Estudios sobre el poder antitumoral de la marihuana

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Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 20:24

El cannabis detiene la metástasis de diferentes tipos de cancer agresivos

http://www.huffingtonpost.com/2012/09/1 ... 98208.html

Cancer de cerebro

British Journal of Cancer (2006) 95, 197–203. doi:10.1038/sj.bjc.6603236 http://www.bjcancer.com
Published online 27 June 2006
A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

M Guzmán1, M J Duarte2, C Blázquez1, J Ravina2, M C Rosa2, I Galve-Roperh1, C Sánchez1, G Velasco1 and L González-Feria2

1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid 28040, Spain
2Department of Neurosurgery, Hospital Universitario de Canarias, La Laguna, Tenerife 38320, Spain

Correspondence: Professor M Guzmán, E-mail: mgp@bbm1.ucm.es; Professor L González-Feria, E-mail: lgferia@yahoo.es

Revised 15 May 2006; Accepted 5 June 2006
Advance online publication 27 June 2006
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Abstract

Δ9-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15–33). Δ9-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.


Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor.
Sánchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramón y Cajal S, Guzmán M.
Source

Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
Abstract

The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313-319, 2000). These compounds act on the brain and some other organs through the widely expressed CB(1) receptor. By contrast, the other cannabinoid receptor subtype, the CB(2) receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB(2) receptor in this action was evidenced by: (a) the prevention by the CB(2) antagonist SR144528 but not the CB(1) antagonist SR141716; (b) the down-regulation of the CB(2) receptor but not the CB(1) receptor in the tumors; and (c) the absence of typical CB(1)-mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB(2) receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-2(-/-) mice was completely blocked by JWH-133 administration at 50 microg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB(2) but not the CB(1) receptor upon JWH-133 challenge and showed that selective activation of the CB(2) receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.


Neuroprotection by Δ9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity


Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Δ9-tetrahydrocannabinol (Δ9-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na+/K+-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Δ9-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB1 cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Δ9-THC, indicating that Δ9-THC afforded protection to neurons via the CB1 receptor. In Δ9-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB1 receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration.


Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

Department of Pharmacology, Chemotherapy and Toxicology (P.M., A.C.), and Department of Pharmacological Sciences, School of Pharmacy, and Center of Excellence for Neurodegenerative Diseases, University of Milan, Milan, Italy (S.C., M.P.A.); and Department of Structural and Functional Biology, Pharmacology Unit and Center of Neuroscience, University of Insubria, Busto Arsizio (Varese), Italy (A.V., D.P.)

Address correspondence to:
Daniela Parolaro, Dept. of Structural and Functional Biology, Pharmacology Unit and Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (Varese), Italy. E-mail: daniela.parolaro@uninsubria.it

Abstract

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC50 of 25 μM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and α-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive 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.


A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma

Sofía Torres1,
Mar Lorente1,
Fátima Rodríguez-Fornés1,
Sonia Hernández-Tiedra1,
María Salazar1,2,
Elena García-Taboada1,
Juan Barcia3,
Manuel Guzmán1,2 and
Guillermo Velasco1,2

+ Author Affiliations

Authors' Affiliations: 1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 2Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and 3Department of Neurosurgery, Hospital Clínico San Carlos, Madrid, Spain

Corresponding Author:
Guillermo Velasco, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, C/José Antonio Novais s/n, 28040 Madrid, Spain. Phone: 34-913944668; Fax: 34-913944672; E-mail: gvd@bbm1.ucm.es

S. Torres and M. Lorente contributed equally to the work.

Abstract

Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM. Mol Cancer Ther; 10(1); 90–103. ©2011 AACR.


http://www.nature.com/bjc/journal/v95/n ... 3236a.html

http://www.ncbi.nlm.nih.gov/pubmed/11479216

http://www.jneurosci.org/content/21/17/6475.abstract

http://jpet.aspetjournals.org/content/3 ... 8.abstract

http://mct.aacrjournals.org/content/10/1/90.abstract
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 20:51

Cancer de mama

Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis.
McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, Limbad C, Liu Y, Debs RJ, Moore DH, Desprez PY.
Source

California Pacific Medical Center, Research Institute, San Francisco, CA 94107, USA. mcallis@cpmcri.org
Erratum in

Breast Cancer Res Treat. 2012 May;133(1):401-4.

Abstract

Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required. 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. We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo. We show that 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. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.


Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.
McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY.
Source

California Pacific Medical Center, Research Institute, 475 Brannan Street, San Francisco, CA 94107, USA. mcallis@cpmcri.org
Abstract

Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. 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. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense Id-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, 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.


Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion.
Nasser MW, Qamri Z, Deol YS, Smith D, Shilo K, Zou X, Ganju RK.
Source

Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
Abstract
BACKGROUND:

Cannabinoids bind to cannabinoid receptors CB(1) and CB(2) and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB(2) may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.
METHODOLOGY/PRINCIPAL FINDINGS:

We observed high expression of both CB(2) and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB(2)-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.
CONCLUSIONS/SIGNIFICANCE:

This study provides novel insights into the crosstalk between CB(2) and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB(2) receptors could be used for developing innovative therapeutic strategies against breast cancer.


Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma.
Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V.
Source

Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche Pozzuoli, Italy.
Abstract

Delta(9)-Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. 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. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells. Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB(2) and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca(2+) and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.


Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. 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: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors.
Results

Our results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, 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.
Conclusions

Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.


Cannabinoids: a new hope for breast cancer therapy?
Caffarel MM, Andradas C, Pérez-Gómez E, Guzmán M, Sánchez C.
Source

Dept. Biochemistry and Molecular Biology I, School of Biology, Complutense University-CIBERNED-IRYCIS, Madrid, Spain.
Abstract

Breast cancer is a very common disease that affects approximately 1 in 10 women at some point in their lives. Importantly, breast cancer cannot be considered a single disease as it is characterized by distinct pathological and molecular subtypes that are treated with different therapies and have diverse clinical outcomes. Although some highly successful treatments have been developed, certain breast tumors are resistant to conventional therapies and a considerable number of them relapse. Therefore, new strategies are urgently needed, and the challenge for the future will most likely be the development of individualized therapies that specifically target each patient's tumor. Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity. Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture. Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer. This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.



The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

Anandamide was the first brain metabolite shown to act as a ligand of “central” CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 μM and 83–92% maximal inhibition at 5–10 μM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 μM anandamide. The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. A stable analogue of anandamide (R)-methanandamide, another endogenous cannabinoid, 2-arachidonoylglycerol, and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation, whereas arachidonic acid was much less effective. These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [3H]CP 55,940 to EFM-19 membranes with an order of potency identical to that observed for the inhibition of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A. Cell proliferation was arrested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1–0.5 μM) doses of anandamide. Anandamide suppressed the levels of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin-induced response, i.e., the expression of the breast cancer cell susceptibility gene brca1. These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor


http://www.ncbi.nlm.nih.gov/pubmed/20859676

http://www.ncbi.nlm.nih.gov/pubmed/18025276

http://www.ncbi.nlm.nih.gov/pubmed/21915267

http://jpet.aspetjournals.org/content/e ... l.pdf+html

http://www.molecular-cancer.com/content/9/1/196

http://www.ncbi.nlm.nih.gov/pubmed/22776349

http://www.pnas.org/content/95/14/8375.full.pdf+html
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 20:53

Cancer de pulmon

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.
Ramer R, Bublitz K, Freimuth N, Merkord J, Rohde H, Haustein M, Borchert P, Schmuhl E, Linnebacher M, Hinz B.
Source

Institute of Toxicology and Pharmacology, Department of General Surgery, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany.
Abstract

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.


Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis.
Preet A, Qamri Z, Nasser MW, Prasad A, Shilo K, Zou X, Groopman JE, Ganju RK.
Source

Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC. We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients. Furthermore, we have shown that the 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%). These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist-mediated effects on tumor growth and metastasis. Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.


Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo

A Preet1, R K Ganju1,2 and J E Groopman1,2

1Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Correspondence: Drs JE Groopman or RK Ganju, Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine Building, 4 Blackfan Circle, Boston, MA 02115, USA. E-mail: jgroopma@bidmc.harvard.edu or rganju@bidmc.harvard.edu

2JEG and RKG share the senior and corresponding authorship.

Received 21 January 2007; Revised 29 May 2007; Accepted 1 June 2007; Published online 9 July 2007.
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Abstract

Δ9-Tetrahydrocannabinol (THC) is the primary cannabinoid of marijuana and has been shown to either potentiate or inhibit tumor growth, depending on the type of cancer and its pathogenesis. Little is known about the activity of cannabinoids like THC on epidermal growth factor receptor-overexpressing lung cancers, which are often highly aggressive and resistant to chemotherapy. In this study, we characterized the effects of THC on the EGF-induced growth and metastasis of human non-small cell lung cancer using the cell lines A549 and SW-1573 as in vitro models. We found that these cells express the cannabinoid receptors CB1 and CB2, known targets for THC action, and that THC inhibited EGF-induced growth, chemotaxis and chemoinvasion. Moreover, signaling studies indicated that THC may act by inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT. THC also induced the phosphorylation of focal adhesion kinase at tyrosine 397. Additionally, in in vivo studies in severe combined immunodeficient mice, there was significant inhibition of the subcutaneous tumor growth and lung metastasis of A549 cells in THC-treated animals as compared to vehicle-treated controls. 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 growth and metastasis of certain lung cancers.


http://www.ncbi.nlm.nih.gov/pubmed/2219 ... t=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/2109 ... t=Abstract

http://www.nature.com/onc/journal/v27/n ... 0641a.html
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 20:55

Cancer de próstata

Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production.
Mimeault M, Pommery N, Wattez N, Bailly C, Hénichart JP.
Source

Institut de Chimie Pharmaceutique Albert Lespagnol, 3 Rue du Professeur Laguesse, BP83, Lille, France.
Abstract
BACKGROUND:

Anandamide (ANA) is an endogenous lipid which acts as a cannabinoid receptor ligand and with potent anticarcinogenic activity in several cancer cell types.
METHODS:

The inhibitory effect of ANA on the epidermal growth factor receptor (EGFR) levels expressed on the EGF-stimulated prostatic cancer cells LNCaP, DU145, and PC3 was estimated by ELISA tests. The anti-proliferative and cytotoxic effects of ANA were also evaluated on these human prostatic cancer cell lines by growth tests, flow cytometric analyses, trypan blue dye exclusion assays combined with the Papanicolaou cytological staining method.
RESULTS:

ANA induced a decrease of EGFR levels on LNCaP, DU145, and PC3 prostatic cancer cells by acting through cannabinoid CB(1) receptor subtype and this leaded to an inhibition of the EGF-stimulated growth of these cells. Moreover, the G(1) arrest of metastatic DU145 and PC3 growth was accompanied by a massive cell death by apoptosis and/or necrosis while LNCaP cells were less sensitive to cytotoxic effects of ANA. The apoptotic/necrotic responses induced by ANA on these prostatic cancer cells were also potentiated by the acidic ceramidase inhibitor, N-oleoylethanolamine and partially inhibited by the specific ceramide synthetase inhibitor, fumonisin B1 indicating that these cytotoxic actions of ANA might be induced via the cellular ceramide production.
CONCLUSIONS:

The potent anti-proliferative and cytotoxic effects of ANA on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers.


The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications
Juan A. Ramos and Fernando J. Bianco1
Author information ► Copyright and License information ►
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Abstract

Prostate cancer is a global public health problem, and it is the most common cancer in American men and the second cause for cancer-related death. Experimental evidence shows that prostate tissue possesses cannabinoid receptors and their stimulation results in anti-androgenic effects. To review currently relevant findings related to effects of cannabinoid receptors in prostate cancer. PubMed search utilizing the terms “cannabis,” “cannabinoids,” “prostate cancer,” and “cancer pain management,” giving preference to most recent publications was done. Articles identified were screened for their relevance to the field of prostate cancer and interest to both urologist and pain specialists. Prostate cancer cells possess increased expression of both cannabinoid 1 and 2 receptors, and stimulation of these results in decrease in cell viability, increased apoptosis, and decreased androgen receptor expression and prostate-specific antigen excretion. It would be of interest to conduct clinical studies utilizing cannabinoids for patients with metastatic prostate cancer, taking advantage not only of its beneficial effects on prostate cancer but also of their analgesic properties for bone metastatic cancer pain.


Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms.
De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L, Orlando P, Di Marzo V.
Source

Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy. l.depetrocellis@cib.na.cnr.it
Abstract
BACKGROUND AND PURPOSE:

Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ(9) -tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. Some of these compounds antagonize transient receptor potential melastatin type-8 (TRPM8) channels, the expression of which is necessary for androgen receptor (AR)-dependent PCC survival.
EXPERIMENTAL APPROACH:

We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS), on AR-positive (LNCaP and 22RV1) and -negative (DU-145 and PC-3) cells, by evaluating cell viability (MTT test), cell cycle arrest and apoptosis induction, by FACS scans, caspase 3/7 assays, DNA fragmentation and TUNEL, and size of xenograft tumours induced by LNCaP and DU-145 cells.
KEY RESULTS:

Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (1-10 µM) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca(2+)). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis.
CONCLUSIONS AND IMPLICATIONS:

These data support the clinical testing of CBD against prostate carcinoma.


http://www.ncbi.nlm.nih.gov/pubmed/1274 ... t=Abstract

http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22594963
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 20:56

Cancer de colon

J Mol Med (Berl). 2012 Aug;90(8):925-34. doi: 10.1007/s00109-011-0856-x. Epub 2012 Jan 10.
Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.
Aviello G, Romano B, Borrelli F, Capasso R, Gallo L, Piscitelli F, Di Marzo V, Izzo AA.
Source

Department of Experimental Pharmacology, Endocannabinoid Research Group, University of Naples Federico II, Naples, Italy.
Abstract

Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3. 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.


http://www.ncbi.nlm.nih.gov/pubmed/22231745

tracto oral

Cannabinoids inhibit cellular respiration of human oral cancer cells.

The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs.
EXPERIMENTAL APPROACH:

A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose.
KEY RESULTS:

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 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 cannabinoidreceptors. Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart.
CONCLUSIONS AND IMPLICATIONS:

These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.


http://www.ncbi.nlm.nih.gov/pubmed/20516734

Cancer de ovarios

Cannabinoid receptors as a target for therapy of ovarian cancer
Farrukh Afaq, Sami Sarfaraz, Deeba N. Syed, Naghma Khan, Arshi Malik, Howard H. Bailey and Hasan Mukhtar

University of Wisconsin, Madison, WI

Ovarian cancer represents one of the leading cause of cancer-related deaths for women and is the most common gynecologic malignancy. In spite of relative low morbidity, ovarian cancer has a high fatality ratio, with overall 5-year survival of less than 30%. At present, there are inadequate treatment options for the management of advanced ovarian cancer, and therefore development of novel approaches for treatment of this disease are needed. Cannabinoids, the active components of Cannabis sativa linnaeous and their derivatives have received considerable attention in recent years due to their diverse pharmacological activities such as cell growth inhibition and tumor regression. To date, two different cannabinoid receptors have been characterized and cloned from mammalian tissues: the "central" CB1 receptor and the "peripheral" CB2 receptor. We found that compared to normal Chinese hamster ovarian (CHO) cells, the expression levels of both cannabinoid receptors CB1 and CB2 were significantly higher in human ovarian cancer cells OVCAR-3 and SKOV-3. We then determined expression levels of the cannabinoid receptors in different grades of human ovarian cancer specimens and employing western blot analysis found that both CB1 and CB2 receptors were expressed. To evaluate the cell growth response of WIN-55,212-2 (a mixed CB1/CB2 agonist) on CHO, OVCAR-3 and SKOV-3 cells, we employed MTT assay. Of interest, our results demonstrated that treatment of CHO cells with WIN-55,212-2 (5-20 µM; 48 h), did not affect cell viability. In sharp contrast, treatment of OVCAR-3 and SKOV-3 cells with WIN-55,212-2 under similar conditions significantly decreased the viability of cells. The decrease in cell viability in OVCAR-3 and SKOV-3 cells suggests the involvement of either or both CB1 and CB2 receptors in the antiproliferative action of cannabinoids. To evaluate the possible implication of CB1 and CB2 receptors in WIN-55,212-2-mediated decrease in cell viability, the effect of selective receptor antagonists was studied. Blocking of both receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this growth inhibitory effect. Further, WIN-55,212-2 treatment of both OVCAR-3 and SKOV-3 cells resulted in G1 arrest in cell cycle progression, which was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner cdk2, 4 and 6. In addition WIN-55,212-2 treatment of both OVCAR-3 and SKOV-3 cells was found to result in induction of apoptosis as determined by PARP cleavage and flow cytometry. We also found that treatment of both OVCAR-3 and SKOV-3 cells with WIN-55,212-2 resulted in down-regulation of the expression of PCNA and VEGF. These results support a new therapeutic approach for the treatment of ovarian cancer. It is also conceivable that with available cannabinoids as lead compounds, non-habit forming agents that have higher biological effects could be developed.


http://www.aacrmeetingabstracts.org/cgi ... 006/1/1084
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 20:59

Hematológicos

Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease.
McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS, Nagarkatti M.
Source

Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract

In the current study, we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers. Exposure of murine tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis. Exposure of EL-4 tumor cells to the synthetic cannabinoid HU-210 and the endogenous cannabinoid anandamide led to significant induction of apoptosis, whereas exposure to WIN55212 was not effective. Treatment of EL-4 tumor-bearing mice with THC in vivo led to a significant reduction in tumor load, increase in tumor-cell apoptosis, and increase in survival of tumor-bearing mice. Examination of a number of human leukemia and lymphoma cell lines, including Jurkat, Molt-4, and Sup-T1, revealed that they expressed CB2 receptors but not CB1. These 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. Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis. Together, the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin.


Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria.
Jia W, Hegde VL, Singh NP, Sisco D, Grant S, Nagarkatti M, Nagarkatti PS.
Source

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, USA.
Abstract

Plant-derived cannabinoids, including Delta9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells, although the precise mechanism remains unclear. In the current study, we investigated the effect of THC on the upstream and downstream events that modulate the extracellular signal-regulated kinase (ERK) module of mitogen-activated protein kinase pathways primarily in human Jurkat leukemia T cells. The data showed that THC down-regulated Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading to translocation of Bad to mitochondria. THC also decreased the phosphorylation of Akt. However, no significant association of Bad translocation with phosphatidylinositol 3-kinase/Akt and protein kinase A signaling pathways was noted when treated cells were examined in relation to phosphorylation status of Bad by Western blot and localization of Bad to mitochondria by confocal analysis. Furthermore, THC treatment decreased the Bad phosphorylation at Ser(112) but failed to alter the level of phospho-Bad on site Ser(136) that has been reported to be associated with phosphatidylinositol 3-kinase/Akt signal pathway. Jurkat cells expressing a constitutively active MEK construct were found to be resistant to THC-mediated apoptosis and failed to exhibit decreased phospho-Bad on Ser(112) as well as Bad translocation to mitochondria. Finally, use of Bad small interfering RNA reduced the expression of Bad in Jurkat cells leading to increased resistance to THC-mediated apoptosis. Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells.



Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation

Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL). In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type (n = 62). A majority of the lymphomas expressed higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid tissue. With the exception of MCL, which uniformly overexpresses both CB1 and CB2, the levels of cannabinoid receptors within other lymphoma entities were highly variable, ranging from 0.1 to 224 times the expression in reactive lymph nodes. Low levels of the splice variant CB1a, previously shown to have a different affinity for cannabinoids than CB1, were detected in 44% of the lymphomas, while CB1b expression was not detected. In functional studies using MCL, Burkitt lymphoma (BL), chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide analog R(+)-methanandamide (R(+)-MA) induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors, but not in BL. In vivo treatment with R(+)-MA caused a significant reduction of tumor size and mitotic index in mice xenografted with human MCL. Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2. © 2008 Wiley-Liss, Inc.


Cannabinoid Receptor-Mediated Apoptosis Induced by R(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma

Kristin Gustafsson,
Birger Christensson,
Birgitta Sander and
Jenny Flygare

+ Author Affiliations

Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge, Stockholm, Sweden

Address correspondence to:
Birgitta Sander, Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge, F-46, SE-14186 Stockholm, Sweden. E-mail: birgitta.sander@ki.se

Abstract

We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB1 and CB2). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of apoptosis after treatment with the synthetic agonists R(+)-methanandamide [R(+)-MA] and Win55,212-2 (Win55; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone) was dependent on both cannabinoid receptors, because pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) (SR144528), specific antagonists to CB1 and CB2, respectively, abrogated caspase-3 activity. Preincubation with the inhibitors 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190) showed that phosphorylation of MAPK p38 was implicated in the signal transduction leading to apoptosis. Treatment with R(+)-MA and Win55 was associated with accumulation of ceramide, and pharmacological inhibition of ceramide synthesis de novo prevented both p38 activation and mitochondria depolarization assessed by binding of 3,3′-dihexyloxacarbocyanine iodide (DiOC6). In contrast, the pancaspase inhibitor z-Val-Ala-Asp(Ome)-CH2F (z-VAD-FMK) did not protect the mitochondrial integrity. Taken together, these results suggest that concurrent ligation of CB1 and CB2 with either R(+)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB1/CB2 may have therapeutic potential for the treatment of mantle cell lymphoma.


http://www.ncbi.nlm.nih.gov/pubmed/12091357

http://www.ncbi.nlm.nih.gov/pubmed/16908594

http://onlinelibrary.wiley.com/doi/10.1 ... 4/abstract

http://molpharm.aspetjournals.org/conte ... 2.abstract
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 21:03

Cancer de piel

Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.
Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, Jorcano JL, Guzmán M.
Source

Project on Cellular and Molecular Biology and Gene Therapy, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
Abstract

Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. 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 morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.


http://www.ncbi.nlm.nih.gov/pubmed/12511587

Cancer Hepático

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy.
Vara D, Salazar M, Olea-Herrero N, Guzmán M, Velasco G, Díaz-Laviada I.
Source

Department of Biochemistry and Molecular Biology, School of Medicine, Alcalá University, Madrid, Spain.
Erratum in

Cell Death Differ. 2011 Jul;18(7):1237.

Abstract

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids--a novel family of potential anticancer agents--on the growth of HCC. We found that Δ(9)-tetrahydrocannabinol (Δ(9)-THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB(2)) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB(2) receptor. We also found that Δ(9)-THC- and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase β was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that Δ(9)-THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC.


http://www.ncbi.nlm.nih.gov/pubmed/21475304


Cancer de Vegiga

http://www.medscape.com/viewarticle/803983
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Fisio » Mar, 12 Nov 2013, 21:04

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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor Cobayahumana » Vie, 15 Nov 2013, 19:03

muy buena info Fisio, este foro se va a convertir en un compendium del saber y la ciencia que en un tiempo tendra muchisima buena informacion, espero que no lo cierres nunca asi queda disponible.

Por mi parte la marihuana la fumo ocasionalmente o en momentos de ocio, no soy adicto a ella y almenos para los dolores musculares me va bien, abre el apetito y de momento no he notado fatiga entrenando, ni ahogos ni toses, y en pesos progreso sin problemas, vere si a largo plazo afecta a algo pero vamos, la cobaya humana de momento no experimenta nada negativo.
El mejor traje que puedes llevar es la desnudez.

https://www.facebook.com/ManuCulturismoAmateur
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Re: Estudios sobre el poder antitumoral de la marihuana

Notapor ZeRaTuL » Lun, 24 Mar 2014, 20:49

Aunque supongo que verás el blog muy escéptico, ultracientífico y típico, te lo enlazo:
http://scienceblog.cancerresearchuk.org ... ce-so-far/

Ya que estoy, y para que podáis contextualizar más el blog, otro enlace:
http://scienceblog.cancerresearchuk.org ... tter_tweet

Y uno de la wiki con tratamientos o productos ineficaces contra el cáncer:
https://en.wikipedia.org/wiki/List_of_i ... treatments

Si no estáis de acuerdo con algo decidlo.

Un abrazo.
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