Treatment with cannabinoids, either THC, the main marijuana-derived It has been previously reported that a high percentage of tumor-bearing MMTV-neu .. Anti-CB1 receptor antibody was generously donated by Dr. Ken Mackie, .. Guzman M, Mechta-Grigoriou F, Sanchez C. JunD is involved in the. A major discovery in cancer in cannabinoid use in cancer treatment is its ability in .. A recent report showed that FAAH is also over-expressed in prostate cancer cells .. Velasco G, Sanchez C, Guzman M. Towards the use of cannabinoids as Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, et al. No other forms of treatment were used while taking the oil. The following is a video on YouTube which profiles Dr Christina Sanchez, Dr Donald Tashkin and Dr Donald Abrams and their findings on cannabis and cancer. used cannabis oil to fight their cancer have reported that it takes around 2 weeks.
Treatment on Dr. Cannabinoids and Reports Sanchez Cancer
Showing of 29 extracted citations. A novel potential effective strategy for enhancing the antitumor immune response in breast cancer patients using a viable cancer cell-dendritic cell-based vaccine. The role of circulating tumor cells in metastatic breast cancer: Clinical Trials and Nanotechnology M.
Anticancer mechanisms of cannabinoids. Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells Sindiswa T. Lukhele , Lesetja Raymond Motadi. Citation Statistics 59 Citations 0 5 10 15 '14 '16 ' Semantic Scholar estimates that this publication has 59 citations based on the available data. Generally speaking, cb 1 signalling mediates neuromodulatory activities, and cb 2 signalling mostly mediates immunomodulatory activities.
Thus, cannabinoid signalling is intrinsically involved in multiple physiologic and homeostatic systems as well as in pathophysiologic mechanisms 1 — 4 , 8 — The main human endocannabinoids are N- arachidonylethanolamide and 2-arachidonlyglycerol.
Those two molecules activate cb 1, cb 2, gpr 55, and transient receptor potential ion channels such as trpv 1 1 — 4 , 8 — Endocannabinoids, acting as retrograde synaptic messengers at neural synapses, are short-lived because they are degraded by fatty acid amide hydrolase. Exogenous cannabinoids, whether pharmaceutical or botanically sourced, mimic and potentiate signalling by the endocannabinoids 1 — 4 , 8 — Exogenous cannabinoids such as botanically derived thc and pharmaceuticals such as nabilone and dronabinol are agonists of both cb 1 and cb 2 1 — 4 , 8 — Cannabidiol functions as an activator of trpv 1, an inhibitor of both cyclooxygenase and lipoxygenases, and reduces N- methyl- d -aspartate toxicity.
The activity of cbd as a negative allosteric inhibitor of cb 1 helps to reduce the cb 1-mediated psychotomimetic effects of thc , thereby increasing its therapeutic potential 11 , 13 , In Canada, more than strains of medical cannabis are available from licensed producers 5. Given the heterogeneity of both the cannabinoid and non-cannabinoid components of those multiple strains, it is not surprising that their complete pharmacologic profiles have not been fully elucidated.
Although much is known about botanically sourced thc and cbd , and the pharmaceutical cannabinoid agents, little clinical data on the pharmacology of terpenoids and flavonoids have been published. Adverse outcomes such as psychotomimetic reactions and hypotension are more likely to occur with recreational cannabis because it tends to be preponderant in thc.
The Cannabis plant yields inactive acidic forms of thc and cbd , namely thc - a and cbd - a. The process of decarboxylation, which occurs through thermal treatment heating or combustion , generates the pharmacologically active formats 15 , Although dried botanical cannabis from licensed producers for medical use is not thermally treated, medical cannabis oils contain cannabinoids that have undergone decarboxylation Tweed Inc.
Personal communication, 18 September Generally speaking, higher bioavailability levels are achieved with smoking and vaporization than with oral ingestion. Peak serum concentrations occur within 2—10 minutes. Absorption of both thc and cbd from the gastrointestinal tract is good, but both molecules undergo extensive first-pass metabolism. Table i summarizes the pharmacokinetic profiles of the various forms of cannabinoid therapies 5 , 17 — As summarized in Table ii , thc and cbd are both processed through the cytochrome P cyp system in the liver 5 , 17 — The effect of cyp 2C9 on thc metabolism is significantly affected by genetic polymorphisms; compared with individuals carrying high-functioning variants, those who carried genetic variants with diminished function experienced a doubling or tripling in thc exposure Furthermore, higher levels of thc and cbd can be observed with concomitant use of strong cyp 3A4 inhibitors.
Although neither thc nor cbd are inducers of cyp enzymes, both are inhibitors of a number of those enzymes, most notably 3A4, the enzyme that has the largest number of commonly used medical drugs as substrates Smoked cannabis has been noted to induce cyp 1A2 Being highly lipophilic, thc and cbd both have a large volume of distribution. They are also highly bound by serum proteins. Although, theoretically, a high incidence of drug—drug interaction by displacement from protein binding sites might be expected, only one case report to date has described the occurrence of an increased normalized ratio and bleeding complications in a patient who smoked recreational cannabis Although the assessment and treatment of pain and other symptoms in patients with advanced cancers has become a standard of care, many patients still have incomplete symptom control That situation persists despite a plethora of pharmaceutical therapies, including opioid analgesics and adjuvant or targeted therapies for example, antiepileptic and antidepressant therapies.
Many oncology physicians are unaware of the potential medical benefits of cannabis 28 and are unwilling or unable to authorize their use. A selective review of the best-supported treatments follows. Cannabinoids, including herbal cannabis and extracts, have been used for the treatment of pain for centuries. There is evidence in historical texts and ancient pharmacopeia of treatment for various pain syndromes—from menstrual cramps to childbirth to headaches 1 — 3.
In terms of cannabinoid use in the modern era, an emerging literature includes systematic reviews that are showing benefit in several areas, including non-cancer pain 34 , Early studies using dronabinol, nabilone, and levonantradol demonstrated benefit, but their methodologies were not as rigorous as in more recent trials, and so the benefits might have been overestimated The few trials using cannabinoids in acute pain have shown essentially no benefit, and present recommendations are against cannabinoid use in the postoperative setting 37 — Cannabinoid treatments for cancer pain have been studied in a few randomized trials, but the evidence has been less than convincing.
Earlier studies published before , as reviewed by Campbell et al. Comparators such as codeine and secobarbital are not commonly used in patients with severe cancer pain, and so it is difficult to extrapolate the results. More recently, two placebo-controlled trials using a cannabis extract nabiximols did show modest benefit when used in addition to opioids and other adjuvant pain medications in patients with chronic cancer pain 40 , Chronic neuropathic pain has received the most focus, with studies looking at the use of pharmaceutical cannabinoids and cannabis and its extracts in a variety of settings posttraumatic neuropathies, diabetic neuropathy, aids -related neuropathic pain, and so on.
Two recent publications confirmed the benefit of cannabinoid use, with twenty-nine randomized studies having been examined and included in separate systematic analyses 34 , Cannabinoids were found to be safe, modestly effective, and a reasonable option for treating chronic neuropathic pain.
Those data have contributed to the revision, by the Canadian Pain Society, of their consensus statement on the treatment of chronic neuropathic pain to include cannabinoids as third-level therapy Inhaled or vaporized cannabis has also been studied, but, again, few randomized trials have been conducted. A recently published meta-analysis demonstrated that 1 in 5—6 patients would benefit from the use of inhaled cannabis treatments for neuropathic pain Controlling nausea and vomiting was one of the initial uses of cannabinoids documented in the modern scientific literature.
In , Sallan et al. Since then, several larger-scale studies—including placebo-controlled randomized studies using dronabinol, nabilone, and cannabis extracts—have been completed. At least two systematic reviews on the topic have shown benefit with the use of cannabinoids, especially pharmaceutical cannabinoids, in patients undergoing chemotherapy 45 , When looking at the use of cannabis or extracts to control nausea and emesis, the picture is not quite as clear. Many of the published studies were observational or uncontrolled, and certainly randomized controlled trial data for cannabis use are in short supply 47 , Preclinical research has established animal models for nausea mouse, shrew , which have shown benefit with the use of cbd That benefit has been especially evident in a model of anticipatory nausea, a condition that has been difficult to treat for patients undergoing longer-term chemotherapy Anecdotal reports to us from patients who routinely smoke or vaporize cannabis containing varying amounts of thc and cbd before chemotherapy confirm improvement in their quality of life as measured by the Edmonton Symptom Assessment System and subsequent appetite and food intake.
Although treatment of some specific body areas abdomen, chest, whole brain with radiotherapy can induce nausea, very few reports of cannabinoid use in those situations have been published, and the reports that exist have used mainly pharmaceutical cannabinoids A recently published placebo-controlled study demonstrated that quality of life for patients with head-and-neck cancers undergoing radiotherapy is not improved with the use of nabilone The authors postulated that nabilone on its own is not potent enough to affect symptoms.
Another recently published study surveyed 15 patients with previously treated head-and-neck cancer about their use of medical cannabis, and all respondents endorsed the benefits of cannabis in the treatment of the long-term residual effects of radiation The data supporting cannabis and cannabinoid use in appetite stimulation is less conclusive than it is in pain or nausea. When used in cancer patients with cachexia, cannabinoids appear to be only modestly effective. A study from the North Central Cancer Trial Group compared the use of an oral cannabinoid dronabinol with oral megestrol acetate and with the two drugs together.
Final results did not show any statistical improvement in weight with dronabinol, either alone or in combination A Swiss-led study using cannabis extract in cancer patients also did not show benefit in terms of appetite or weight gain, and the trial was closed early after a mandated review A small Canadian study using oral dronabinol in advanced cancer patients demonstrated improved sense of taste and subsequent increased protein consumption.
That change did not translate to weight gain, but patients did express improvement in quality of life measurements More promising results were seen in studies of the non-cancer population. A study of response to smoked cannabis, dronabinol, or placebo in patients with aids demonstrated that the patients using smoked cannabis experienced the greatest weight gain 3.
An earlier study in patients with dementia treated with either dronabinol or placebo documented an increase in appetite, increased weight gain, and modulated aggressive behaviour Although the main use of cannabinoids in patients with cancer and palliative patients has been symptom management, there could be other roles for these molecules in the treatment of malignancies.
In one of the first reports of cannabinoids having antitumour effects, extracts of cannabis were shown to inhibit the growth of lung adenocarcinoma cells in vitro An in vivo mouse model produced similar results. Preclinical studies have investigated cannabinoid activity in several malignancies lung, glioma, thyroid, lymphoma, skin, pancreas, endometrium, breast, prostate 59 — 61 , demonstrating antiproliferative, anti-metastatic, antiangiogenic, and proapoptotic effects reviewed by Velasco et al.
Cannabis has not been studied clinically as a treatment for malignancy. The only clinical study published to date that used cannabinoids enrolled patients with glioblastoma multiforme and was based on extensive preclinical work by the same investigators Their small study 9 patients showed the safety of intracranial administration of thc and demonstrated antiproliferative effects in some of the patients.
All patients eventually progressed and died, but not because of any effects of the extract. The investigators are actively continuing their clinical and research work, focusing on tumours of the central nervous system Oncologists might be concerned that cannabinoids could reduce the effectiveness of established chemotherapy agents.
Several authors have investigated cannabis extracts used in tandem with a variety of chemotherapy agents in vitro and in animal models, showing synergism in reducing cell numbers, and no negative effect on anticancer function.
Cell cultures from pancreatic 64 , glioma 65 , gastric 66 , lung 67 , and colon 68 cancers have been investigated using a range of antineoplastic agents, including gemcitabine, temozolomide, paclitaxel, and 5-fluorouracil. Synergism in inducing cancer cell death is a common finding, which bodes well for the possibility of human clinical trials in future Despite the emerging evidence of antineoplastic activity, some older in vitro studies demonstrated cancer cell proliferation and loss of immune-mediated cancer suppressor activity after treatment with cannabinoid preparations 58 , Some studies have even shown discordant results depending on the concentration of cannabinoids: Thus, conflicting evidence points to the need for sober second thought before outright recommendations of cannabinoids for cancer patients can be made.
But again, mice and rats are not people, and what is observed in vitro does not necessarily translate into clinical medicine. The preclinical evidence that cannabinoids might have direct anticancer activity is provocative as well, but more research is warranted.
Currently, several clinical studies using cannabinoids in cancer therapy are registered at http: An Israeli group is studying the use of cannabis extracts cannabidiol in patients whose cancers are resistant to the usual chemotherapy protocols NCT Two more studies in the preliminary stages include the safety of dexanabinol in patients with advanced cancers NCT, NCT and cannabis high cbd concentration for pain and inflammation in lung carcinomas NCT When a patient is referred to our outpatient clinic with a request for medical cannabis, several questions come to mind: Most of our patients have either tried medical cannabis or read about its role in symptom control.
Those who have tried it recreationally or for medical purposes can accurately reflect on the benefits or the adverse effects experienced, which makes the discussion somewhat easier. Those who have little knowledge and less experience require a complete discussion with respect to the benefits, the possible adverse effects, the process of application and authorization, and the cost which is borne by the patient, because it is not covered by provincial or private medical insurance.
Table iii lists our contraindications to authorization, which are similar to those published by Health Canada 70 , the College of Family Physicians of Canada 71 , and the Canadian Medical Protective Association It should be noted that no special license or additional certification is necessary to authorize the use of medical cannabis, but a working knowledge of cannabis as already presented is helpful for oncology professionals who are considering a patient request.
Once the decision is made to support authorization, the choice of which licensed producer and product to use can be somewhat difficult for some patients. The small size of the cannabinoid-treated groups is due to the very few second or third tumors appeared early enough to last 40 days in the animals before the end of the treatment 90 days after the appearance of the first tumor.
Of interest, cannabinoids not only impaired tumor growth, but also blocked tumor generation per se. Consequently, total tumor burden was strikingly decreased by cannabinoids Fig. There was also a delay in the appearance of the subsequent tumors in these animals. Thus, the average latency for the generation of a second tumor in vehicle-treated, THC-treated and JWHtreated animals was 33, 46 and 54 days, respectively. As mentioned in the Methods section, only the first tumor in each animal was treated peritumorally with cannabinoids.
However, we detected a remarkable growth-inhibitory effect of cannabinoids in those tumors appeared in second place Fig. We next analyzed the proliferative potential of cancer cells and found that it was reduced by both THC and JWH, as indicated by a decreased number of Kipositive cells in cannabinoid-treated tumors Fig. Cannabinoid administration also increased the number of cleaved active caspase 3-positive cells within the tumors, indicating that these compounds induce cancer cell death by apoptosis Fig.
Tumor vascularization was also impaired by cannabinoids, as both THC and JWH decreased the number of blood vessels in the tumors, as determined by CD31 staining Fig. To evaluate the possible contribution of the immune response to cannabinoid antitumoral action, we analyzed by immunofluorescence the degree of immune infiltration in the tumors. The percentage of CDpositive cells differentiated hematopoietic cells except erythrocytes and platelets within the tumors was very low in all the samples tested and no significant differences between experimental groups were detected Fig.
These data suggest that cannabinoid treatment does not affect the infiltration of immune cells into the tumor parenchyma. Cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis in vivo.
Cell nuclei are in blue. Quantifications of Kipositive cells A , active caspasepositive cells B , the number of blood vessels C and CDpositive area D in the tumors are shown in the corresponding graphs. It has been previously reported that a high percentage of tumor-bearing MMTV-neu animals develop metastases in the lungs [ 9 ]. Specifically, we detected lung metastases Fig.
The cell morphology, tumor architecture, and overexpression of the neu transgene mRNA in these lung structures confirmed the metastatic nature of the lesions Figs.
THC reduced the percentage of animals with lung metastases Fig. Although JWH did not decrease this proportion, it significantly reduced the magnitude of the lesions. Thus, half of the metastases in this experimental group were detectable only by microscopic analysis Fig. As it was observed for the primary breast tumors, cannabinoid treatment did not alter the histopathology of the metastases, and the three experimental groups presented similar solid adenocarcinomas Additional file 1: No sign of metastasis was detected in any of the other organs analyzed brain, spleen, liver, kidneys -by histological analysis- and bones -by X-rays in any of the experimental groups data not shown.
Cannabinoids inhibit breast cancer metastasis to the lungs in vivo. A Metastatic lung nodules pointed by arrows. B Percentage of animals with lung metastases. These latter lesions were found only in JWHtreated animals. C Gelatin zymographies of vehicle- and cannabinoid-treated tumors. Four representative tumors are shown per experimental group. Non-contiguous parts of the same gel are shown. Data are expressed in arbitrary units.
Degradation of the extracellular matrix is a crucial step in the metastatic process, especially during tumor cell intravasation and extravasation [ 10 ]. Matrix metalloproteinases MMPs have long been associated with this process owing to their ability to degrade the components of the extracellular matrix. To analyze whether cannabinoid administration affects MMP activity we conducted gelatin zymographies. Conversely, cannabinoids did not change the amount of MMP9 transcripts Additional file 1: S4A and enhanced its protein levels Additional file 1: S4B , indicating that they regulate MMP9 post-transcriptionally.
We next aimed at characterizing the mechanism underlying cannabinoid antitumoral effect. It is well established that several types of human cancers are associated with deregulation of signaling via ErbB members [ 1 ].
In particular, ErbB2 overexpression correlates, for instance, with tumor size, increased metastatic potential, and higher histological grade, implying that ErbB2 confers a strong proliferative and survival advantage to tumor cells [ 11 ]. To assess whether cannabinoids modulate the expression of endogenous ErbB2 and of the rat ErbB2 ortologue neu, which is ectopically expressed in our animal model, we conducted real-time quantitative PCR determinations upon THC and JWH treatment.
However, no significant changes were detected Fig. THC inhibits Akt in vivo. Eight representative tumors are shown. Optical densities are expressed in arbitrary units. To determine the importance of Akt inhibition in cannabinoid antitumoral action we conducted different experiments with the cell line N Likewise, the growth rate of N THC also decreased cell proliferation of two different ErbB2-overexpressing breast cancer cell lines of human origin Additional file 1: S5 , suggesting that human ErbB2-positive breast tumor cells may be sensitive to cannabinoid antitumoral action as well.
Of interest, overexpression of a myristoylated i. To further support the importance of Akt in cannabinoid antitumoral action, subcutaneous xenografts were generated in nude mice with N As shown in Fig.
The same effect was observed with JWH Fig. Akt downregulation is involved in cannabinoid antitumoral action. A and B Viability of N C Growth of N E Phospho-Akt and total Akt levels in N Moreover, the use of this antibody has been associated with important cardiotoxic side effects severe congestive heart failure and decrease in left ventricular ejection fraction [ 14 ]. Consequently, extensive efforts should be made to find novel agents for the treatment of ErbB2-positive breast tumors.
Our results demonstrate that, in spontaneously aroused ErbB2-overexpressing breast tumors, cannabinoids inhibit tumor generation, growth, vascularization, and metastasis. Although a cannabinoid-based monotherapy might be potentially effective for ErbB2-positive breast tumors, it would be interesting to analyze the effect of these compounds in combination with other anticancer treatments.
Thus, it is worth noting that Trastuzumab, the most relevant targeted therapy for ErbB2-positive tumors so far, has a modest median overall response when used as a first-line agent, an efficacy that is clearly enhanced when used in combination with other chemotherapeutic agents [ 14 ]. Additionally, Akt overactivation has been detected in a significant percentage of primary human breast cancers, in which it is associated to enhanced resistance to Trastuzumab [ 14 , 15 ]. Our results show that downregulation of Akt is involved in cannabinoid antitumoral action.
The antitumoral potential of cannabinoids has been documented both in vitro and in animal models of cancer [ 7 , 8 ]. These compounds inhibit breast cancer cell proliferation in vitro through processes that include cell cycle arrest [ 16 - 21 ], hormone and growth-factor receptor modulation [ 18 , 22 , 23 ], and apoptosis induction [ 17 , 20 , 21 ].
The in vivo approaches followed so far have been mostly based on xenograft models [ 20 , 21 ], which are helpful but limited tools. These models rely on the propagation of cancer cell lines in immunodeficient mice at ectopic or orthotopic sites and lack crucial features of patients' tumors such as the actual tumor architecture and the interactions with the tumor microenvironment including non-cancerous surrounding tissue, vasculature and immune cells and diminished genetic heterogeneity [ 24 ].
In contrast to xenografted animals, in the mutant mice used in this study tumors appear spontaneously and after long latency periods, recruit and generate blood vessels, and penetrate the vasculature giving rise to distant metastases [ 9 ]. These features parallel the human pathology much more closely and make the MMTV-neu mice a clinically relevant model of ErbB2-driven breast cancer. Remarkably, this is, to the best of our knowledge, the first report supporting that cannabinoids hamper not only tumor growth but also tumor generation.
Recently, Qamri and coworkers and DuBois and coworkers, by using two different genetic models of cancer, demonstrated that JWH delays the appearance of breast tumors [ 21 ] and that the loss of CB 1 receptors accelerates intestinal adenoma growth [ 25 ], respectively, and Izzo et al.
These and our data suggest that the endocannabinoid system has a physiological protective role against tumorigenesis, in line with the general idea that this system contributes to maintain homeostasis in health and disease [ 6 ].
Data presented herein show that cannabinoids modulate MMP activity.
Cannabinoids as therapeutic agents in cancer: current status and future implications
Sanchez and her team have been studying cancer and cannabinoid treatment, (cancer cells) were dying in the clean way,” Dr. Sanchez says. Read 58 publications, and contact Cristina Sanchez on ResearchGate, the effects of cannabinoids on some cancer-associated symptoms, a large body of evidence Here we report the in vivo antitumor effectiveness of this immunotoxin on. Cannabinoid treatments for cancer pain have been studied in a few randomized trials, but the evidence very few reports of cannabinoid use in those situations have been published, and the reports that exist To quote Dr. Donald Abrams28 : .. Velasco G, Sanchez C, Guzman M. Anticancer mechanisms of cannabinoids.