Norml of Florida | Working to Reform Marijuana Laws. es3.infoina Sanchez explains how cannabis kills cancer cells. 4. Cannabis Kills Cancer Cells – Molecular Biologist Cristina Sánchez PhD. Cristina Sánchez is a molecular biologist from Complutense University in Madrid Spain. She has been studying cannabis for fifteen years and has discovered that cannabis sends a message to cancer cells to. Dr. Christina Sanchez and Dr. Manuel Guzman have done some Sees Pre- Clinical Evidence That "Cannabis Kills Breast Cancer Cells".
Sanchez Cannabis – & Cancer Christina
The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors.
We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors. 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. Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.
Almost one third of them overexpresses the ErbB2 tyrosine kinase receptor Her2 in humans, Neu in rats , a member of the EGF receptor family [ 1 ]. Although no specific ligand for ErbB2 has been identified yet, this receptor is the preferred heterodimerization partner of the family [ 2 ].
ErbB2-overexpressing breast tumors are characterized by very aggressive clinical courses and decreased survival rates, mostly due to the poorly differentiated, highly proliferative and highly invasive nature of their constituent cells [ 2 ].
All these characteristics make ErbB2-overexpressing tumors less responsive to conventional therapies. One of the most recent advances in the treatment of these tumors is the use of a humanized neutralizing monoclonal antibody against ErbB2 Trastuzumab [ 3 ].
The existence of this considerable population of non-responding and relapsing patients urges the search for novel treatments. The therapeutic potential of cannabinoids, the active compounds of marijuana and their derivatives, has been known for centuries. There is increasing evidence supporting that they might be beneficial in various pathological contexts such as pain, inflammation, eating disorders, and brain damage, amongst others [ 5 , 6 ].
Cannabinoids exert most of their actions by binding to and activating specific G protein-coupled receptors. To date, two cannabinoid receptors, namely CB 1 and CB 2 , have been cloned and characterized from mammalian tissues, the main difference between them being their tissue expression pattern.
Thus, while CB 1 receptors are ubiquitously located, with their highest presence found in the central nervous system, CB 2 receptor expression is mostly restricted to particular elements of the immune system [ 5 , 6 ]. During the last decade, evidence has accumulated suggesting that cannabinoids might be useful for the treatment of cancer.
These compounds exert anti-proliferative, pro-apoptotic, anti-angiogenic, and anti-invasive effects in different cell-culture and animal models of cancer [ 7 , 8 ].
Here, we used a genetically engineered animal model of ErbB2-driven metastatic breast cancer the MMTV-neu mouse to analyze the antitumoral potential of cannabinoids in this particularly aggressive pathology. Selective overexpression of neu in the mammary epithelium results in the spontaneous development of focal mammary tumors after a long latency months [ 9 ].
We first analyzed whether ErbB2-positive human breast tumors express cannabinoid targets i. We performed an immunohistochemical analysis of CB 1 and CB 2 receptors in 87 grade 3 invasive breast ductal carcinomas and 6 non-tumoral mammary samples by tissue microarrays. Moreover, we detected no significant CB 1 or CB 2 receptor immunoreactivity in non-transformed mammary tissue data not shown.
ErbB2-positive human breast tumors express cannabinoid receptors. We then analyzed the effect of cannabinoids on tumor progression in a well established and clinically relevant animal model of ErbB2-driven metastatic breast cancer, the MMTV-neu mouse.
We first observed that our MMTV-neu colony develops breast tumors after a long latency period similar to that previously reported [ 9 ]. Overexpression of the rat ErbB2 transgene neu in the tumors was verified by real-time quantitative PCR Additional file 1: Treatment with cannabinoids, either THC, the main marijuana-derived cannabinoid in terms of abundance and potency, or JWH, a synthetic CB 2 receptor-selective agonist, strongly slowed down tumor growth Fig.
These compounds, however, did not change the histomorphologic features of the tumors. Thus, the three different experimental groups generated focal, ductal, solid, well vascularized mammary tumors surrounded by a non-invasive hyperplasic mammary epithelium Fig.
Cannabinoids inhibit breast tumor growth in vivo and the number of tumors generated per animal. A Volume time-course scale bar: Scale bars from left to right: C Percentage of animals with 1, 2, 3, 4 or more tumors at the end of the treatment 90 days in each experimental group.
D Total tumor burden total tumor volume per animal determined 90 days after cannabinoid or vehicle treatment. E Volume of the tumors appeared in second, third or subsequent positions, 40 days after their appearance. 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. Although this is the only clinical trial designed specifically to analyse the safety of combined treatments, it is important to note that many trials have been carried out with medicated cannabinoids on oncological populations following conventional antitumour treatments.
For example, with Sativex alone, seven clinical trials have so far been carried out to analyse its effect on oncological pain among cancer patients.
None of the subjects reported negative interactions between the medications. Likewise, no negative effects have been detected associated with the combination of drugs in other tests performed to analyse the analgesic effect of cannabinoid drugs in cases of neuropathic pain caused by the chemotherapy itself.
Finally, and no less importantly, it is important to remember that one of the very few authorised medical uses of cannabinoid drugs is for the treatment of nausea and vomiting caused by chemotherapy. In principle, at least, this suggests that the combination of the two therapeutic strategies should not cause any problem.
While it is true that the accumulated preclinical and clinical evidence to date suggests that cannabis may be used safely in combination with chemotherapy and radiotherapy, there are a number of issues that still need to be examined in greater detail.
One of them is the possible interference of cannabinoids —especially CBD— with the cytochrome p CYP detoxification system.
This system is responsible for metabolising many different compounds including many of the drugs we habitually take , oxidising them and thus transforming them into metabolites which are non-toxic for the body.
It has been described that both THC and, in particular, CBD are capable of inhibiting certain CYP isoforms 7 , which might increase the half-life of the treatments processed by these enzymes, as a result of the non-metabolisation of the drugs. Other compounds used by these patients, such as tamoxifen, are administered in the form of prodrugs, which only activate when processed by CYP.
Thus the combination of these prodrugs with cannabinoids could, in principle, reduce the bioavailability of the corresponding active forms. Finally, many of the drugs used by cancer patients antitumour drugs, anti-depressants, stomach protectors, analgesics, etc. However, none of these potential interactions appears significant enough to advise against the combined use of cannabis and other therapies. Secondly, the as-yet scanty clinical experience suggests that such interactions can easily be managed by making small alterations to the dosage.
For example, a potentially negative interaction has been described between CBD and clobazam Onfi , a benzodiazepine that is used as a coadjuvant in forms of epilepsy that do not respond to conventional treatments. The combined use of the two drugs was associated with greater levels of clobazam in plasma and an increase in its side effects following a typical pattern of excess dose. These were easily reduced by lowering the dose of this compound 8. It is therefore important that patients who use cannabis for medicinal purposes report to their doctor to enable them to take these possible interactions into account and if necessary, adjust the dose of any treatment they are receiving.
Another issue that requires further analysis is the possible interference between cannabinoid treatments containing CBD and antioxidant supplements. This cannabinoid produces antitumour responses in different cell and animal models of cancer. Although the molecular mechanisms by which this effect occurs are very varied, one of the ones that appears to have greatest weight is the generation of reactive oxygen species 2 , precisely the type of compounds on which antioxidants exercise an effect.
One might therefore consider whether the antioxidant supplements could interfere with the potential anti-tumour action of CBD. Indeed, the use of antioxidants during antitumour therapy is still controversial among oncologists. On the one hand, the toxic effects on non-tumour cells of oxidative stress generated by the tumours themselves or by the therapy could be countered with antioxidant supplements. However, these supplements might block the harmful effects of the oxidative stress on the tumour cells.
For the time being, the consensus appears to be that there is still not enough scientific evidence to support the use of antioxidants in cancer patients during anti-tumour treatments 9. Finally, another issue that requires additional study is the use of cannabis during treatment with immunotherapy. This is a type of therapeutic strategy that is increasingly being used in the area of oncology.
Its ultimate aim is to stimulate the patient's immune response so that it destroys the tumour cells. It has been widely demonstrated that different elements of the immune system B and T lymphocytes, macrophages, monocytes, etc.
Results from some preclinical and clinical studies indicate that cannabinoids exercise immunosuppressant effects 10 , which could pose a potential problem when cannabis treatments are combined with immunotherapy. However, there is no evidence whatsoever that the use even chronic of cannabis is associated with the appearance or aggravation of infectious diseases or tumours, even in immunocompromised individuals, such as for example HIV patients In any case, more research, both preclinical and clinical, is urgently needed to resolve all these queries and in order to be able to offer rigorous information to both patients and the health professionals who accompany them in their treatments.
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Cannabinoides y sistema inmune. The term 'refractory epilepsy' is used to describe cases in which epileptic fits are so frequent
Cannabis and chemotherapy
Molecular biologist Christina Sanchez from Madrid Complutense University, Spain explains how cannabinoids (chemical compounds, which includes THC - the. Santos Mañes,2 Manuel Guzmán,1 and Cristina Sánchez corresponding author 1 Supplemental Figure 2: Cannabinoids inhibit breast tumor growth in vivo . THC reduced the percentage of animals with lung metastases (Fig. .. Guzman M, Mechta-Grigoriou F, Sanchez C. JunD is involved in the. Read 58 publications, and contact Cristina Sanchez on ResearchGate, the of Cannabis sativa, trigger antitumor responses in different models of cancer.