Category Archives: Cancer

Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts.

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The Journal of Biological Chemistry

“Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options…

Marijuana and its derivatives have been used in medicine for many centuries, and presently there is an emerging renaissance in the study of the therapeutic effects of cannabinoids…

In addition, cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines…

These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.

Consistent with our observation that AEA has antiproliferative and proapoptotic properties, cannabinoids of various origins (endogenous, plant-derived, or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.

In conclusion, we have clearly demonstrated opposing actions of the endocannabinoids AEA and 2-AG on cholangiocarcinoma cell proliferation and have shown that these actions are via a cannabinoid receptor-independent but lipid raft-mediated pathway. Furthermore we have shown that the antiproliferative/proapoptotic actions of AEA are mediated via an accumulation of ceramide and the recruitment of the Fas death receptor into the lipid rafts. Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA would prove beneficial for the treatment of this devastating disease.”

http://www.jbc.org/content/282/17/13098.long

The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration.

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“Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma.

The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers.

We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells.

Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors.

THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis.

THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells.

Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.” http://www.ncbi.nlm.nih.gov/pubmed/19916793 

“Cholangiocarcinoma is an epithelial cell malignancy arising from varying locations within the biliary tree showing markers of cholangiocyte differentiation. The most contemporary classification based on anatomical location includes intrahepatic, perihilar, and distal cholangiocarcinoma… Understanding of cholangiocarcinoma biology, the oncogenic landscape of this disease, and its complex interaction with the tumour microenvironment could lead to optimum therapies with improvement in patient survival… Hopefully, personalised or precision medicine is in the near future for the treatment of cholangiocarcinoma” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069226/

 “Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts.”   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731530/

“Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy after hepatocellular cancer. CC accounts for approximately 10%-25% of all hepatobiliary malignancies. CC is a rare malignancy in Western countries, but more common in Asia. There are several established risk factors for CC, including parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established potential risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125451/

“Cholangiocarcinoma is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long-term inflammation, injury, and reparative biliary epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof-printing workers.”  http://www.ncbi.nlm.nih.gov/pubmed/24895231

http://www.thctotalhealthcare.com/category/cholangiocarcinoma/

The use of cannabinoids as anticancer agents.

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“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer.

Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death.

In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration.

The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.

In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989

“… cannabinoids have been shown to alleviate nausea and vomit induced by chemotherapy and several cannabinoid-based medicines [Marinol (THC) and Cesamet (nabilone, a synthetic analogue of THC)] are approved for this purpose. Cannabinoids also inhibit pain, and Sativex (a standardized cannabis extract) has been approved in Canada for the treatment of cancer-associated pain. Other potential palliative effects of cannabinoids in oncology include appetite stimulation and attenuation of wasting. In addition to these palliative actions of cannabinoids in cancer patients, THC and other cannabinoids exhibit antitumour effects in animal models of cancer… a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer… In conclusion there exist solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical studies aimed at testing them as single agents or in combinational therapies are urgently needed.” http://www.sciencedirect.com/science/article/pii/S0278584615001190

Marijuana kills brain cancer, new study confirms

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“The active molecules in cannabis kill brain cancer — another study has revealed.”

“Scientists using an extract of whole-plant marijuana rich in pot’s main psychoactive ingredient THC as well as cannabidiol (CBD) showed “dramatic reductions in tumor volumes” of a type of brain cancer.”  http://blog.sfgate.com/smellthetruth/2014/11/18/marijuana-kills-brain-cancer-new-study-confirms/

“Marijuana kills brain cancer, new study confirms. The active molecules in cannabis kill brain cancer — another study has revealed.” http://blog.seattlepi.com/marijuana/2014/11/18/marijuana-kills-brain-cancer-new-study-confirms/#13130101=0

“Marijuana Kills Brain Cancer Cells. Researchers have found that the THC in marijuana causes brain cancer cells to die in both mice and humans.”  http://www.nbcphiladelphia.com/news/health/Marijuana_Kills_Brain_Cancer_Cells_All__National_.html

“Marijuana Kills Brain Cancer, New Study Confirms” http://cancerguide.byethost8.com/marijuana-kills-brain-cancer-new-study-confirms-sfgate-blog/

http://www.thctotalhealthcare.com/category/brain-cancer/

Cannabisin B induces autophagic cell death by inhibiting the AKT/mTOR pathway and S phase cell cycle arrest in HepG2 cells.

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“This study investigates the anticancer properties of cannabisin B, purified from hempseed hull, in HepG2 human hepatoblastoma cells.

The results indicate that cannabisin B significantly inhibited cell proliferation by inducing autophagic cell death rather than typical apoptosis.

Cell viability transiently increased upon the addition of a low concentration of cannabisin B but decreased upon the addition of high concentrations.

Cannabisin B-induced changes in cell viability were completely inhibited by pre-treatment with 3-methyladenine (3-MA), indicating that the induction of autophagy by cannabisin B caused cell death.

Additionally, cannabisin B induced S phase cell cycle arrest in a dose-dependent manner.

Moreover, cannabisin B was found to inhibit survival signaling by blocking the activation of AKT and down-stream targets of the mammalian target of rapamycin (mTOR).

These findings suggest that cannabisin B possesses considerable antiproliferative activity and that it may be utilised as a promising chemopreventive agent against hepatoblastoma disease.”

http://www.ncbi.nlm.nih.gov/pubmed/23411211

http://www.thctotalhealthcare.com/category/liver-cancer-2/

Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients’ cells.

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“Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas…

These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.

CB1 is implicated in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in several physio-pathological conditions. We shed light on previously unrecognized molecular mechanism of CB1-mediated modulation of human glioma progression and provide the first and original demonstration of CB1-STAT3 axis as a new target and predictor biomarkers of the benefit from specific therapies.

Indeed CB1 antagonism capable of tumoral cell division’ control while making the glioma immunovisible and engaging the immune system to fight it may represent a hopeful alternative to other established chemotherapeutics.

Because different aspects of glioma biology have been separately targeted with very limited success, we speculate that CB1 inhibitors which enclose in the same molecule cytotoxic potential and high activity to boost competent immune surveillance mechanisms, at a degree that seems to be correlated to the levels of CB1 immunoreactivity, might have profound implications for exploring new therapeutic anti-glioma actions.”

http://www.ncbi.nlm.nih.gov/pubmed/26008966

http://www.thctotalhealthcare.com/category/gllomas/

The evolving role of the endocannabinoid system in gynaecological cancer.

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Image result for "Human reproduction update" 2015 Jul-Aug

“The ‘endocannabinoid system’ (ECS), comprising endogenous ligands (endocannabinoids) and their regulating enzymes, together with the cannabinoid receptors, has attracted a great deal of attention because it affects not only all facets of human reproduction, from gametogenesis through to parturition and beyond, but also targets key mechanisms affecting some hallmarks of cancer.

Recent evidence showing that cannabinoid receptors play a very important role in the development of malignancies outside of the reproductive organs suggests a similar role for the ECS in the establishment or continued development of gynaecological malignancy.

More than 2100 sources were obtained from which only 112 were specifically important to the topic. Analysis of those articles supports a role of the ECS in gynaecological cancers but leaves many gaps in our knowledge that need to be filled.

 

How some of the relevant receptors are activated and cause changes in cell phenotypes that progress to malignancy remains undiscovered and an area for future research. Increasing evidence suggests that malignant transformation within the female genital tract could be accompanied by deregulation of components of the ECS, acting through rather complex cannabinoid receptor-dependent and receptor-independent mechanisms.

 

The paucity of studies in this area suggests that research using animal models is needed to evaluate endocannabinoid signalling in cancer networks. Future randomized clinical studies should reveal whether endocannabinoids or their derivatives prove to be useful therapeutic targets for gynaecological and other cancers.”

http://www.ncbi.nlm.nih.gov/pubmed/25958409

Downstream effects of endocannabinoid on blood cells: implications for health and disease.

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“Endocannabinoids (eCBs), among which N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are the most biologically active members, are polyunsaturated lipids able to bind cannabinoid, vanilloid and peroxisome proliferator-activated receptors. Depending on the target engaged, these bioactive mediators can regulate different signalling pathways, at both central and peripheral levels.

The biological action of eCBs is tightly controlled by a plethora of metabolic enzymes which, together with the molecular targets of these substances, form the so-called “endocannabinoid system”.

The ability of eCBs to control manifold peripheral functions has received a great deal of attention, especially in the light of their widespread distribution in the body.

In particular, eCBs are important regulators in blood, where they modulate haematopoiesis, platelet aggregation and apoptosis, as well as chemokine release and migration of immunocompetent cells.

Here, we shall review the current knowledge on the pathophysiological roles of eCBs in blood. We shall also discuss the involvement of eCBs in those disorders affecting the haematological system, including cancer and inflammation.

Knowledge gained to date underlines a fundamental role of the eCB system in blood, thus suggesting that it may represent a therapeutic promise for a broad range of diseases involving impaired hematopoietic cell functions.”

http://www.ncbi.nlm.nih.gov/pubmed/25957591

Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1.

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“The anti-tumor properties of cannabinoids have recently been evidenced, mainly with delta9-tetrahydrocannabinol (THC).

Here we investigated whether the most potent endogenous cannabinoid, arachidonylethanolamide (AEA), could be a candidate.

We observed that AEA induced apoptosis in long-term and recently established glioma cell lines via aberrantly expressed vanilloid receptor-1 (VR1).

In contrast with their role in THC-mediated death, both CB1 and CB2 partially protected glioma against AEA-induced apoptosis.

These data show that the selective targeting of VR1 by AEA or more stable analogues is an attractive research area for the treatment of glioma.”

http://www.ncbi.nlm.nih.gov/pubmed/15453094

http://www.thctotalhealthcare.com/category/gllomas/

Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1.

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“Delta(9)-Tetrahydrocannabinol, the active agent of Cannabis sativa, exhibits well-documented antitumor properties, but little is known about the possible effects mediated by endogenous cannabinoids on human tumors. In the present study, we analyzed the effect of arachidonyl ethanolamide (AEA) on cervical carcinoma (CxCa) cell lines.

The major finding was that AEA induced apoptosis of CxCa cell lines via aberrantly expressed vanilloid receptor-1, whereas AEA binding to the classical CB1 and CB2 cannabinoid receptors mediated a protective effect…

Overall, these data suggest that the specific targeting of VR1 by endogenous cannabinoids or synthetic molecules offers attractive opportunities for the development of novel potent anticancer drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/15047233

http://www.thctotalhealthcare.com/category/cervical-cancer/