus, use of cannabinoids may place individuals at greater risk for the development and progression of Kaposi's sarcoma.”

Llewellyn et al2324 assessed risk factors for oral carcinoma among 116x patients under 45 years old in the UK, finding tobacco and alcohol to be associated with modest increased risk and consumption of fruit and vegetable to be associated with modest reduced risk, no effect was found for cannabis use. Liang et al25, studying factors associated with head & neck squamous cell carcinoma (HNSCC), reported “After adjusting for potential confounders (including smoking and alcohol drinking), 10 to 20 years of marijuana use was associated with a significantly reduced risk of HNSCC [odds ratio (OR)(10-<20 years versus never users), 0.38; 95% confidence interval (CI), 0.22-0.67]. Among marijuana users moderate weekly use was associated with reduced risk (OR(0.5-<1.5 times versus <0.5 time), 0.52; 95% CI, 0.320.85). The magnitude of reduced risk was more pronounced for those who started use at an older age (OR(15-<20 years versus never users), 0.53; 95% CI, 0.30-0.95; OR(> or =20 years versus never users), 0.39; 95% CI, 0.17-0.90; P(trend) < 0.001).” and concluded “moderate marijuana use is associated with reduced risk of HNSCC” Feng et al26

investigated factors associated with nasopharyngeal carcinoma (NPC) in North Africa, reporting “marijuana smoking significantly elevated NPC risk

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independently of cigarette smoking, suggesting dissimilar carcinogenic mechanisms between cannabis and tobacco”

Established Therapeutic Uses - Side effects of chemotherapy and Cachexia The powerful drugs used in cancer chemotherapy effectively kill reproducing cells, including both the malignant tumour cells and also, as a side effect, many cells continually reproducing such as hair follicle cells and those lining the gut, leading to severe nausea & vomiting. These side effects can be very severe and many patients find these difficult or impossible to tolerate, falling into a wasting syndrome through malnutrition brought on by a combination of reduced appetite and poor gastrointestinal efficiency, which can itself shorten life expectancy. There is variation between the effects of different anti-cancer drugs. Cisplatin, one of the most effective chemotherapy agents, induces vomiting in over 99% of patients not taking an antiemetic, with around 10 vomiting episodes per dose, although methotrexate causes emesis in under 10% of patients272829 There are also variations in the efficacy and side effects between conventional drugs used to treat nausea and vomiting. The BMA30 listed the side effects of commonly-used anti-emetic drugs as follows: (a) Phenothiazines (prochlorperazine, haloperidol) - severe dystonic reactions, drowsiness, dry mouth, blurred vision, urinary retention, hypotension (low blood pressure), allergic reactions, occasional jaundice. (b) Metoclopramide - acute dystonic reactions, facial and muscle spasms, drowsiness, restlessness, diarrhoea, depression (c) Domperidone - acute dystonic reactions (d) SSRAs (Ondansetron, gransisetron) - constipation, headache, altered liver function.31 Levitt32 in an early review presentation, suggested:“The use of cannabinoids as cancer chemotherapy anti-emetics represents, in essence, the use of a drug with a relatively undefined mechanism of action to treat the side effects of other drugs, also with relatively undefined mechanisms of action, which are being used to treat cancer, a disease or series of diseases the precise nature of which remains enigmatic.” Since Levitt’s review, there

have been major advances in cannabinoid pharmacology and in understanding of the cancer disease process. In particular, research by Herkenham et al3334 demonstrated the presence of numerous cannabinoid receptors in the nucleus of the solitary tract, a brain center that is important in the control of vomiting35. The main beneficial effects reported from use of cannabinoids are a reduction in the incidence and severity of nausea and vomiting (emesis), and stimulation of appetite, together reducing the severity of cachexia - wasting syndrome - in patients receiving chemotherapy treatment. Jamshidi & Taylor36 discovered “intrahypothalamic anandamide initiates appetite by stimulation of CB1 receptors, thus providing evidence on the involvement of hypothalamic

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Cannabinoids & Cancer

endocannabinoids in appetite initiation.” Inui concluded “cannabinoids... act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would 38 extend patient survival and improve quality of life.” Machado Rocha et al compared

effects of cannabinoids (dronabinol, Nabilone & cannabis) with alternative anti-emetic drugs (neuroleptics, levonantradol), in a meta-analysis of published studies, finding “demonstration of superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs and placebo. The adverse effects were more intense and occurred more often among patients who used cannabinoids” Abrahamov et

al39 reported the effects of a study of delta-8-THC in children suffering from haematological cancers and undergoing chemotherapy, noting “Vomiting was 40 completely prevented. The side effects observed were negligible.”. Lockwood reported a case history of “Marihuana and alcohol intolerance” in a Hodgkin's disease patient. In a 2003 review, Croxford41 noted “Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease”, similarly, Walsh et al42 noted “The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia.” Grotenhermen43 agreed “Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, 44 neuroprotection and induction of apoptosis in cancer cells.” Parker et al concluded “endogenous cannabinoids play a role in modulation of nausea”. Zurcher45

recommended cannabinoids for treatment of cancer-induced anorexia. In a review of Nabilone efficacy in cancer patients, Ware et al46 concluded “The cannabinoids exert antiemetic effects via agonism of cannabinoid receptors (CB1 and CB2). Clinical trials have demonstrated the benefits of nabilone in cancer chemotherapy patients”

Cotter47, reviewing studies of chemotherapy-induced nausea and vomiting (CINV), reported “Cannabinoids are effective in controlling CINV, and oral THC and smoked marijuana have similar efficacy. However, smoked marijuana may not be accessible or safe for all patients with cancer. Also, these drugs have a unique side-effect profile that may include alterations in motor control, dizziness, dysphoria, and decreased concentration. This synthesis shows that cannabinoids are more effective than placebo and comparable to antiemetics such as prochlorperazine and ondansetron for CINV.”

However Taskhin et al warned “The potential for marijuana smoking to predispose to the development of respiratory malignancy is suggested by several lines of evidence, including the presence of potent carcinogens in marijuana smoke and their resulting deposition in the lung, the occurrence of premalignant changes in bronchial biopsies obtained from smokers of marijuana in the absence of tobacco, impairment of antitumor immune defenses by delta9tetrahydrocannabinol, and several clinical case series in which marijuana smokers were disproportionately over represented among young individuals who developed upper or lower respiratory tract cancer. Additional well designed epidemiological and immune monitoring studies are required to determine the potential causal relationship between marijuana use and 48 the development of respiratory infection and/or cancer.” and Russmann et al reported a

case history of a patient suffering a fatal stroke after smoking cannabis during a

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session of cisplatin chemotherapy for testicular cancer. In a general review, Drewe49 noted “Chronic marijuana smoking is associated with increased toxicity and the risk of cancer of the respiratory tract. There is evidence of disturbance of the immune system and 50 teratogenic effects of chronic cannabis use”. Gardner et al found methanandamide “resulted in an increased rate of tumor growth” in mouse lung cells, but noted “methanandamide augments tumor growth by a cannabinoid receptor-independent pathway” In a review of cancer pain therapies, Farquhar-Smith51 concluded “Cannabinoids may be a useful addition to current analgesic treatments. The evidence supports a possible role for cannabinoids in refractory cancer pain. However, to realize the full potential of cannabinoids suggested by preclinical data, it is likely that peripheral CB1 or CB2 receptors or modulation of endocannabinoids will have to be targeted to achieve analgesia without dose limiting side effects.”

Clinical Trials involving THC: Sallan et al (1975)52 found 10mg THC ‘significantly more effective’ than placebo at reducing nausea and vomiting in 22 chemotherapy patients. Chang et al53 (1979) found 10mg oral or 17mg smoked THC to decrease methotrexate-induced nausea and vomiting compared to placebo in 14 of 15 patients. Frytak et al54 found 15mg THC better than placebo at inhibiting prochorperazine-induced emesis, but noted some of the 116 gastrointestinal cancer patients to find the side effects (sedation, ‘high’ dysphoria, hypotension & tachycardia) intolerable. Orr & McKearnan55 found 7mg THC to be more effective than prochlorperazine and placebo in 55 patients, of which 82% reported a high. Lucas & Laszlo56 found 15mg or 2x5mg THC more effective than placebo or standard regimes. However Chang et al57 found 3-hourly oral (10mg) or smoked (17.4mg) THC ineffective compared with placebo in a small study of 8 patients receiving adriamycin and cyclophosphamide. Niedhart et al58 compared THC and Haloperidol in 52 chemotherapy patients finding no difference in efficacy between the two drugs. Gralla et al59 found 10mg THC more effective than placebo, but less effective than metoclopramide in controlling cisplatininduced vomiting in a 27-patient study. Ungerleider et al60 in a large study of 214 patients, found 4-hourly 7.5-12.5mg THC and 10mg prochlorperazine equally effective in reducing nausea and vomiting, but noted THC was preferred by more patients. Lane et al61 found significant improvement both with THC (10mg dronabinol) and prochlorperazine, and the combination more effective than either alone in abolishing nausea and vomiting in 62 patients. Clinical Trials involving Nabilone: Nagy et al62 studied 47 patients receiving cisplatin, finding nabilone more effective than prochlorperazine or placebo in reducing nausea & vomiting caused by cisplatin. Herman et al63 found similar results with 113 patients receiving cisplatin, cyclophosphamide & mustine therapy. Einhorn et al64 studied 100 chemotherapy patients, finding nabilone significantly more effective than prochlorperazine and preferred by 75% of patients, but noted lethargy and hypotension, similar results found in studies of 114 patients by Wada et al65, in 36 patients by Levitt et al66, 18 patients by

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Johannson et al67, 26 patients by Ahmedzal et al68 and 24 patients by Niranan & Mattison69. Jones et al70 found ‘significant reduction in nausea and vomiting with nabilone compared to placebo’ in a study of 54 patients and noted acceptable side effects to include dizziness (65%) and drowsiness (51%). Niederle et al71 found nabilone significantly better than alizapride in reducing cisplatininduced nausea & vomiting in 20 patients. Pomeroy et al72 found nabilone superior to domperidone in reducing vomiting episodes among 38 patients, as did Dalzell et al73 in a study of 23 children, finding that despite more side effects it was preferred by two thirds of respondents, and a study of 30 children by Chan et al74 found nabilone superior to prochlorperazine. Studies involving natural cannabis: Vinciguerra et al75 studied 56 cancer patients unresponsive to conventional antiemetic agents, who were asked to rate the effectiveness of marijuana compared to prior chemotherapy cycles. Smoked marijuana was rated as "moderately effective" or "highly effective." by 78% of patients. The authors concluded that marijuana had antiemetic efficacy, but no control group was used and the patient population varied with respect to prior marijuana use or THC therapy. A double-blind, cross-over, placebocontrolled study by Levitt et al76 compared smoked marijuana with oral THC among 20 patients receiving a variety of chemotherapy drugs. The efficacy was similar, with 25% of patients achieving complete control over vomiting. Seven patients (35%) indicated apreference for oral THC over marijuana; 4 patients (20%) preferred smoked marijuana and 9 patients (45%) expressed no preference. Neither study investigated the time course of antiemetic control, advantages of self-titration with the smoked marijuana, or ability of patients to swallow the pills. Patients with severe vomiting are unlikely to be able to swallow or keep pills down long enough for them to take effect. The onset of drug effect is much faster with smoked THC in cannabis than it is for oral delivery777879, and the differences in cannabinoid content of smoked cannabis compared to the oral THC route can alter the users perceptions and subjective effects. Haney et al80 reported smoked cannabis to make users feel ‘mellow’ whereas oral THC did not. . Although many cannabis users claim that smoking the drug provides more effective relief from vomiting than oral THC, no controlled studies have yet been published which firmly establish this to be the case. The British Medical Association81 concluded: “Cannabinoids are undoubtedly effective as anti-emetic agents in vomiting induced by anti-cancer drugs” and that “Systematic trials of the effectiveness of cannabinoids in combatting vomiting resulting from different chemotherapy agents should be carried out”. The United States Institute of Medicine report82 concluded: “In patients already experiencing severe nausea or vomiting, pills are generally ineffective, because of the difficulty in swallowing or keeping a pill down, and slow o nset of the drug effect. Thus an inhalation (but, preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea.” ... “It is possible that the harmful effects of smoking marijuana for a limited period of time might be outweighed by the antiemetic benefits of

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marijuana, at least for, patients for whom standard antiemetic therapy is ineffective and who suffer from debilitating emesis. Such patients should be evaluated on a case by case basis”

Reviewing options for pain relief in palliative care and the unsuitability of opiates in such circumstances, Carter et al83 argued for “reclassifying cannabis in the context of improving palliative care and reducing opioid-related morbidity” The House of Lords Science & Technology Select Committee made the following findings and recommendations in 199884: “...cannabis and cannabinoids are likely to be of benefit as anti-emetics only to the small proportion of patients who do not respond to existing treatments, or possibly in the treatment of the delayed stages of emesis which can occur for some days following cancer chemotherapy, and which do not respond well to the serotonin antagonists. Nevertheless, cannabinoids are undoubtedly effective as anti–emetics and more research in this field might explore their use in combination with the serotonin antagonists, help to determine for which patients they are most appropriate, and examine the potential of the allegedly less psychoactive cannabinoid D8–THC, for which there have been encouraging preliminary clinical results” “Unlike cannabis itself, the cannabinoid THC (dronabinol) and its analogue nabilone are already accepted by the Government as having medical value -- producing the anomaly that, while cannabis itself is banned as a psychoactive drug, THC, the principal substance which makes it psychoactive, is in legitimate medical use. Some of our witnesses are prepared to contemplate wider medical use of the cannabinoids, but not of cannabis itself. We disagree, since some users of both find cannabis itself more effective. We do, however, welcome the inclusion of THC in the trials proposed by the Asscher group, in like-for-like comparison with cannabis itself” “Dronabinol (THC), though not licensed in this country, has already been moved to Schedule 2 to the Misuse of Drugs Regulations, and nabilone is a licensed medicine and not a controlled drug; so no Government action is required in either case to permit clinical trials or indeed prescription. ...we recommend that the Government should raise the matter of rescheduling the remaining cannabinoids with the WHO in due course, in order to facilitate research.” “Our principal reason for recommending that the law be changed, to make legal the use of cannabis for medical purposes, is compassionate. Illegal medical use of cannabis is quite widespread; it is sometimes connived at and even in some cases encouraged by health professionals; and yet at present it exposes patients and in some cases their carers to all the distress of criminal proceedings, with the possibility of serious penalties. We acknowledge that, if our recommendation were implemented, the United Kingdom would be moving out of step with many other countries; we consider that the Government should not be afraid to give a lead in this matter in a responsible way.”

Anti-tumour activity In 1975 Munson85 first noted cannabinoids (delta9-THC, delta8-THC, and cannabinol CBN, but not CBD) to suppress Lewis lung carcinoma cell growth. Recent scientific advances in the study of cannabinoid receptors and endocannabinoids have produced exciting new leads in the search for anticancer treatments, with CB1 and CB2 agonists (like THC) associated with tumour regression, reduced proliferation and blood supply to tumours(Angiogenesis86), and apoptosis (programmed cell-suicide) among cells of various cancer types. Vidinskiy et al87 noted “in the late 1990s… possible mechanisms of antitumour action were identified - apoptosis induction, direct cell cycle arrest 88 and angiogenesis and metastasis inhibition” Pushkarev et al noted “proapoptotic, pronecrotic and protective, antiapoptotic effects of cannabinoids and, especially Nacylethanolamines”

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Blazquez et al89 reported “Cannabinoids, the active components of marijuana and their derivatives, induce tumor regression in rodents... Inhibition of tumor angiogenesis may allow new 90 strategies for the design of cannabinoid-based antitumoral therapies.” Fowler et al concluded “the antiproliferative effects of anandamide were not solely mediated by either its hydrolysis to produce arachidonic acid or its CB receptor-mediated activation of phospholipase A(2) since palmitoyltrifluoromethyl ketone did not prevent the response to 91 anandamide.” Recht et al found a metabolite of THC ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) to be “a potent anti-inflammatory agent without psychoactive properties... Its very favorable toxicity profile, including lack of psychoactivity, 92 makes it suitable for chronic usage.” Bifulco et al reported endocannabinoids to “inhibit cell growth, invasion and metastasis of thyroid, breast and prostate tumours. The chief events of endocannabinoids in cancer cell proliferation are reported highlighting the correspondent signalling involved in tumour processes: regulation of adenylyl cyclase, cyclic AMP-protein kinase-A pathway and MEK-extracellular signal-regulated kinase signalling cascade.”

Ramer et al93 found “a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive 94 cancers.” Hu et al noted “the orphan G protein-coupled receptor 55 (GPR55) was proposed to be an atypical cannabinoid receptor. In this issue of Oncogene, two groups demonstrated that GPR55 is expressed in various cancer types in an aggressiveness-related manner”

Parolaro et al95 concluded “Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors” Bifulco & Di Marzo96 reviewed studies of antitumour activity and concluded “Recently, evidence has accumulated indicating that stimulation of cannabinoid receptors by either THC or the endocannabinoids influence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to anti-tumour effects both in vitro and in vivo. This evidence is reviewed here and suggests that future anti-cancer therapy might be developed from our knowledge of how the endocannabinoid system controls the growth and metastasis of malignant cells.”

Patsos et al97 concluded “there is accumulating evidence that [cannabinoids] could also be useful for the inhibition of tumour cell growth by modulating key survival signalling pathways” Carracedo98 noted “By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential 99 mediator of cannabinoid antitumoral action” Ligresti et al tested cannabidiol,

cannabigerol, cannabichromene, cannabidiol acid and THC acid, and

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compared using Cannabis extracts (enriched in either cannabidiol or THC) to pure cannabinoids, finding “Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth (IC(50) between 6.0 and 10.6 microM), with significantly lower potency in noncancer cells. The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency.”

Some researchers have investigated the link between mental and spiritual state and cancer remission, associating the cannabinoid system with the expression of pleasure on the one hand and stress on the other. Lissoni et al100 reviewed the effect of psychospiritual state on cancer growth or suppression, noting “Stress, anxiety and depressive states are associated with immunosuppression and enhanced frequency of tumors. On the other hand, the states of sexual pleasure and spiritual joy enhance the immune efficacy, by counteracting tumor onset and dissemination. The biochemistry of pleasure and immunostimulation is mainly mediated by pineal indoles and cannabinergic substances, whereas that of stress, anxiety and depression is associated with enhanced production of adrenal steroids, opioids and catecholamines.”

Lung Cancers Studying lung cancers in mice, Preet et al101 found “Tumor samples from THC-treated animals revealed antiproliferative and antiangiogenic effects of THC. Our study suggests that cannabinoids like THC should be explored as novel therapeutic molecules in controlling the 102 growth and metastasis of certain lung cancers.” Ramer et al reported “cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness”

Ramer et al103, studying human lung cancer cell cultures, noted “Cannabidiol caused a profound inhibition of A549 cell invasion, accompanied by a decreased expression and secretion of PAI-1. Cannabidiol's effects on PAI-1 secretion and invasion were suppressed by antagonists to CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1. Recombinant human PAI-1 and PAI-1 siRNA led to a concentration-dependent up- and down-regulation of invasiveness, respectively, suggesting a crucial role of PAI-1 in A549 invasiveness. Evidence for a causal link between cannabidiol's effects on PAI-1 and invasion was provided by experiments showing a reversal of its anti-invasive action by addition of 104 recombinant PAI-1 at non-proinvasive concentrations.” Athanasiou et al reported “Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Delta-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis.”

Preet et al105, investigating non-small cell lung cancer (NSCLC) cell cultures found “treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells. We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2. In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion. In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%).”

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Breast Cancers Di Marzo et al106 noted the “anti-proliferative effect of anandamide in human breast cancer cells” was enhanced by Palmitoylethanolamide. De Petrocellis et al107 considered this effect to be mediated by CB1 and vanilloid receptors. Grimaldi et al108 concluded “CB1 receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB1 receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to 109 inhibit its metastatic diffusion in vivo” Sarnataro et al found the CB1-receptor antagonist SR141716 “inhibits human breast cancer cell growth via a CB1R lipid 110 raft/caveolae-mediated mechanism” McAllister et al reported “CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness.” Laezza et

al111 found the anandamide analog, Met-F-AEA, to control human breast cancer cell migration via the RHOA/RHO kinase signaling pathway. Qamri et al112 tested the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 on breast cancer cells, reporting “Mice treated with JWH133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumorsuppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.”

Studying a breast cancer model in mice, Caffarel et al113 reported “both Delta9tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2… Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based 114 therapies for the management of ErbB2-positive breast cancer.” Caffarel et al found

delta-9-THC to inhibit cell cycle progression in human breast cancer cells, later noting115 “cannabinoids regulate JunD … [and] JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression”

McAllister et al116 reported “CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer.”

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Shrivastava et al117 reported “CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation… Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis… highlight[ing] the value of continued investigation into the potential use of CBD as an antineoplastic agent.”

However Takeda et al118 noted THC to stimulate growth of MCF-7 breast cancer cells modulated by COX-2 inhibitors and aromatase. Bowel Cancers Studying the effect of cannabinoid receptor agonists and antagonists on different types of colorectal cancer cells, Ligresti et al119 found “Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB(1) antagonist SR141716A, but not by the CB(2) antagonist SR144528, and is mimicked by CB(1)-selective, but not CB(2)-selective, agonists. In DLD-1 cells, both CB(1) and CB(2) receptors mediate inhibition of proliferation.”

Gustafsson et al120 tested a number of synthetic cannabinoids on human colorectal cancer cells in vitro, noting “The compounds examined produced cytotoxic, rather than 121 antiproliferative effects, by a mechanism not involving CB receptors” Santoro et al reported “rimonabant (SR141716) is able to inhibit colorectal cancer cell growth at different stages of colon cancer pathogenesis inducing mitotic catastrophe in vitro” Gazzerro et al122 reported that “combined synergic effect of SR141716 and oxaliplatin improves the blocking of colon cancer cell proliferation.” Thapa et al123 found hexahydrocannabinol analogs had no receptor affinity but induced apopotosis in human colon cancer cells, also finding they inhibited proliferation and angiogenesis124 Gustsafsson et al125 concluded “The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of 126 a poorer prognosis in stage II microsatellite stable tumour patients.” Aviello et al reported “Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.”

In a study of CB1-receptor gene expression in bowel cancer patients, Bedoya et al127 reported “A large number of patients with mutation in the CNR1 gene were observed. These preliminary findings highlight the importance of further studies in the use of cannabinoid 128 analogs as receptor ligands to analyze potential therapeutic effects” Cianchi et al reported “either CB1 or CB2 receptor activation induces apoptosis through ceramide de 129 novo synthesis in colon cancer cells” Wang et al found “loss or inhibition of CB1 accelerated intestinal adenoma growth in Apc(Min/+) mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via down-regulation of the antiapoptotic factor survivig”

Greenhough et al130 suggested “an important role for CB1 receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 131 receptor, may represent a novel strategy for colorectal cancer therapy” Patsos et al

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concluded “anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may also be used in the 132 eradication of tumour cells that have become resistant to apoptosis.” Patsos et al reported “anandamide can induce cell death in the apoptosis-resistant HCT116 Bax-/133 colorectal cell line” Proto et al concluded “Our results partially elucidated the role of EC system in the molecular mechanisms enrolled by steroids in the inhibition of colon cancer cell growth and strongly suggested that targeting the EC system could represent a promising tool to improve the efficacy of CRC treatments.”

Izzo et al134 reported “pharmacological enhancement of endocannabinoid levels (through inhibition of endocannabinoid hydrolysis) reduces the development of precancerous lesions in 135 the mouse colon” and noted “recent data highlight… the emerging role of CB(2) receptor as a critical target able to counteract hypermotility in pathophysiological states, gut 136 inflammation and possibly colon cancer” Izzo & Camilleri noted “Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids - via direct or indirect activation of CB(1) and/or CB(2) receptors - exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.”

Leukaemia & Lymphomas Joseph et al137 noted anandamide to inhibit migration of tumour cells and Tlymphocytes via activity at CB1-receptors. Piszcz et al138 found “original evidence for the existence of cannabinoid receptors on B-lymphocytes in chronic lymphocytic leukaemia patients. The receptors are thought to be a new structure that can modify the course of the disease and may be considered as a new target in leukaemia treatment.” Liu et al139 concluded “a combination approach with THC and established cytotoxic agents 140 may enhance cell death in vitro” Jia et al noted that delta9-THC induced

apoptosis in Jurkat leukemia T cells. Herrera et al141 considered their data to “support a role for [mitogen-activated protein kinases] in CB2 receptor-induced apoptosis of 142 human leukaemia cells” McKallip et al noted “Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in 143 tumor burden and an increase in apoptotic tumors in vivo.” However Joosten et al

postulated that an overabundance of CB2 receptors in transgenic mice may increase predisposition to leukaemia, and Jorda et al144 concluded “a major function of Cb2 receptor expressed on myeloid leukemia cells or normal splenocytes is stimulation of migration”

In a study of lymphobastomas, McKallip et al145 found “human tumor cells were also susceptible to apoptosis induced by THC, HU-210, anandamide, and the CB2-selective agonist JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel 146 anticancer agents to selectively target and kill tumors of immune origin.” Islam et al noted a “high expression of the cannabinoid receptor 1 (CB1) gene in all Mantle Cell 147 Lymphoma cases analysed” Rayman et al found expression of the peripheral

cannabinoid receptor CB2 to have no effect on clinical outcome in diffuse

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large B-cell lymphomas. Rayman et al148 concluded “CB2 receptor expression pattern may be abnormal in [Non-Hodgkins Lymphoma]”

Flygare et al149 concluded “cannabinoid receptors may be considered as potential therapeutic targets in [mantle cell lymphoma]” Gustafsson et al150 concluded “targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.” Wasik et al151 noted “In [mantle cell lymphoma] cannabinoids mainly reduce cell proliferation and induce cell death. Importantly, our recent findings demonstrate that cannabinoids may induce either apoptosis or another type of programmed cell death, cytoplasmic vacuolation/paraptosis in MCL. The signalling to death has been partly characterized.”

Pancreatic Cancers Fogli et al, studying pancreatic cancer cells, found cannabinioids to “produce a 152 significant cytotoxic effect via a receptor-independent mechanism” Carracedo et al concluded “cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer”

Michalski et al153 reported “Cannabinoids exert antiproliferative properties in a variety of malignant tumors, including pancreatic ductal adenocarcinoma (PDAC)… changes in the levels of endocannabinoid metabolizing enzymes and cannabinoid receptors on pancreatic 154 cancer cells may affect prognosis and pain status of PDAC patients.” Donadelli et al noted “The combined [gemcitabine/cannabinoid] treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects.”

Skin Cancers In a study of skin cancers, Casanova et al155 found “In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel 156 morphology and decreased expression of proangiogenic factors” Bifulco et al found

an analogue of anandamide to inhibit oncogene-mediated tumour growth via CB1-receptor activity. Blazquez et al157 reported “Activation of [CB1 & CB2] receptors decreased growth, proliferation, angiogenesis and metastasis, and increased apoptosis, of melanomas in mice” Zheng et al158 noted “CB1/2 receptors play a key role in UV-induced inflammation and skin cancer 159 development.” Zhao et al noted “High expression of CB2 in squamous cell carcinoma suggests an important role of CB2 in the tumorigenesis and development of squamous cell 160 carcinoma.” Scuderi et al reported “antiproliferative effects of the cannabinoid agonist WIN upon human melanoma cells”

Luca et al161 noted the CB1/CB2 receptor agonist WIN-55,212-2 to reduce viability of human Kaposi's sarcoma cells in vitro. 14

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Prostate Cancers Mimeault et al162, studying prostate cancer, reported “The potent anti-proliferative and cytotoxic effects of (anandamide) on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive 163 prostatic cancers.” Chung et al found high cannabinoid CB(1) receptor

immunoreactivity to be associated with disease severity and outcome in prostate cancer. Fowler et al164 noted that high tumour CB(1) receptor expression at diagnosis was associated with a poorer prognosis. Sarfaraz et al165 concluded “WIN-55,212-2 or other non-habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer” Sarfaraz et al166 later noted WIN55212-2 - cannabinoid receptor agonist, induced apoptosis of human prostate cancer cells. Sreevalsan et al167 reported the induction of apoptosis by cannabinoids in prostate and colon cancer cells to be phosphatase dependent. Nithipatikom et al168 noted “cellular 2-AG, acting through the CB1 receptor, is an endogenous inhibitor of invasive prostate cancer cells” They later noted169 “unique CB1 signaling and support the model that [endocannabinoids], through their autocrine activation of CB1 and subsequent repression of 170 RhoA activity, suppress migration in prostate carcinoma cells” Olea-Herrero noted “the involvement of CB(2)-mediated signalling in the in vivo and in vitro growth inhibition of prostate cancer cells and suggests that CB(2) agonists have potential therapeutic interest and 171 deserve to be explored in the management of prostate cancer” later reporting “CB2 agonists may offer a novel approach in the treatment of prostate cancer by decreasing cancer epithelial cell proliferation”

Diaz-Laviada172 concluded “Accumulating evidence indicate that the endocannabinoid system is dysregulated in prostate cancer, suggesting that it has a role in prostate homeostasis. Overexpression of several components of the endocannabinoid system correlate with prostate cancer grade and progression, potentially providing a new therapeutic target for prostate cancer. Moreover, several cannabinoids exert antitumoral properties against prostate cancer, reducing xenograft prostate tumor growth, prostate cancer cell proliferation and cell migration… the therapeutic potential of cannabinoids against prostate cancer is very promising”

Bone Cancers In mice, Hald et al173 found the CB1 receptor agonist WIN55,212-2 “reduced pain related behavior and expression of spinal glial fibrillary acidic protein in the bone cancer 174 pain model but not in the neuropathic pain model” Khasabova et al concluded “manipulation of peripheral endocannabinoid signaling is a promising strategy for the 175 management of bone cancer pain” Idris concluded “cannabinoid receptor ligands show a great promise in the treatment of bone diseases associated with accelerated osteoclastic bone resorption including osteoporosis, rheumatoid arthritis and bone metastasis”

Lozano-Ondoua et al176 studied the effect of AM1241, a CB(2) agonist on pain and bone density in a bone cancer model in mice, finding “The systemic administration of AM1241 acutely or for 7days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the

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incidence of cancer-induced bone fractures.” Curto-Reyes et al concluded “The use of drugs that activate CB(2) receptors could be a useful strategy to counteract bone cancerinduced pain symptoms.”

Brain Cancers In a 2002 review. Guzman et al178 concluded “cannabinoid administration induces regression of malignant gliomas in rodents by a mechanism that may involve sustained ceramide generation and extracellular signal-regulated kinase activation. In contrast, most of the experimental evidence indicates that cannabinoids may protect normal neurons from toxic insults, such as glutamatergic overstimulation, ischaemia, and oxidative damage. Regarding immune cells, low doses of cannabinoids may enhance proliferation, whereas high doses of 179 cannabinoids usually induce growth arrest or apoptosis.” In 2003 Guzman added “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.”

Goncharov et al180 found Delta9-THC to increase glioma cell death produced by oxidative stress. Studying the effects on human glioma cells Massi et al181 reported “CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent” Velasco et al182 noted “Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from 183 death.” Blazquez et al concluded “Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas” resulting in reduced tumour size. Contassot et al184 observed “[arachidonylethanolamide] (AEA) induced apoptosis in long-term and recently established glioma cell lines via aberrantly expressed vanilloid receptor-1 (VR1). In contrast with their role in THC-mediated death, both CB1 and CB2 partially protected glioma 185 against AEA-induced apoptosis” Vaccani et al noted CBD to inhibit human

glioma cell migration with no apparent effect of CB1 or CB2 receptor antagonists, concluding “These results reinforce the evidence of antitumoral properties 186 of CBD, demonstrating its ability to limit tumor invasion” Sanchez et al reported “growth of the rat glioma (one of the most malignant forms of cancer) is inhibited by psychoactive cannabinoids” and that “local administration of (a) selective CB(2) agonist... 187 induced a considerable regression of malignant tumors”. Jacobsson et al concluded “the antiproliferative effects of the endocannabinoids upon (rat glioma) cells are brought about by a mechanism involving combined activation of both vanilloid receptors and to a lesser extent cannabinoid receptors”

Gomez del Pulgar188 et al found THC to cause death of glioma cells due to local synthesis of ceramide, and demonstrated189 a neuroprotective effect of cannabinoids on astrocytes. Duntsch et al190 tested KM-233, a selective CB2receptor agonist against Delta-9-THC in promoting cell-death among human glioma cells, finding both to be equally effective. Held-Feindt et al191 noted “CB1 receptor agonists reduced elevated cyclic AMP levels and slightly reduced proliferation

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of glioma cells in vitro, but did not induce apoptosis. We conclude that cannabinoid therapy of human gliomas targets not only receptors on tumor, but also on other cell types.” De

Lago et al192 found anandamide reuptake inhibitors caused rapid toxicity to C6 glioma cells. Massi et al193 found “a different sensitivity to the anti-proliferative effect of CBD in human glioma cells and non-transformed cells that appears closely related to a selective ability of CBD in inducing ROS production and caspase activation in tumor cells” Aguado et al194 reported “cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in 195 the management of malignant gliomas” Lorente et al noted “Delta9Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the ability of these compounds to induce apoptosis of tumor 196 cells.” Wu et al noted “the expression levels of cananbinoid receptors, CB1 and CB2, were elevated in human glioma tissues. The changes of anandamide and 2-AG contents in different stages of gliomas may qualify them as the potential endogenous biomarkers for glial tumor malignancy”

McAllister et al197 found cannabinoids (delta-9-THC & WIN 55,212-2) to selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. Guzman et al198 conducted a clinical trial of intracranial THC injections into glioblastoma multiforme tunours finding the procedure to be safe, and indicating “possible antiproliferative action on tumour cells” Galanti et al199 concluded “Delta(9)-THC is shown to significantly affect viability of GBM [glioblastoma multiforme] cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain 200 tumors.” In 2008 reviews, Parolaro & Massi concluded “cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts. A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects” Calatozzolo et al201 noted “A potential role of cannabinoids, particularly of CB2 agonists devoid of psychotropic side effects, in glioma therapy could have a basis in glioblastomas, because they were all positive, though weakly, to CB2.”

Investigating the effects of THC and CBD on human glioblastoma cell cultures, Marcu et al202 reported “Delta(9)-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Delta(9)-THC may improve the overall effectiveness of Delta(9)-THC in the treatment of glioblastoma in cancer patients.” De Jesus et al203 reported “CB(1) receptor immunoreactivity was significantly lower in glioblastoma multiforme (-43%, n=10; p<0.05) than in normal post-mortem brain tissue (n=16). No significant differences were found for astrocytoma (n=6) and meningioma (n=8) samples. Conversely, CB(2) receptor immunoreactivity was significantly greater in membranes of glioblastoma multiforme (765%, n=9; p<0.05) and astrocytoma (471%, n=4; p<0.05) than in control brain tissue (n=10).”

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Foroughi et al204 reported the case studies of “two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case. During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression.” Widmer et al205 reported “Human U373MG glioma cells are sensitive only to very high, pharmacologically irrelevant concentrations of cannabinoids [>5µg/ml THC], so it seems unlikely that cannabinoids would constitute promising molecules for treating malignant astrocytoma; they do not induce glioma cell death at doses that could be applied safely to humans.”

Petersen et al206 compared endocannabinoid metabolism in two types of brain carcinoma tissue with non-cancerous brain tissue and concluded “The enhanced level of the 2-arachidonoyl glycerol, anandamide and other N-acylethanolamines detected in the two types of tumour tissue may possibly act as endogenous anti-tumour mediators by stimulation of both cannabinoid and non-cannabinoid receptor-mediated mechanisms.”

Rubovitch et al207 demonstrated CB1-receptor-agonist modulated stimulation of calcium ion uptake in neuroblastoma cells. Studying paediatric cancers, Ellert-Miklaszewska et al208 reported “CB2 receptor expression depends primarily on the histopathological origin of the brain tumor cells and differentiation state, reflecting the tumor grade.”

In a 2007 review, Cudaback & Stella209 noted “evidence supporting the use of cannabinoids 210 for treatment of brain tumors” Velasco et al concluded “cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential 211 antitumoral activity of cannabinoids.” Salazar et al reported “THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.”

Other Cancers Thyroid: In a study of thyroid cancer cells, Portella et al212 noted “Stimulation of cannabinoid CB1 receptors ... inhibits the growth of a rat thyroid cancer cell-derived tumor in athymic mice” and concluded “CB1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and 213 metastasis” In mice with thyroid cancers, Bifulco et al noted “endocannabinoids tonically control tumor growth in vivo by both CB1-mediated and non-CB1-mediated mechanisms and that, irrespective of the molecular mechanism of their anti-proliferative action, inhibitors of their inactivation might be used for the development of novel anti-cancer 214 drugs.” In thyroid cancer, Shi et al reported “CB2 overexpression may contribute to the regression of human anaplastic thyroid tumor in nude mice following IL-12 gene transfer.

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Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma” Cozzolino et al215 reported “(Met-F-AEA), a metabolically stable analogue of anandamide, [was associated with] growth inhibition in cell lines derived from thyroid carcinomas. Growth inhibition was associated with a high level of CB1 receptor expression, suggesting that the cytotoxic effect is due to interaction with the CB1 receptor.”

Pituitary: Gonzalez et al216 found reduced CB1-receptor activity to be associated with development of pituitary cancers, noting “estrogen-induced pituitary hyperplastia 217 was associated with a marked reduction in CB1 receptors” Pagotto et al found elevated CB1 receptor activity and endocannabinoids in tumorous pituitary gland cells, noting “The results of this study point to a direct role of cannabinoids in the regulation of human pituitary hormone secretion.” Liver: Xu et al218 noted “CB1 and CB2 have potential as prognostic indicators and suggest possible beneficial effects of cannabinoids on prognosis of patients with HCC [human 219 hepatocellular carcinoma].” Pellerito et al found the synthetic cannabinoid

WIN 55,212-2 to sensitizehepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Stomach: In gastric cancer cell cultures, Miyato et al220 found anandamide “stimulated proliferation at concentrations under 1 microM, while it strongly suppressed proliferation 221 through the induction of apoptosis at 10 microM” Xian et al found “The cannabinoid agonist WIN 55,212-2 inhibited the proliferation of human gastric cancer cells in a dosedependent manner and that this effect was mediated partially by the CB(1) receptor. We also found that WIN 55,212-2 induced apoptosis and down-regulation of the phospho-AKT expression in human gastric cancer cells. Furthermore, WIN 55,212-2 treatment inhibited the invasion of gastric cancer cells, and down-regulated the expression of MMP-2 and VEGF-A through the cannabinoid receptors. Our results open the possibilities in using cannabinoids 222 as a new gastric cancer therapy.” Park et al reported “treatment of gastric cancer cells with a cannabinoid agonist significantly decreased cell proliferation and induced apoptosis… cannabinoid agonist[s] can reduce gastric cancer cell proliferation”

Bile Duct: Studying bile duct carcinomas, Leelawat et al223 found “THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis. THC also decreased actin 224 polymerization and reduced tumor cell survival in anoikis assay.” Huang et al reported “GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma”

Womb/Cervix: Studying cannabinoid receptor distributions in endometrial carcinoma samples, Guida et al225 reported “the endocannabinoid system seems to play an important role in human endometrial carcinoma, and modulation of CB(2) activity/expression 226 may account for a tumor-suppressive effect” In cervical cancer, Ramer & Hinz found “Without modifying migration, MA and THC caused a time- and concentrationdependent suppression of HeLa cell invasion” and concluded “Cannabinoids may… offer a therapeutic option in the treatment of highly invasive cancers.”

Mouth: Studying metabolism of human oral cancer cells, White et al227 reported “A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was

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the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the 228 cannabinoid receptors.” Saghafi et al reported “a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer.”

Kidney: Comparing renal cancer samples with uninvaded kidney tissues, Larringa et al229 found “a marked downregulation of CB₁ protein in tumor tissue; CB₂ was not expressed. The obtained data suggest a possible implication of the endocannabinoid system in renal carcinogenesis”

Summary & Conclusions Cancer Risk: Cannabis smoke, like tobacco smoke, contains a number of carcinogens. Smoking of cannabis releases a number of non-cannabinoid carcinogens into the lungs and upper respiratory tract, and a number of researchers (notably Tashkin and colleagues) have identified pre-cancerous changes in lung cells. It would be logical to expect a substantial increase in the risk of lung and other cancers among regular and long-term smokers of cannabis. Effective epidemiological studies are limited by the legal status of cannabis and the willingness of patients to admit to an illegal activity to their doctors or to researchers. As a result the few studies which have been conducted can be criticised for small sample sizes (hundreds rather than thousands) and inadequate control methods for other factors such as tobacco use. Studies in North Africa and New Zealand have suggested there to be an increased risk of developing lung cancer from cannabis smoking, and two studies have suggested an increased risk of testicular cancer, although other studies have found little or no evidence of increased risk or even reduced risk of certain cancers. It is likely that the antitumour activity of THC, CBD and other cannabinoids is responsible for reducing the risk from non-cannabinoid components of cannabis smoke. There is no evidence that cannabinoids in themselves are carcinogenic, e.g. if administered orally or via other non-smoking related methods. Cancer Chemotherapy: Although other recently developed anti-emetics are as effective or more effective than oral THC, nabilone or smoked cannabis, for certain individuals unresponsive to conventional anti-emetic drugs, the use of smoked cannabis can provide relief more effectively than oral preparations which may be difficult to swallow or be expelled in vomit before having a chance to take effect. The psychoactive/euphoriant effects of THC or smoked cannabis may provide an improvement in mood, whereas several conventional preparations e.g. phenothiazines such as haloperidol (known as ‘major tranquillisers’ and also used in the treatment of psychoses such as schizophrenia), may produce

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unwanted side effects such as excessive sedation, flattening of mood, and/or distressing physical ‘extrapyramidal’ symptoms such as uncontrolled or compulsive movements. A 1991 US survey230 found public support for marijuana use by cancer patients. In the USA, synthetic THC (Dronabinol) is available for use as an adjunct to cancer chemotherapy treatment, and in the UK, both the British Medical Association and House of Lords recognised the potential for use of cannabinoids in preventing nausea and vomiting. Direct anti-cancer activity of cannabinoids. There is substantial and growing scientific evidence of direct anti-tumour activity of cannabinoids, specifically CB1 and CB2 agonists (reversed by antagonists) and also of CBD, over a wide range of cancer types. Disorders of the endocannabinoid system have been implicated in the regulation of cancer cell growth and development with high numbers of receptors in cancer cell cultures, and antitumour effects have been found to be mediated by known cannabinoid receptor interactions. Indeed, the complex interactions of endogenous cannabinoids and receptors is leading to greater scientific understanding of the mechanisms by which cancers develop. The antitumour activity has led in laboratory animals and in-vitro human tissues to regression of tumours, reductions in vascularisation (blood supply) and metastases (secondary tumours), as well as direct inducement of death (apoptosis) among cancer cells. Cannabis-based medicines would appear to offer great promise as effective anti-cancer therapies, particularly in conjunction with existing or novel (geneticallytailored) chemotherapies. Matthew J Atha BSc MSc LLB Independent Drug Monitoring Unit © IDMU Ltd - 12th April 2012

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Cannabinoids & Cancer

12th April 2012

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Cannabinoids & Cancer

12th April 2012

Ramer R, Hinz B. [2008] Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst. 100(1):59-69. Epub 2007 Dec 25. Whyte DA, Al-Hammadi S, Balhaj G, Brown OM, Penefsky HS, Souid AK. [2010] Cannabinoids inhibit cellular respiration of human oral cancer cells. Pharmacology. 85(6):328-35. Epub 2010 Jun 2. Saghafi N, Lam DK, Schmidt BL. [2011] Cannabinoids attenuate cancer pain and proliferation in a mouse model. Neurosci Lett. 488(3):247-51. Epub 2010 Nov 19. Larrinaga G, Sanz B, Pérez I, Blanco L, Cándenas ML, Pinto FM, Gil J, López JI. [2010] Cannabinoid CB₁ receptor is downregulated in clear cell renal cell carcinoma. J Histochem Cytochem. 58(12):1129-34. Epub 2010 Sep 17. Treaster JB. [1991] Survey finds support for marijuana use by cancer patients.NY Times (Print). 1991 May 1;:D22.