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.
Cannabinoids Reports Dr. Sanchez and Cancer Treatment on
Cannabinoids inhibit key signaling targets in triple negative breast cancer which has worse prognosis in patients. CBD enhances the interaction between beclin1 and Vps34; it inhibits the association between beclin1 and Bcl-2 [ 63 ]. Thus, cannabinoids along with COX-2 inhibitors or other chemotherapeutic agents may represent as novel chemopreventive tools for the treatment of breast cancer. Prostate cancer is the most common malignancy among men of all races and is one of the leading causes of cancer death in this population.
JWH triggered a de novo synthesis of ceramide, which induced cell death, followed by JNK c-Jun N-terminal kinase activation and Akt inhibition [ 76 ]. Interestingly, R -methanandamide was shown to have a mitogenic effect on LNCaP cells at very low doses [ 46 , 75 ].
A recent report showed that FAAH is also over-expressed in prostate cancer cells and the inhibition of FAAH can enhance the survival of cancer patient [ 80 - 81 ]. Lung cancer has one of the highest mortality rates among cancer-suffering patients. These results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models.
Melanoma is the mainly cause of skin cancer—related deaths worldwide. CB1 and CB2 receptors are expressed in normal skin and skin tumors of mice and humans [ 85 ]. C57 and HaCa4 and reduces malignant tumors in nude mice [ 85 ]. WIN, or JWH induced G1 cell cycle arrest on melanoma cells, via inhibition of p-Akt and hypophosphorylation of the pRb retinoblastoma protein tumor suppressor [ 85 ].
Pancreatic cancer is one of the most aggressive and devastating human malignancies. Cannabinoid receptors on pancreatic cancer cells may affect prognosis and pain status of PDAC patients [ 86 ]. Cannabinoid administration leads to apoptosis of pancreatic tumor cells via CB2 receptor and ceramide-dependent up-regulation of p8 and ATF-4 and TRB3 stress—related genes [ 87 ].
Chondrosarcoma and osteosarcoma are the most frequent primary bone cancers [ 89 ]. Bone metastases are a frequent complication of cancer and the most frequent type of pain related to cancer. Breast cancer and prostate cancer mainly metastasize to bone which act as a fertile soil for the growth of secondary tumors [ 90 ].
The skeletal endocannabinoid system plays a significant role in regulating bone mass and bone turnover. The expression levels of CB1 and CB2 receptors were analyzed in bone cancer patient using immunohistochemistry [ 91 ]. Bone metastatic patient has severe pain so cannabinoids can attenuate pain and hyperalgesia [ 92 ].
Sativex is the combination of deltatetra-hydrocannabinol and cannabidiol, used to treat pain in cancer [ 92 ]. Effects of subcutaneously administered WIN55, on weight bearing and mechanical hyperalgesia were consistent with cannabinoid receptor mediated anti-nociception [ 93 ]. WIN55, also attenuates tumour-evoked mechanical hyperalgesia following local intraplantar administration through activation of CB1 and CB2 receptors [ 95 ].
Injection of CP55 produced anti-nociceptive properties in the tail flick test and suppressed mechanical hyperalgesia in NCTC or melanoma BF10 xenografted bone tumor model [ 96 ]. Indeed, intraplantar administration of AEA reduces mechanical hyperalgesia, URB increases AEA levels and decreases hyperalgesia in a model of calcaneous bone cancer pain [ 91 ]. However, intrathecal administration of either URB or MGL URB inhibitors failed to produce anti-nociception when tested for spontaneous flinches, limb use and weight bearing [ 97 ].
Moreover, the CB1 agonist arachidonoylchloroethylamide ACEA produces anti—nociceptive properties following intrathecal administration in this model; ACEA suppressed spontaneous flinches and increased limb use and weight bearing [ 97 ]. AM produces significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures [ 94 , 98 ]. Administration of JWH and AM attenuated tumor-evoked tactile allodynia and thermal hyperalgesia by reducing NR2B-dependent activity [ 98 - 99 ].
JWH increased survival without the major side effects of current therapeutic options. Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer, exhibit high resistance to conventional chemotherapies.
CB2 expression levels were higher in glioblastoma tissues in comparison to CB1. Selective CB2 agonists may become important targets for the treatment of glioma. Cannabinoids, inhibit tumor growth in animal models by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The growth inhibitory effect of these cannabinoids is prevented by blocking ceramide synthesis, and the expression of the stress protein p8 [ - ].
The activation of this pathway was necessary for the antitumor action of cannabinoids in vivo [ ]. Glioma cells develop resistance to cannabinoid treatment due to the upregulation of Amphiregulin EGFR family ligand and the growth factor midkine Mdk [ - ]. Amphiregulin expression was associated with increased ERK activation and Mdk mediated its protective effect through ALK which interferes with autophagic cell death [ ]. The silencing of amphiregulin and Mdk or ALK pharmacological inhibition can overcome drug resistance of glioma to cannabinoids antitumoral action.
Furthermore, to improve the efficacy of cannabinoids action, microencapsulation methods were used which facilitates a sustained release of the two cannabinoids for several days [ ]. In contrast, cannabinoids decreased cell viability as assessed by metabolic activity. The persistent expression of mammalian homolog of Atg8 with microtubule-associated protein-1 light chain-3 II LC3 II and p62, as well as the lack of protection from chloroquine, indicates that lysosomal degradation is not involved in this cytoplasmic vacuolation process, distinguishing from classical autophagy [ ].
Paraptosis-like cell death-a third type of a programmed cell death occurred in response to cannabinoids [ ]. Oral cancer is mainly occurs in the mouth including lips, tongue and throat. Smoking, tobacco chewing and alcohol consumption increases the incidence of oral cancer. Radiation therapy and surgery is the common treatment for oral cancer. Marijuana smoking increases the incidence of head and neck cancer in young people but its constituent, cannabinoids have anti-tumor properties.
Thyroid carcinoma is the most aggressive form which occurs in thyroid gland. IL gene transfer in to anaplastic thyroid carcinoma cell line ARO has anti-tumorigenic effect [ ]. This effect was observed due to the activation of cannabinoid receptor. Migration and invasion are characteristic features of cancer cells. Carcinoma cells that are invasive have higher migratory potential which helps them to disseminate into the surrounding tissues and spread to other organs, ultimately leading to metastasis [ ].
Angiogenesis, which involves growth of new vasculature has been shown to be closely related to cancer metastasis. Developing novel anti-invasive and anti-angiogenic targets would be more effective in inhibiting metastasis at earlier stage [ ].
In lung cancer, CBD inhibits invasion of A cells both in vitro and in vivo that was accompanied by up-regulation of tissue inhibitor of matrix metalloproteinase-1 TIMP-1 and decreased expression of plasminogen activator inhibitor-1 PAI-1 [ - ]. In skin cancer, treatment of WIN, or JWH caused impairment of tumor vascularization and decreased expression of proangiogenic factors such as VEGF, placental growth factor, and angiopoietin-2 [ 85 ].
In glioma, [ ], one study reveals that CBD also inhibits angiogenesis by modulating MMP-2 pathway and Id-1 gene expression in glioblastoma cells [ - ]. CBD inhibits cell proliferation and invasion of 4T1 cells mammary metastatic cell line and reduces primary tumor volume as well as lung metastasis in 4T1-xenografted orthotopic model of nude mice [ - ].
This anti-metastatic effect was mediated by downregulation of Id-1 a basic helix-loop-helix transcription factor inhibitor , ERK and also by inhibiting the ROS pathway. Furthermore, CBD reduced the number of metastatic foci in 4T1- tail vein injected syngenic model. Cancer stem cells CSC are part of the tumor cell population. Though they might be very less in number, they have the ability to self renew and replicate to produce enormous cancer cell types.
CSCs have been shown to be drug resistant with higher invasive and metastatic potential [ ]. Studies show that cannabinoid receptors are involved in differentiation of neural progenitors from ectoderm and hematopoietic progenitors from mesoderm. CB1 and CB2 receptor activation modulate proliferation and differentiation of daughter progenitors. It involved partial regulation by cannabinoid receptors leading to oxidative stress, necrosis coupled with apoptosis. These open further investigation on the function of cannabinoids and the link between stem cell and tumor progression.
Increased ROS production has been associated with triggering of apoptosis [ ]. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers [ - ].
The combination of cannabinoids and gemcitabine, a nucleoside analogue used in cancer chemotherapy, synergistically inhibit pancreatic adenocarcinoma cell growth by a ROS-mediated autophagy induction without affecting normal fibroblasts [ ]. Cannabidiol CBD -induced endoplasmic reticulum stress mediated cell death of MDA-MB breast cancer cells, with the coexistence of autophagy and apoptosis [ 63 ]. In primary lymphocytes, treatment with CBD induced caspase 8 induced apoptosis which was mediated by oxidative stress.
Similar result has been reported in glioma cells where CBD causes oxidative stress and higher enzymatic activities of glutathione reductase and glutathione peroxidase. KM induced mitochondrial depolarization, cleaved caspase 3, significant cytoskeletal contractions, and redistribution of the Golgi-endoplasmic reticulum structures in U87MG human GBM cells [ ].
Cancer is a type of inflammatory disease, where immune cells infiltrate into the tumor site and secrete factors which enhance the prospects of proliferation, angiogenesis and metastasis [ ]. Hence, it is important to identify anti-cancer agents that target the immune related cancer environment.
In glioma, WIN, caused accumulation of ceramide which is essential for cell death and it also had anti-inflammatory effects [ ]. Cannabinoids exert a direct anti-proliferative effect on tumors of different origin. They have been shown to be anti-migratory and anti-invasive and inhibit MMPs which in turn degrade the extra-cellular matrix ECM , thus affecting metastasis of cancer to the distant organs. Also, cannabinoids modulate other major processes in our body like energy metabolism, inflammation, etc.
These data are derived not only from cell culture systems but also from more complex and clinically relevant animal models. Before cannabinoids could be used in clinical trials, there is need to explore more knowledge on several issues such as anti-tumorigenic and anti-metastatic mechanisms as well as which type of cancer patient populations would be more responsive for cannabinoid based therapies. Data presented in this review suggest that cannabinoids derived from different sources regulate differently signaling pathways, modulate different tumor cell types and host physiological system.
It is important to understand which of the cannabinoid receptors are expressed and activated in different tumors as each receptor follows a different signaling mechanism. Furthermore, endocannabinoids- AEA and 2-AG are broken down into secondary metabolites like prostaglandin PGE 2 and epoxyeicosatetraenoic acid EE which enhance tumor growth and metastasis in diverse cancer types.
Understanding the exact signaling by which cannabinoids function will eventually lead to targeted clinical approach. Also, the difference in cellular response to cannabinoids in different cancer types might be due to the effect of the tumor environment which involves inflammatory cells, fibroblasts, endothelial cells, macrophages, etc.
Thus, there is a need for an integrative understanding of the role of cannabinoids with respect to the tumor and its microenvironment. The diversity of affecting multiple signaling pathways might pave way for developing cannabinoids that selectively obstruct a particular pathway, thus opening avenues for specific targeted treatments.
Moreover, cannabinoids are more specific to cancer cells than normal cells. The administration of single cannabinoids might produce limited relief compared to the administration of crude extract of plant containing multiple cannabinoids, terpenes and flavanoids. Thus, combination of cannabinoids with other chemotherapeutic drugs might provide a potent clinical outcome, reduce toxicity, increase specificity and overcome drug resistance complications. Additional findings in in vitro and in vivo models are needed to support studies at preclinical setting.
The authors disclose no competing interests. National Center for Biotechnology Information , U. Journal List Oncotarget v. Published online Jul Author information Article notes Copyright and License information Disclaimer. Received May 19; Accepted Jul This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article has been cited by other articles in PMC. Abstract The pharmacological importance of cannabinoids has been in study for several years. Cannabinoid receptors, cannabinoid agonists, cancer, signaling. Cannabinoid and its receptor Cannabinoids can be classified into three groups based on their source of production; endogenous cannabinoids endocannabinoids , phytocannabinoids and synthetic cannabinoids Fig.
Table I Cannabinoid's structure and its role in different physiological processes. Docosatetraenyl ethanolamide CB1 agonist neuromodulatory and immunomodulatory [ ]. Oleamide CB1 agonist neuromodulatory and immunomodulatory [ ]. Open in a separate window. Cannabinoids and their classification This figure illustrates how cannabinoids are divided into three main categories according to their availability in nature.
Endogenous cannabinoids Endogenous cannabinoids which are produced in our body include lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters and ethers that bind to CB1 or CB2 receptors. Phytocannabinoids Phytocannabinoids are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.
Synthetic cannabinoids Synthetic cannabinoids have been extensively used as a pharmacological agent, both in vitro and in vivo , to obtain more detailed insight of cannabinoid action, in order to evaluate their potential clinical use. Cannabinoid mediated signaling in cancer cells Cannabinoids activate CB1 or CB2 receptor which in turn modulates diverse signaling targets.
Table II Role of cannabinoid in different cancers and its associated signaling. Cannabinoids Anti-cancer effect and its mechanism of action Anandamide 1 Breast cancer: Suppression of nerve growth factor Trk receptors and prolactin receptors Prostate cancer: Attenuates mechanical hyperalgesia HU 1 Prostate cancer: MMPs pathway 3 Skin cancer: Mitogenic at low doses 4 Glioma: Role of cannabinoids in regulation of cancer growth One of the important aspects of an effective anti-tumor drug is its ability to inhibit proliferation of cancer cells.
Cannabinoids and breast cancer Breast cancer is one of the most common human malignancies and the second leading cause of cancer-related deaths in women, and its incidence in the developing world is on the rise [ 40 - 41 ].
Cannabinoids and prostate cancer Prostate cancer is the most common malignancy among men of all races and is one of the leading causes of cancer death in this population.
Cannabinoids and lung cancer Lung cancer has one of the highest mortality rates among cancer-suffering patients. Cannabinoids and skin cancer Melanoma is the mainly cause of skin cancer—related deaths worldwide.
Cannabinoids and pancreatic cancer Pancreatic cancer is one of the most aggressive and devastating human malignancies. Cannabinoids and bone cancer Chondrosarcoma and osteosarcoma are the most frequent primary bone cancers [ 89 ].
Cannabinoids and glioma Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer, exhibit high resistance to conventional chemotherapies. Cannabinoids and oral cancer Oral cancer is mainly occurs in the mouth including lips, tongue and throat. Cannabinoids and head and neck cancer Marijuana smoking increases the incidence of head and neck cancer in young people but its constituent, cannabinoids have anti-tumor properties.
Cannabinoids and thyroid carcinoma Thyroid carcinoma is the most aggressive form which occurs in thyroid gland. Role of cannabinoids in pro-metastatic mechanisms like angiogenesis, migration and invasion Migration and invasion are characteristic features of cancer cells. An extremely versatile and easily cultivatable plant, Cannabis was used by ancient cultures for food, fibre, and medicinal purposes 1 — 4. In the 20th century, it was a topic of much folklore, pop culture, controversy, and loathing.
The chemical characterization of the main active elements from the Cannabis plant and the identification of human cannabinoid receptors have together served as validation and a scientific platform to launch further research into the utility of cannabinoids in the health care arena. Thus, cannabis and its derivatives hold much promise and potential as bona fide therapeutic agents. Moreover, a paradigm shift, fueled by an almost exponential expansion of basic scientific and clinical research since the end of the 20th century, is showing that cannabinoids have beneficial effects beyond pain and symptom management and could be entering into the domain of disease modulation 1.
Starting in the early s, Canada was one of the first of a growing number of countries to legalize botanical Cannabis for medical purposes 5. Medical cannabis in Canada is cultivated under quality-controlled conditions and contains reproducible levels of the main cannabinoid and non-cannabinoid substances.
Moreover, the composition of medical cannabis can be tailored to meet the particular needs of the patient. The Cannabis genus has two main species—namely, Cannabis sativa and Cannabis indica 1 — 4.
The Cannabis plant generates more than chemical compounds, of which approximately 80 are cannabinoid compounds and more than are non-cannabinoid compounds 1 — 4. From a health care perspective, the most clinically relevant compounds include the cannabinoid agents thc and cbd , and the non-cannabinoid terpenoids and flavonoids 1 — 4. Medical cannabis can be dispensed in a dried botanical format that might be smoked, vaporized, brewed as tea, or cooked as edible food products 1 — 4.
More recently in Canada, medical cannabis extracts compounded in organic edible oils can be orally ingested, administered through vaporization, or applied topically 7. Anecdotally, experienced users say that, compared with C. That difference might be attributable to different thc: However, the purported differences between the two plants might also be a result of different levels of other components such as terpenes and flavonoids 1 — 4.
The endogenous opioid and cannabinoid systems are the only chemical systems in the human body that have survived more than million years of human evolution 1 — 4. Interestingly, the endogenous cannabinoid system might have evolved millions of years before the evolution of the Cannabis plant itself 1. The endogenous cannabinoid system is composed of all cannabinoid receptors, endogenous ligands endocannabinoids , second messengers, and endocannabinoid degradation pathways, most notably the fatty acid amide hydrolase system 1 — 4 , 7 — Although an understanding of the endogenous cannabinoid system is far from complete, two human receptors, cb 1 and cb 2, have currently been defined and cloned 1 — 4 , 8 — A third putative human cannabinoid receptor, gpr 55, is currently in the process of being characterized 8 — Cannabinoid receptors are ubiquitous and have an estimated to-1 preponderance over opioid receptors in humans 1 — 4.
Furthermore, unlike opioid receptors, which are located only extracellularly, cannabinoid receptors are also expressed on intracellular organelles such as mitochondria, the Golgi apparatus, and nuclei The cannabinoid receptors that are located on cell membranes are functionally coupled with G proteins 1 — 4 , 8 — The cb 1 receptors are located mostly on neural tissue within the central nervous system and afferent nociceptors.
The cb 2 receptors, although located mostly in immune system tissues such as spleen, tonsils, lymph nodes, mast cells, macrophages, and lymphocytes, are also expressed within the central nervous system through their presence on microglia. 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 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. Although MMPs have been traditionally associated to metastasis due to their ability to degrade the extracellular matrix, it has been recently shown that several members of this family provide a protective effect in different stages of cancer progression [ 27 ].
Although this MMP may promote the angiogenic switch in some experimental tumors [e. This protective effect might derive from its capacity to generate angiogenesis inhibitors such as angiostatin and tumstatin [ 27 ]. The inhibition of MMP2 by cannabinoids shown here, in line with that previously reported by Bifulco and coworkers in thyroid cancer cells [ 30 ] and our group in gliomas [ 31 ], may be of special relevance considering that high tumor levels of this metalloproteinase have been correlated with poor prognosis in breast cancer [ 32 ].
Potential antitumoral therapies based on the use of cannabinoids might be limited by their well known psychotropic actions such as dizziness, dry mouth, tiredness, muscle weakness, euphoria, myalgia and palpitations [ 6 , 35 ].
Since most -if not all- of the psychoactive effects of cannabinoids are produced by the activation of central CB 1 receptors [ 5 , 6 ], one reasonable approach would be targeting CB 2 receptors selectively. Moreover, our results also i show that an elevated percentage of high grade ErbB2-positive human breast tumors express CB 2 receptors, and ii that a very low fraction of them express CB 1 receptors.
Taken together, these data suggest that activation of CB 2 in this particular population of patients would be an efficient strategy to treat breast tumors without triggering psychoactive effects. A correlation between tumor aggressiveness and CB 2 receptor expression in breast cancer has been previously reported: Of interest, this receptor is scarcely expressed in non-transformed mammary tissue [data presented here and [ 17 , 21 ]].
In summary, our results, which were obtained in a clinically relevant animal model of ErbB2-positive breast cancer, suggest that these highly aggressive and low responsive tumors could be efficiently treated with non-psychoactive CB 2 -selective agonists without affecting the surrounding healthy tissue.
Two representative tissue cores 1 mm of diameter of each one were included in a tissue microarray. The main clinical pathology and molecular features of this series had been previously reported [ 36 ]. Tissue sections were subjected to a heat-induced antigen retrieval step prior to exposure to the primary antibody.
Anti-CB 1 receptor antibody was generously donated by Dr.
Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition
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.