Cannabis: Your Heart Hero

More and more Americans are being classified as obese.  With obesity comes other complications such as cardiovascular disease.  Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease.  The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common.  It is estimated that one-third of Americans die from cardiovascular disease so it is no wonder that scientists have been hard at work trying to find a cure.   Below you will see studies where science has looked at cannabis compounds when applied to CVD.  Please feel free to share and I encourage all do their own research as well ~ Cherry Girl

Targeting Cannabinoid Receptor CB(2 ) in Cardiovascular Disorders: Promises and Controversies
“Cardiovascular disease is the leading cause of death and disability worldwide, which can be largely attributed to atherosclerosis, a chronic inflammation of the arteries… the lipid endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the cardiovascular system. The discovery that delta-9-tetrahydrocannabinol (Δ9-THC), the main active constituent of marijuana, inhibited atherosclerotic plaque progression via a cannabinoid 2 (CB(2) ) receptor-dependent anti-inflammatory mechanism.

Endocannabinoid System in Cardiovascular Disorders – New Pharmacotherapeutic Opportunities
The evidence so far gathered shows that the modulation of ECS (as agonism or antagonism of its receptors) is an enormous potential field for research and intervention in multiple areas of human pathophysiology. The development of selective drugs for the CB1 and CB2 receptors may open a door to new therapeutic regimens.

Never Fear Cannabis Is Here! How Cannabis Can Help With Fear, Anxiety, and Other Psychiatric Disorders

Nearly 19 million Americans suffer from a  psychiatric disorder which could include disorders such as specific phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder and post-traumatic stress disorder.  Many veterans returning from war have found cannabis to be a relief from PTSD.  Below you will studies where science has studied the effects of cannabis compounds when applied to psychiatric disorders.  Please feel free to share and I encourage all to do their own research as well ~ Cherry Girl

The Endocannabinoid System in the Processing of Anxiety and Fear and How CB1 Receptors May Modulate Fear Extinction 
The endocannabinoid system recently emerged as an important modulator of many neuronal functions. Among them, the control of anxiety and acquired fear represents nowadays one of the most interesting fields of research.  Finally, a neurobiological model possibly able to implement the role of the endocannabinoid system in these processes will be proposed.

CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity During Extinction of Conditioned Fear in Mice
Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory.  We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.

Extinction of Emotional Response As A Novel Approach of Pharmacotherapy of Anxiety Disorders 
The patogenesis of anxiety may be related to the process of an extinction of aversive memories… Studies on molecular and cellular mechanisms responsible for individual fear extinction may serve as the basis of search for more effective forms of clinical treatment… ligands stimulating endogenous cannabinoid system… these substances stimulate different central mechanisms, they appear to act synergistically, to improve the behavioural therapy.

Enhancing Cannabinoid Neurotransmission Augments the Extinction of Conditioned Fear
the findings in the present study suggest that augmenting eCB-mediated neurotransmission by inhibition of eCB transport or breakdown may provide a novel mechanism for enhancing the extinction of fear. As such, eCB reuptake inhibitors may serve as useful adjuncts in the treatment of anxiety disorders (such as PTSD, panic disorder, and OCD) as well as drug addiction and other disorders that respond to behavioral treatments utilizing extinction processes.

The Endogenous Cannabinoid System Controls Extinction of Aversive Memories
Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct.  We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.

The Endocannabinoid system and Extinction Learning
As several human psychiatric disorders, such as phobia, generalized anxiety disorders, and posttraumatic stress disorder (PTSD) appear to involve aberrant memory processing and impaired adaptation to changed environmental conditions, the hope has been fuelled that the endocannabinoid system might be a valuable therapeutic target for the treatment of these disorders.

Bringing the War Back Home: Mental Health Disorders Among 103,788 US Veterans Returning From Iraq and Afghanistan Seen at Department of Veterans Affairs Facilities
Co-occurring mental health diagnoses and psychosocial problems were detected early and in primary care medical settings in a substantial proportion of OEF/OIF veterans seen at VA facilities. Targeted early detection and intervention beginning in primary care settings are needed to prevent chronic mental illness and disability.

Psychosis and Trauma. Theorical Links Between Post-Traumatic and Psychotic Symptoms
The links between psychotic and psycho-traumatic symptoms are complex and multidirectional; this co-occurrence is a factor of seriousness. The clinician, while paying attention to these symptoms, has to distinguish the structure of the personality of the subject to articulate the psychotherapy and the pharmacological treatment. Further investigational studies may determine whether antipsychotics will enhance treatment response in PTSD patients with psychotic features.

Cash “Cashy” Hyde: Children’s Cancer and Cannabis

Hearing your child has cancer is one of the worst things a parent can be faced with.  Watching your child go through chemo can be a horrifying experience in itself.  When news broke that a father was treating his son’s cancer with cannabis people were shocked.  There was reactions all over the board but we watched as the oil worked.  Cashy, as he is known has been diagnosed with Malignant and Aggressive Cancer classified as a PNET Brain Tumor.  He was able to replace the toxic drugs he was on with cannabis oil instead.  Below are studies that show how cannabis treats Brain Tumors.  With more research we can prove that cannabis does have medicinal value and can greatly aid or cure many ailments.  These are published medical studies that I encourage you to research and share your findings with everyone.  Spread the truth!
Information gathered by David Worrell edited by Cherry Girl
Please visit the Cashy Hyde Foundation Website for more on this amazing little boy!   

Hypothesis: Cannabinoid Therapy For the Treatment of Gliomas?
‎”Cannabinoids induce apoptosis of glioma cells in culture… In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas.”
“Hypothesis: cannabinoid therapy for the treatment of gliomas?”
Velasco G, Galve-Roperh I, Sánchez C, Blázquez C, Guzmán M.
SourceDepartment of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Avenida Complutense, sn, 28040 Madrid, Spain.

Abstract
Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer. Current therapeutic strategies for the treatment of glioblastoma multiforme are usually ineffective or just palliative. During the last few years, several studies have shown that cannabinoids-the active components of the plant Cannabis sativa and their derivatives–slow the growth of different types of tumours, including gliomas, in laboratory animals. Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas.”
http://www.ncbi.nlm.nih.gov/pubmed/15275820

A Pilot Clinical Study of Delta9-tetrahydrocannabinol In Patients With Recurrent Glioblastoma Multiforme
‎”Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis.The primary end point of the study was to determine the safety of intracranial THC administration.Cannabinoid delivery was safe and could be achieved without overt psychoactive effects.The fair safety profile of THC, together with its 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.”
‎A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I, Sánchez C, Velasco G, González-Feria L. Source Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid 28040, Spain. mgp@bbm1.ucm.es

Abstract
Delta(9)-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). Delta(9)-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.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360617/?tool=pubmed

Cannabinoids and Gliomas
“Cannabinoids, the active components of Cannabis sativa L., inhibit the growth of different types of tumor cells, including glioma cells. Cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the antitumoral activity of cannabinoids.”
Cannabinoids and gliomas. Velasco G, Carracedo A, Blázquez C, Lorente M, Aguado T, Haro A, Sánchez C, Galve-Roperh I, Guzmán M.
Source Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.

Abstract
Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances–the endocannabinoids–that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.”
http://www.ncbi.nlm.nih.gov/pubmed/17952650

Cannabinoids As Potential New Therapy For the Treatment of Gliomas
“Gliomas constitute the most frequent and malignant primary brain tumors. Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics) for their treatment are only palliative and survival diagnosis is normally 6-12 months. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts. A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.”
Cannabinoids as potential new therapy for the treatment of gliomas.
Parolaro D, Massi P. Source Department of Structural & Functional Biology, Pharmacology Section, Center of Neuroscience, University of Insubria, Via A da Giussano 10, Busto Arsizio (VA), Italy. daniela.parolaro@uninsubria.it

Abstract
Gliomas constitute the most frequent and malignant primary brain tumors. Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics, e.g., temozolomide, carmustin or carboplatin) for their treatment are only palliative and survival diagnosis is normally 6-12 months. The development of new therapeutic strategies for the management of gliomas is therefore essential. Interestingly, cannabinoids have been shown to exert antiproliferative effects on a wide spectrum of cells in culture. Of interest, cannabinoids have displayed a great potency in reducing glioma tumor growth either in vitro or in animal experimental models, curbing the growth of xenografts generated by subcutaneous or intratecal injection of glioma cells in immune-deficient mice. Moreover, cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts. A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.”
http://www.ncbi.nlm.nih.gov/pubmed/18088200

The Stress-Regulated Protein P8 Mediates Cannabinoid-Induced Apoptosis of Tumor Cells
‎”One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells.We identify the stress-regulated protein p8 as an essential mediator of cannabinoid antitumoral action. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.”
The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Carracedo A, Lorente M, Egia A, Blázquez C, García S, Giroux V, Malicet C, Villuendas R, Gironella M, González-Feria L, Piris MA, Iovanna JL, Guzmán M, Velasco G. Source Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.

Abstract
One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.”
http://www.ncbi.nlm.nih.gov/pubmed/16616335

Down-Regulation of Tissue Inhibitor of Metalloproteinases-1 in Gliomas: A New Marker of Cannabinoid Antitumoral Activity?
“Cannabinoids, the active components of Cannabis sativa L., inhibit tumor growth by inducing apoptosis of tumor cells and inhibiting tumor angiogenesis. We evaluated the effects of cannabinoids on the expression of tissue inhibitors of metalloproteinases (TIMPs), which play critical roles in the acquisition of migrating and invasive capacities by tumor cells. Delta(9)-tetrahydrocannabinol (THC) down-regulated TIMP-1. As TIMP-1 up-regulation is associated with high malignancy and negative prognosis of numerous cancers, TIMP-1 down-regulation may be a hallmark of cannabinoid-induced inhibition of glioma progression.”
Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity? Blázquez C, Carracedo A, Salazar M, Lorente M, Egia A, González-Feria L, Haro A, Velasco G, Guzmán M. Source Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.

Abstract
Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and inhibiting tumor angiogenesis. It has also been reported that cannabinoids inhibit tumor cell invasiveness, but the molecular targets of this cannabinoid action remain elusive. Here we evaluated the effects of cannabinoids on the expression of tissue inhibitors of metalloproteinases (TIMPs), which play critical roles in the acquisition of migrating and invasive capacities by tumor cells. Local administration of Delta(9)-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated TIMP-1 expression in mice bearing subcutaneous gliomas, as determined by Western blot and immunofluorescence analyses. This cannabinoid-induced inhibition of TIMP-1 expression in gliomas (i) was mimicked by JWH-133, a selective CB(2) cannabinoid receptor agonist that is devoid of psychoactive side effects, (ii) was abrogated by fumonisin B1, a selective inhibitor of ceramide synthesis de novo, and (iii) was also evident in two patients with recurrent glioblastoma multiforme (grade IV astrocytoma). THC also depressed TIMP-1 expression in cultures of various human glioma cell lines as well as in primary tumor cells obtained from a glioblastoma multiforme patient. This action was prevented by pharmacological blockade of ceramide biosynthesis and by knocking-down the expression of the stress protein p8. As TIMP-1 up-regulation is associated with high malignancy and negative prognosis of numerous cancers, TIMP-1 down-regulation may be a hallmark of cannabinoid-induced inhibition of glioma progression.”
http://www.ncbi.nlm.nih.gov/pubmed/17675107

Inhibition of Cancer Cell Invasion By Cannabinoids Via Increased Expression of Tissue Inhibitor of Matrix Metalloproteinases-1
‎”Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.”
Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1.
Ramer R, Hinz B. Source Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, Rostock D-18057, Germany.

Abstract
BACKGROUND: Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion.

METHODS: Matrigel-coated and uncoated Boyden chambers were used to quantify invasiveness and migration, respectively, of human cervical cancer (HeLa) cells that had been treated with cannabinoids (the stable anandamide analog R(+)-methanandamide [MA] and the phytocannabinoid delta9-tetrahydrocannabinol [THC]) in the presence or absence of antagonists of the CB1 or CB2 cannabinoid receptors or of transient receptor potential vanilloid 1 (TRPV1) or inhibitors of p38 or p42/44 mitogen-activated protein kinase (MAPK) pathways. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting were used to assess the influence of cannabinoids on the expression of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). The role of TIMP-1 in the anti-invasive action of cannabinoids was analyzed by transfecting HeLa, human cervical carcinoma (C33A), or human lung carcinoma cells (A549) cells with siRNA targeting TIMP-1. All statistical tests were two-sided.

RESULTS: Without modifying migration, MA and THC caused a time- and concentration-dependent suppression of HeLa cell invasion through Matrigel that was accompanied by increased expression of TIMP-1. At the lowest concentrations tested, MA (0.1 microM) and THC (0.01 microM) led to a decrease in invasion (normalized to that observed with vehicle-treated cells) of 61.5% (95% CI = 38.7% to 84.3%, P < .001) and 68.1% (95% CI = 31.5% to 104.8%, P = .0039), respectively. The stimulation of TIMP-1 expression and suppression of cell invasion were reversed by pretreatment of cells with antagonists to CB1 or CB2 receptors, with inhibitors of MAPKs, or, in the case of MA, with an antagonist to TRPV1. Knockdown of cannabinoid-induced TIMP-1 expression by siRNA led to a reversal of the cannabinoid-elicited decrease in tumor cell invasiveness in HeLa, A549, and C33A cells.

CONCLUSION: Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.”
http://jnci.oxfordjournals.org/content/100/1/59.long

Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression
‎”Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity.”
Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression Cristina Blázquez1, María Salazar1, Arkaitz Carracedo1, Mar Lorente1, Ainara Egia1, Luis González-Feria2, Amador Haro1, Guillermo Velasco1, and Manuel Guzmán1 
+ Author Affiliations 1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain and 2Department of Neurosurgery, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain  

Abstract
Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis. It has also been reported that these compounds inhibit tumor cell spreading, but the molecular targets of this cannabinoid action remain elusive. Here, we evaluated the effect of cannabinoids on matrix metalloproteinase (MMP) expression and its effect on tumor cell invasion. Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas generated in mice, as determined by Western blot, immunofluorescence, and real-time quantitative PCR analyses. This cannabinoid-induced inhibition of MMP-2 expression in gliomas (a) was MMP-2–selective, as levels of other MMP family members were unaffected; (b) was mimicked by JWH-133, a CB2 cannabinoid receptor–selective agonist that is devoid of psychoactive side effects; (c) was abrogated by fumonisin B1, a selective inhibitor of ceramide biosynthesis; and (d) was also evident in two patients with recurrent glioblastoma multiforme. THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression by RNA interference and cDNA overexpression experiments proved that down-regulation of this MMP plays a critical role in THC-mediated inhibition of cell invasion. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knocking-down the expression of the stress protein p8. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116828/?tool=pubmed

Prostate Cancer and Cannabis:Cause and CURE

Cannabis has been used for thousands of years as a natural remedy for many ailments but only recently has modern science began to recognize the curing power of cannabis.  In 2011 alone there were about 240,890 new cases and about 33,720 deaths from prostate cancer.  Below are studies that show how cannabis can be an effective therapy for prostate cancer.   With more research we can prove that cannabis does have medicinal value and can greatly aid or cure many ailments.  These are published medical studies that I encourage you to research and share your findings with everyone.  Spread the truth!
Information gathered by David Worrell edited by Cherry Girl

Cause:

CXCL12 / CXCR4 / CXCR7 Chemokine Axis And Cancer Progression
‎”CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression.” Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, Taichman RS, Pienta KJ, Wang J. SourceDepartment of Biochemistry and Molecular & Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China. Erratum in Cancer Metastasis Rev. 2011 Jun;30(2):269-70.

Chemokine Family and Their Cognate Receptors

Abstract
Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175097/?tool=pubmed 

Schematic representation showing the role of microenvironment in tumor cell CXCR4 receptor activation in both the primary and metastatic sites.

CURE:

Cannabinoid Receptor CB2 Modulates the CXCL12/CXCR4-Mediated Chemotaxis of T Lymphocytes
‎”Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes.
Ghosh S, Preet A, Groopman JE, Ganju RK.
SourceDivision of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Abstract
Cannabinoids have been shown to influence the immune system. However, their immunomodulatory effects have not been extensively studied. In this investigation, we have observed that both primary and Jurkat T cells express a functional cannabinoid receptor 2 (CB(2)). Furthermore, both the synthetic cannabinoids CP55,940 and WIN55,212-2, as well as the CB(2)-selective agonist JWH-015, caused a significant inhibition of the chemokine CXCL12-induced and CXCR4-mediated chemotaxis of Jurkat T cells, as well as their transendothelial migration. Involvement of the CB(2) receptor was further confirmed by partial reversal of the inhibition using the CB(2)-specific antagonist, AM630. Similarly, CP55,940 and JWH-015 inhibited the CXCL12-induced chemotaxis of primary CD4(+) and CD8(+) T lymphocytes. Further investigation of signaling studies to delineate the mechanism of inhibition revealed that cannabinoids enhance CXCL12-induced p44/42 MAP kinase activity. However, enhanced MAP kinase activity was not responsible for the inhibition of chemotaxis. This suggests that cannabinoids differentially regulate CXCR4-mediated migration and MAP kinase activation in T cells. Cannabinoids were also found to downregulate the PMA-enhanced enzyme activity of matrix metalloproteinase-9, which is known to play an important role in transendothelial migration. This study provides novel information regarding cannabinoid modulation of functional effects in T cells.”
http://www.ncbi.nlm.nih.gov/pubmed/16503355

The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis
“These results suggest prostate cancers may be influenced by the CXCL12:CXCR4 pathway during metastasis. This pathway would provide a novel target for therapeutic intervention.”
‎”The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis.  Arya M, Patel HR, McGurk C, Tatoud R, Klocker H, Masters J, Williamson M.  Source Prostate Cancer Research Centre, Institute of Urology,University College London, UK. manit_arya@hotmail.com

Abstract
AIM: Chemokines or chemotactic cytokines are known to be important in the directional migration or chemotaxis of leucocytes in conditions of homeostasis and in inflammatory or immunological responses. However, the role of chemokines is extending beyond their involvement in mediating leucocyte trafficking with an increasing body of evidence suggesting these proteins are intimately involved in many stages of tumour development and progression. Our aim was to study the role of the CXCL12:CXCR4 chemokine ligand:receptor complex in determining the organ-specific metastasis of prostate cancer. MATERIALS and

METHODS: CXCR4 mRNA expression was determined by RT-PCR in 3 metastatic prostate cancer cell lines DU145, LNCaP and PC3, the primary prostate cancer cell line 1542 CPT3X and the normal prostate epithelial cell lines 1542 NPTX and Pre 2.8. This was followed by Taqman quantitative PCR analysis of CXCR4 mRNA in these cell lines. Flow cytometry analysis was then used to measure the expression of the CXCR4 receptor protein on the cell surface. The influence of the receptor on cell migration was studied using Transwell, Migration Assays. Finally, Taqman quantitative PCR was performed on RNA obtained from laser microdissected fresh primary prostate tumour and benign tissue samples from patients.

RESULTS: In DU145, LNCaP and PC3 CXCR4 mRNA expression was approximately 1000, 400 and 21 times respectively that of 1542 NPTX, Pre 2.8 and 1542 CPT3X. In patient primary tumour samples and patient benign tissue specimens CXCR4 mRNA expression was similar to that of the metastatic cell line DU145. Flow cytometry analysis showed that significantly higher levels of the CXCR4 receptor were present on the cell surface of the 3 metastatic cell lines. Migration studies revealed that chemotaxis of the metastatic cell lines PC3 and DU145 was enhanced by CXCL12 ligand and inhibited by antibody to CXCR4. CXCL12 did not influence the migration of the normal prostate epithelial cell line 1542 NPTX.

CONCLUSIONS: We have demonstrated that human prostate cell lines derived from metastases express functional CXCR4 receptor and that CXCL12 ligand enhances their migratory capabilities. Also, laser microdissected primary patient tumours and patient benign tissue specimens express CXCR4 mRNA at high levels (it is suggested that post-transcriptional modification of the CXCR4 receptor plays a major role in regulating protein expression). These results suggest prostate cancers may be influenced by the CXCL12:CXCR4 pathway during metastasis. This pathway would provide a novel target for therapeutic intervention.”
http://www.ncbi.nlm.nih.gov/pubmed/15844659

Toke and Poke:Cannabis and Breast Cancer

October is Breast Cancer Awareness month and its in full swing.  To help celebrate the lives lost as well as saved, we have gathered research that shows cannabis to be a useful treatment option not only for symptoms but for cancer itself.  With more research we can prove that cannabis does have medicinal value and can greatly aid or cure many ailments.  These are published medical studies that I encourage you to research and share your findings with everyone.  Spread the truth!
Information gathered by David Worrell edited by Cherry Girl
Self examination is still a great way for early detection so don’t for get to toke and poke at least once a month.  (Video at bottom or page)

Cause:

Activation of Multiple Cancer-Associated Genes At the ERBB2 Amplicon in Breast Cancer
The ERBB2 (neu/HER2) oncogene, located at chromosome 17q12, is one of the most intensively studied genes in cancer, especially in breast cancer.
Kauraniemi P, Kallioniemi A. SourceLaboratory of Cancer Biology, University of Tampere and Tampere University Hospital, 33014 Tampere, Finland. paivikki.kauraniemi@uta.fi

Abstract
During the past decade the role of the ERBB2 (neu/HER2) oncogene as an important predictor of patient outcome and response to various therapies in breast cancer has been clearly established. This association of ERBB2 aberrations with more aggressive disease and poor clinical outcome, together with the high prevalence of such alterations in breast cancer, has also made ERBB2 an attractive target for therapy. A specific antibody-based therapy, Herceptin, directed against the extracellular domain of the ERBB2 receptor tyrosine kinase, was recently developed and several clinical trials have shown the therapeutic efficacy of this drug against ERBB2-positive breast cancer. However, a relatively large fraction of patients does not benefit from Herceptin treatment, indicating that other factors beyond ERBB2 itself must influence therapy response in ERBB2-positive tumors. It is well known that amplification of the 17q12-q21 region is the most common mechanism for ERBB2 activation in breast cancer and that it leads to simultaneous activation of several other genes. These co-amplified and co-activated genes may have an impact on disease progression and the clinical behavior of ERBB2-positive tumors and thus represent important targets of research. In this paper we discuss the current knowledge on the structure of the ERBB2 amplicon, the genes involved, and their possible contribution to breast cancer pathogenesis.”
http://erc.endocrinology-journals.org/content/13/1/39.long

CURE:

Cannabinoids Reduce ErbB2-Driven Breast Cancer Progression Through Akt Inhibition
“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 reduce ErbB2-driven breast cancer progression through Akt inhibition.  Caffarel MM, Andradas C, Mira E, Pérez-Gómez E, Cerutti C, Moreno-Bueno G, Flores JM, García-Real I, Palacios J, Mañes S, Guzmán M, Sánchez C.
SourceDept, Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.

Abstract
BACKGROUND: 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 Delta9-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.”

The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Ast

‎”The high expression level of CB1 and CB2 receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics, unless AKT is concomitantly inhibited, or cannabinoids are applied at concentrations that bypass CB1 and CB2 receptors, yet still activate ERK1/2.” So, for astrocytomas, cannabinoids can only be used if they inhibit AKT and activate ERK1/2.
“The expression level of CB1 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas. Cudaback E, Marrs W, Moeller T, Stella N.
SourceDepartment of Pharmacology, University of Washington, Seattle, Washington, United States of America.

Abstract
BACKGROUND: Cannabinoids represent unique compounds for treating tumors, including astrocytomas. Whether CB(1) and CB(2) receptors mediate this therapeutic effect is unclear.

PRINCIPAL FINDINGS: We generated astrocytoma subclones that express set levels of CB(1) and CB(2), and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to ERK1/2. In contrast, cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT. Remarkably, cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB(1), CB(2) and AKT, but still through a mechanism involving ERK1/2.

SIGNIFICANCE: The high expression level of CB(1) and CB(2) receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics, unless AKT is concomitantly inhibited, or cannabinoids are applied at concentrations that bypass CB(1) and CB(2) receptors, yet still activate ERK1/2.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806825/?tool=pubmed

Cannabidiol Induces Programmed Cell Death In Breast Cancer Cells By Coordinating the Cross-Talk Between Apoptosis and Autophagy
‎”Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells.”
“Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy.
Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A. Source Division of Experimental Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. abailugu@bidmc.harvard.edu

Abstract
Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated. Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation. Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. Western blot analysis confirmed these findings. We showed that CBD induces endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1. Analyzing further the cross-talk between the autophagic and apoptotic signaling pathways, we found that beclin1 plays a central role in the induction of CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances the interaction between beclin1 and Vps34, it inhibits the association between beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells. CBD increased the generation of reactive oxygen species (ROS), and ROS inhibition blocked the induction of apoptosis and autophagy. Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent.”
http://www.ncbi.nlm.nih.gov/pubmed/21566064

Medical Marijuana Stops Spread of Breast Cancer – NBC NEWS